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Sample records for association study implicates

  1. The estrogen hypothesis of schizophrenia implicates glucose metabolism: association study in three independent samples

    DEFF Research Database (Denmark)

    Olsen, Line; Hansen, Thomas; Jakobsen, Klaus D.

    2008-01-01

    not feasible task. We undertook these challenges by using an established clinical paradigm, the estrogen hypothesis of schizophrenia, as the criterion to select candidates among the numerous genes experimentally implicated in schizophrenia. Bioinformatic tools were used to build and priorities the signaling...... networks implicated by the candidate genes resulting from the estrogen selection. We identified ten candidate genes using this approach that are all active in glucose metabolism and particularly in the glycolysis. Thus, we tested the hypothesis that variants of the glycolytic genes are associated...

  2. Results of Associated Implication Algebra on a Partial Ordered Set

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Some sufficient and necessary conditions that implication algebra on a partial ordered set is associated implication algebra are obtained, and the relation between lattice H implication algebra and associated implication algebra is discussed. Also, the concept of filter is proposed with some basic properties being studied.

  3. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    DEFF Research Database (Denmark)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ...

  4. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.; Nwulia, Evaristus A.; Nyholt, Dale R.; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Potash, James B.; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnstroem, Karola; Reif, Andreas; Ribases, Marta; Rice, John P.; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Sergeant, Joseph A.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Sonuga-Barke, Edmund J. S.; Cair, David St.; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sutdiffe, James S.; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; Van den Oord, Edwin J. C. G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zoellner, Sebastian; Devlin, Bernie; Kelsoe, John R.; Sklar, Pamela; Daly, Mark J.; O'Donovan, Michael C.; Craddock, Nicholas; Kendler, Kenneth S.; Weiss, Lauren A.; Wray, Naomi R.; Zhao, Zhaoming; Geschwind, Daniel H.; Sullivan, Patrick F.; Smoller, Jordan W.; Holmans, Peter A.; Breen, Gerome

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ove

  5. Association study in Alzheimer’s disease of single nucleotide polymorphisms implicated with coffee consumption

    Directory of Open Access Journals (Sweden)

    Victor Junji Yamamoto

    2015-06-01

    Full Text Available Background There is evidence from animal and in vitro models of the protective effects of caffeine in Alzheimer’s disease. The suggested mechanisms through which caffeine may protect neurons against Alzheimer’s disease pathology include the facilitation of beta-amyloid clearance, upregulation of cholinergic transmission, and increased neuronal plasticity and survival. Epidemiological studies support that Alzheimer’s disease patients consume smaller amounts of coffee beverages throughout their lives as compared to age-matched cognitively healthy individuals. Objective The aim of the present study was to determine whether the negative association between Alzheimer’s disease and coffee consumption may be influenced by a common genetic predisposition, given the fact that the pattern of coffee consumption is determined by both environmental and genetic factors. Method We conducted an in silico search addressing the association between genetic polymorphisms related to coffee consumption and the diagnosis of Alzheimer’s disease. We further investigated the interactions between genes located in regions bearing these polymorphisms. Results Our analysis revealed no evidence for a genetic association (nor interaction between related proteins involving coffee consumption and Alzheimer’s disease. Discussion The negative association between Alzheimer’s disease and coffee consumption suggested by epidemiological studies is most likely due to environmental factors that are not necessarily regulated by genetic background.

  6. Fine-scale population structure of Malays in Peninsular Malaysia and Singapore and implications for association studies.

    Science.gov (United States)

    Hoh, Boon-Peng; Deng, Lian; Julia-Ashazila, Mat Jusoh; Zuraihan, Zakaria; Nur-Hasnah, Ma'amor; Nur-Shafawati, Ab Rajab; Hatin, Wan Isa; Endom, Ismail; Zilfalil, Bin Alwi; Khalid, Yusoff; Xu, Shuhua

    2015-07-22

    Fine scale population structure of Malays - the major population in Malaysia, has not been well studied. This may have important implications for both evolutionary and medical studies. Here, we investigated the population sub-structure of Malay involving 431 samples collected from all states from peninsular Malaysia and Singapore. We identified two major clusters of individuals corresponding to the north and south peninsular Malaysia. On an even finer scale, the genetic coordinates of the geographical Malay populations are in correlation with the latitudes (R(2) = 0.3925; P = 0.029). This finding is further supported by the pairwise FST of Malay sub-populations, of which the north and south regions showed the highest differentiation (FST [North-south] = 0.0011). The collective findings therefore suggest that population sub-structure of Malays are more heterogenous than previously expected even within a small geographical region, possibly due to factors like different genetic origins, geographical isolation, could result in spurious association as demonstrated in our analysis. We suggest that cautions should be taken during the stage of study design or interpreting the association signals in disease mapping studies which are expected to be conducted in Malay population in the near future.

  7. Population structure and linkage disequilibrium in oat (Avena sativa L.): implications for genome-wide association studies.

    Science.gov (United States)

    Newell, M A; Cook, D; Tinker, N A; Jannink, J-L

    2011-02-01

    The level of population structure and the extent of linkage disequilibrium (LD) can have large impacts on the power, resolution, and design of genome-wide association studies (GWAS) in plants. Until recently, the topics of LD and population structure have not been explored in oat due to the lack of a high-throughput, high-density marker system. The objectives of this research were to survey the level of population structure and the extent of LD in oat germplasm and determine their implications for GWAS. In total, 1,205 lines and 402 diversity array technology (DArT) markers were used to explore population structure. Principal component analysis and model-based cluster analysis of these data indicated that, for the lines used in this study, relatively weak population structure exists. To explore LD decay, map distances of 2,225 linked DArT marker pairs were compared with LD (estimated as r²). Results showed that LD between linked markers decayed rapidly to r² = 0.2 for marker pairs with a map distance of 1.0 centi-Morgan (cM). For GWAS, we suggest a minimum of one marker every cM, but higher densities of markers should increase marker-QTL association and therefore detection power. Additionally, it was found that LD was relatively consistent across the majority of germplasm clusters. These findings suggest that GWAS in oat can include germplasm with diverse origins and backgrounds. The results from this research demonstrate the feasibility of GWAS and related analyses in oat.

  8. A genome-wide association study of Cloninger’s Temperament scales: Implications for the evolutionary genetics of personality

    OpenAIRE

    Verweij, Karin J.H.; Zietsch, Brendan P.; Medland, Sarah E.; Gordon, Scott D.; Benyamin, Beben; Nyholt, Dale R.; McEvoy, Brian P.; Sullivan, Patrick F.; Heath, Andrew C.; Pamela A F Madden; Henders, Anjali K.; Montgomery, Grant W.; Martin, Nicholas G.; Wray, Naomi R

    2010-01-01

    Variation in personality traits is 30% to 60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger’s temperament scales in a sample of 5117 individuals, in order to identify common genetic variants underlying variation in personality. Participants’ scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for associ...

  9. A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder

    Science.gov (United States)

    Sellgren, C M; Kegel, M E; Bergen, S E; Ekman, C J; Olsson, S; Larsson, M; Vawter, M P; Backlund, L; Sullivan, P F; Sklar, P; Smoller, J W; Magnusson, P K E; Hultman, C M; Walther-Jallow, L; Svensson, C I; Lichtenstein, P; Schalling, M; Engberg, G; Erhardt, S; Landén, M

    2016-01-01

    Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder. PMID:26666201

  10. Genome-wide association study knowledge-driven pathway analysis of alcohol dependence implicates the calcium signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Li Danni; Li Jinming; Guo Yanfang

    2014-01-01

    Background Alcohol dependence (AD) is a serious and common public health problem.The identification of genes that contribute to the AD variation will improve our understanding of the genetic mechanism underlying this complex disease.Previous genome-wide association studies (GWAS) and candidate gene genetic association studies identified individual genes as candidates for alcohol phenotypes,but efforts to generate an integrated view of accumulative genetic variants and pathways under alcohol drinking are lacking.Methods We applied enrichment gene set analysis to existing genetic association results to identify pertinent pathways to AD in this study.A total of 1 438 SNPs (P <1.0×10-3) associated to alcohol drinking related traits have been collected from 31 studies (10 candidate gene association studies,19 GWAS of SNPs,and 2 GWAS of copy number variants).Results Among all of the KEGG pathways,the calcium signaling pathway (hsa04020) showed the most significant enrichment of associations (21 genes) to alcohol consumption phenotypes (P=5.4×10-5).Furthermore,the calcium signaling pathway is the only pathway that turned out to be significant after multiple test adjustments,achieving Bonferroni P value of 0.8×10-3 and FDR value of 0.6×10-2,respectively.Interestingly,the calcium signaling pathway was previously found to be essential to regulate brain function,and genes in this pathway link to a depressive effect of alcohol consumption on the body.Conclusions Our findings,together with previous biological evidence,suggest the importance of gene polymorphisms of calcium signaling pathway to AD susceptibility.Still,further investigations are warranted to uncover the role of this pathway in AD and related traits.

  11. A genome-wide association study of Cloninger's temperament scales: Implications for the evolutionary genetics of personality

    NARCIS (Netherlands)

    Verweij, K.J.H.; Zietsch, B.P.; Medland, S.E.; Gordon, S.D.; Benyamin, B.; Nyholt, D.R.; McEvoy, B.P.; Sullivan, P.F.; Heath, A.C.; Madden, P.A.F.; Henders, A.K.; Montgomery, G.W.; Martin, N.G.; Wray, N.R.

    2010-01-01

    Variation in personality traits is 30-60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger's temperament scales in a sample of 5117 individuals, in

  12. A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies.

    Science.gov (United States)

    Huyghe, Jeroen R; Fransen, Erik; Hannula, Samuli; Van Laer, Lut; Van Eyken, Els; Mäki-Torkko, Elina; Aikio, Pekka; Sorri, Martti; Huentelman, Matthew J; Van Camp, Guy

    2011-03-01

    The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.

  13. Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity

    DEFF Research Database (Denmark)

    Hägg, Sara; Ganna, Andrea; Van Der Laan, Sander W;

    2015-01-01

    ) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci......To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions...... with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation...

  14. Genome-wide association studies: results from the first few years and potential implications for clinical medicine.

    Science.gov (United States)

    Hirschhorn, Joel N; Gajdos, Zofia K Z

    2011-01-01

    Most common diseases and quantitative traits are heritable: determined in part by genetic variation within the population. The inheritance is typically polygenic in that combined effects of variants in numerous genes, plus nongenetic factors, determine outcome. The genes influencing common disease and quantitative traits remained largely unknown until the implementation in 2006 of genome-wide association (GWA) studies that comprehensively surveyed common genetic variation (frequency>5%). By 2010, GWA studies identified>1,000 genetic variants for polygenic traits. Typically, these variants together account for a modest fraction (10%-30%) of heritability, but they have highlighted genes in both known and new biological pathways and genes of unknown function. This initial effort prefigures new studies aimed at rarer variation and decades of functional work to decipher newly glimpsed biology. The greatest impact of GWA studies may not be in predictive medicine but rather in the development over the next decades of therapies based on novel biological insights.

  15. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

    Science.gov (United States)

    Saccone, Scott F; Hinrichs, Anthony L; Saccone, Nancy L; Chase, Gary A; Konvicka, Karel; Madden, Pamela A F; Breslau, Naomi; Johnson, Eric O; Hatsukami, Dorothy; Pomerleau, Ovide; Swan, Gary E; Goate, Alison M; Rutter, Joni; Bertelsen, Sarah; Fox, Louis; Fugman, Douglas; Martin, Nicholas G; Montgomery, Grant W; Wang, Jen C; Ballinger, Dennis G; Rice, John P; Bierut, Laura Jean

    2007-01-01

    Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

  16. Genome-Wide Association Study Reveals Genetic Architecture of Eating Behaviors in Pigs and its Implications for Humans Obesity by Comparative Genome Mapping

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage;

    2013-01-01

    This study was aimed at identifying genomic regions controlling feeding behaviors inDanish Duroc boars and its potential implications for eating behaviors in humans.Individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of dailyvisits to feeder (NVD), time spent to eat...... chromosome (SSC) 14 was very strongly associated with NVD (p =9.6E-07). Thirty six SNPs were located in genome regions where QTLs havepreviously been reported...... for geneticimprovement of pig feed efficiency. The results of pig-human comparative genemapping revealed some important genomic regions and/or genes on the humangenome that may influence eating behavior in human and consequently affect thedevelopment of obesity and metabolic syndromes. This is the first...

  17. Genome-wide association study reveals genetic architecture of eating behavior in pigs and its implications for humans obesity by comparative mapping

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage;

    2013-01-01

    are important for genetic improvement of pig feed efficiency. We have also conducted pig-human comparative gene mapping to reveal key genomic regions and/or genes on the human genome that may influence eating behavior in human beings and consequently affect the development of obesity and metabolic syndrome......This study was aimed at identifying genomic regions controlling feeding behavior in Danish Duroc boars and its potential implications for eating behavior in humans. Data regarding individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD......1, PTPN4, MTMR4 and RNGTT) and positive regulation of peptide secretion genes (GHRH, NNAT and TCF7L2) were highly significantly associated with feeding behavior traits. This is the first GWAS to identify genetic variants and biological mechanisms for eating behavior in pigs and these results...

  18. Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study.

    Science.gov (United States)

    Perlis, Roy H; Moorjani, Priya; Fagerness, Jesen; Purcell, Shaun; Trivedi, Madhukar H; Fava, Maurizio; Rush, A John; Smoller, Jordan W

    2008-11-01

    Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C(16)) score < or =5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.

  19. Spatial and temporal associations of road traffic noise and air pollution in London: Implications for epidemiological studies.

    Science.gov (United States)

    Fecht, Daniela; Hansell, Anna L; Morley, David; Dajnak, David; Vienneau, Danielle; Beevers, Sean; Toledano, Mireille B; Kelly, Frank J; Anderson, H Ross; Gulliver, John

    2016-03-01

    Road traffic gives rise to noise and air pollution exposures, both of which are associated with adverse health effects especially for cardiovascular disease, but mechanisms may differ. Understanding the variability in correlations between these pollutants is essential to understand better their separate and joint effects on human health. We explored associations between modelled noise and air pollutants using different spatial units and area characteristics in London in 2003-2010. We modelled annual average exposures to road traffic noise (LAeq,24h, Lden, LAeq,16h, Lnight) for ~190,000 postcode centroids in London using the UK Calculation of Road Traffic Noise (CRTN) method. We used a dispersion model (KCLurban) to model nitrogen dioxide, nitrogen oxide, ozone, total and the traffic-only component of particulate matter ≤2.5μm and ≤10μm. We analysed noise and air pollution correlations at the postcode level (~50 people), postcodes stratified by London Boroughs (~240,000 people), neighbourhoods (Lower layer Super Output Areas) (~1600 people), 1km grid squares, air pollution tertiles, 50m, 100m and 200m in distance from major roads and by deprivation tertiles. Across all London postcodes, we observed overall moderate correlations between modelled noise and air pollution that were stable over time (Spearman's rho range: |0.34-0.55|). Correlations, however, varied considerably depending on the spatial unit: largest ranges were seen in neighbourhoods and 1km grid squares (both Spearman's rho range: |0.01-0.87|) and was less for Boroughs (Spearman's rho range: |0.21-0.78|). There was little difference in correlations between exposure tertiles, distance from road or deprivation tertiles. Associations between noise and air pollution at the relevant geographical unit of analysis need to be carefully considered in any epidemiological analysis, in particular in complex urban areas. Low correlations near roads, however, suggest that independent effects of road noise and

  20. Study of association and molecular analysis of human papillomavirus in breast cancer of Indian patients: Clinical and prognostic implication

    Science.gov (United States)

    Islam, Saimul; Dasgupta, Hemantika; Roychowdhury, Anirban; Bhattacharya, Rittwika; Mukherjee, Nupur; Roy, Anup; Mandal, Gautam Kumar; Alam, Neyaz; Biswas, Jaydip; Mandal, Shyamsundar; Roychoudhury, Susanta

    2017-01-01

    Objectives Human papillomavirus (HPV) causes tumors primarily Cervical cancer. Recently, inconsistent reports came up in Breast cancer (BC) too. In India, despite treatment 70,218 BC patients die each year. So, we explored the association of HPV, if any, with BC prognosis in Indian pre-therapeutic (PT) and Neo-adjuvant chemotherapy (NACT) patients with subsequent analysis of HPV profile. Methods HPV prevalence was checked and analysis of physical status, copy number, genome variation, promoter methylation and expression (mRNA and protein) of the prevalent subtype was done. Results High prevalence of HPV was observed in both PT (64.0%) and NACT (71.0%) cases with significant association with younger (20–45 yrs) PT patients. Interestingly, HPV infection was significantly increased from adjacent normal breast (9.5%, 2/21), fibro adenomas (30%, 3/10) to tumors (64.8%, 203/313) samples. In both PT and NACT cases, HPV16 was the most prevalent subtype (69.0%) followed by HPV18 and HPV33. Survival analysis illustrated hrHPV infected PT patients had worst prognosis. So, detailed analysis of HPV16 profile was done which showed Europian-G350 as the most frequent HPV16 variant along with high rate of integration. Moreover, low copy number and hyper-methylation of P97 early promoter were concordant with low HPV16 E6 and E7 mRNA and protein expression. Notably, four novel variations (KT020838, KT020840, KT020841 and KT020839) in the LCR region and two (KT020836 and KT020837) in the E6 region were identified for the first time along with two novel E6^E7*I (KU199314) and E6^E7*II (KU199315) fusion transcript variants. Conclusion Thus, significant association of hrHPV with prognosis of Indian BC patients led to additional investigation of HPV16 profile. Outcomes indicated a plausible role of HPV in Indian BC patients. PMID:28245287

  1. Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2

    Science.gov (United States)

    Huang, Jie; Huffman, Jennifer E.; Yamkauchi, Munekazu; Trompet, Stella; Asselbergs, Folkert W.; Sabater-Lleal, Maria; Trégouët, David-Alexandre; Chen, Wei-Min; Smith, Nicholas L.; Kleber, Marcus E.; Shin, So-Youn; Becker, Diane M.; Tang, Weihong; Dehghan, Abbas; Johnson, Andrew D.; Truong, Vinh; Folkersen, Lasse; Yang, Qiong; Oudot-Mellakh, Tiphaine; Buckley, Brendan M.; Moore, Jason H.; Williams, Frances M.K.; Campbell, Harry; Silbernagel, Günther; Vitart, Veronique; Rudan, Igor; Tofler, Geoffrey H.; Navis, Gerjan J.; DeStefano, Anita; Wright, Alan F.; Chen, Ming-Huei; de Craen, Anton J.M.; Worrall, Bradford B.; Rudnicka, Alicja R.; Rumley, Ann; Bookman, Ebony B.; Psaty, Bruce M.; Chen, Fang; Keene, Keith L.; Franco, Oscar H.; Böhm, Bernhard O.; Uitterlinden, Andre G.; Carter, Angela M.; Jukema, J. Wouter; Sattar, Naveed; Bis, Joshua C.; Ikram, Mohammad A.; Sale, Michèle M.; McKnight, Barbara; Fornage, Myriam; Ford, Ian; Taylor, Kent; Slagboom, P. Eline; McArdle, Wendy L.; Hsu, Fang-Chi; Franco-Cereceda, Anders; Goodall, Alison H.; Yanek, Lisa R.; Furie, Karen L.; Cushman, Mary; Hofman, Albert; Witteman, Jacqueline CM.; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Wilson, James F.; Westendorp, Rudi G.J.; Kathiresan, Sekar; Reilly, Muredach P.; Tracy, Russell P.; Polasek, Ozren; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Cambien, Francois; Stott, David J.; Lowe, Gordon D.; Spector, Timothy D.; Meigs, James B.; Marz, Winfried; Eriksson, Per; Becker, Lewis C.; Morange, Pierre-Emmanuel; Soranzo, Nicole; Williams, Scott M.; Hayward, Caroline; van der Harst, Pim; Hamsten, Anders; Lowenstein, Charles J.; Strachan, David P.; O'Donnell, Christopher J.

    2014-01-01

    Objective Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA. Approach and Results Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke. Conclusions We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release. PMID:24578379

  2. Dynamics of membrane protein/amphipol association studied by Förster resonance energy transfer: implications for in vitro studies of amphipol-stabilized membrane proteins.

    Science.gov (United States)

    Zoonens, Manuela; Giusti, Fabrice; Zito, Francesca; Popot, Jean-Luc

    2007-09-11

    Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep membrane proteins (MPs) water-soluble while stabilizing them biochemically. We have examined the factors that determine the size and dispersity of MP/APol complexes and studied the dynamics of the association, taking as a model system the transmembrane domain of Escherichia coli outer membrane protein A (tOmpA) trapped by A8-35, a polyacrylate-based APol. Molecular sieving indicates that the solution properties of the APol largely determine those of tOmpA/APol complexes. Achieving monodispersity depends on using amphipols that themselves form monodisperse particles, on working in neutral or basic solutions, and on the presence of free APols. In order to investigate the role of the latter, a fluorescently labeled version of A8-35 has been synthesized. Förster resonance energy transfer measurements show that extensive dilution of tOmpA/A8-35 particles into an APol-free medium does not entail any detectable desorption of A8-35, even after extended periods of time (hours-days). The fluorescent APol, on the other hand, readily exchanges for other surfactants, be they detergent or unlabeled APol. These findings are discussed in the contexts of sample optimization for MP solution studies and of APol-mediated MP functionalization.

  3. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    NARCIS (Netherlands)

    N. Kato (Norihiro); M. Loh (Marie); F. Takeuchi (Fumihiko); N. Verweij (Niek); X. Wang (Xu); W. Zhang (Weihua); T. NKelly (Tanika); D. Saleheen; B. Lehne (Benjamin); I.M. Leach (Irene Mateo); A. Drong (Alexander); J. Abbott (James); S. Wahl (Simone); S.-T. Tan (Sian-Tsung); W.R. Scott (William R.); G. Campanella (Gianluca); M. Chadeau-Hyam (Marc); U. Afzal (Uzma); T.S. Ahluwalia (Tarunveer Singh); M.J. Bonder (Marc Jan); P. Chen (Ping); A. Dehghan (Abbas); T.L. Edwards (Todd L.); T. Esko (Tõnu); M.J. Go (Min Jin); S.E. Harris (Sarah); J. Hartiala (Jaana); S. Kasela (Silva); A. Kasturiratne (Anuradhani); C.C. Khor; M.E. Kleber (Marcus); H. Li (Huaixing); Z.Y. Mok (Zuan Yu); M. Nakatochi (Masahiro); N.S. Sapari (Nur Sabrina); R. Saxena (Richa); A.F. Stewart (Alexandre F.); L. Stolk (Lisette); Y. Tabara (Yasuharu); A.L. Teh (Ai Ling); Y. Wu (Ying); J.-Y. Wu (Jer-Yuarn); Y. Zhang (Yi); I. Aits (Imke); A. Da Silva Couto Alves (Alexessander); S. Das; R. Dorajoo (Rajkumar); J. CHopewell (Jemma); Y.K. Kim (Yun Kyoung); R. WKoivula (Robert); J. Luan (Jian'An); L.-P. Lyytikäinen (Leo-Pekka); Q. NNguyen (Quang); M.A. Pereira (Mark A); D. Postmus (Douwe); O. TRaitakari (Olli); M. Scannell Bryan (Molly); R.A. Scott (Robert); R. Sorice; V. Tragante (Vinicius); M. Traglia (Michela); J. White (Jon); K. Yamamoto (Ken); Y. Zhang (Yonghong); L.S. Adair (Linda); A. Ahmed (Alauddin); K. Akiyama (Koichi); R. Asif (Rasheed); T. Aung (Tin); I. Barroso (Inês); A. Bjonnes (Andrew); T.R. Braun (Timothy R.); H. Cai (Hui); L.-C. Chang (Li-Ching); C.-H. Chen; C-Y. Cheng (Ching-Yu); Y.-S. Chong (Yap-Seng); F.S. Collins (Francis); R. Courtney (Regina); G. Davies (Gail); G. Delgado; L.D. Do (Loi D.); P.A. Doevendans (Pieter); R.T. Gansevoort (Ron); Y. Gao; T.B. Grammer (Tanja B); N. Grarup (Niels); J. Grewal (Jagvir); D. Gu (D.); G. SWander (Gurpreet); A.L. Hartikainen; S.L. Hazen (Stanley); J. He (Jing); C.K. Heng (Chew-Kiat); E.J.A. Hixso (E. James Ames); A. Hofman (Albert); C. Hsu (Chris); W. Huang (Wei); L.L.N. Husemoen (Lise Lotte); J.-Y. Hwang (Joo-Yeon); S. Ichihara (Sahoko); M. Igase (Michiya); M. Isono (Masato); J.M. Justesen (Johanne M.); T. Katsuya (Tomohiro); M. GKibriya (Muhammad); Y.J. Kim; M. Kishimoto (Miyako); W.-P. Koh (Woon-Puay); K. Kohara (Katsuhiko); M. Kumari (Meena); K. Kwek (Kenneth); N.R. Lee (Nanette); J. Lee (Jeannette); J. Liao (Jie); W. Lieb (Wolfgang); D.C. Liewald (David C.); T. Matsubara (Tatsuaki); Y. Matsushita (Yumi); T. Meitinger (Thomas); E. Mihailov (Evelin); L. Milani (Lili); R. Mills (Rebecca); K. Mononen (Kari); M. Müller-Nurasyid (Martina); T. Nabika (Toru); E. Nakashima (Eitaro); H.K. Ng (Hong Kiat); K. Nikus (Kjell); T. Nutile; T. Ohkubo (Takayoshi); K. Ohnaka (Keizo); S. Parish (Sarah); L. Paternoster (Lavinia); H. Peng (Hao); A. Peters (Annette); S. TPham (Son); M.J. Pinidiyapathirage (Mohitha J.); M. Rahman (Mahfuzar); H. Rakugi (Hiromi); O. Rolandsson (Olov); M.A. Rozario (Michelle Ann); D. Ruggiero; C. Sala (Cinzia); R. Sarju (Ralhan); K. Shimokawa (Kazuro); H. Snieder (Harold); T. Sparsø (Thomas); W. Spiering (Wilko); J.M. Starr (John); D.J. Stott (David J.); D. OStram (Daniel); T. Sugiyama (Takao); S. Szymczak (Silke); W.H.W. Tang (W.H. Wilson); L. Tong (Lin); S. Trompet (Stella); V. Turjanmaa (Väinö); H. Ueshima (Hirotsugu); A.G. Uitterlinden (André); S. Umemura (Satoshi); M. Vaarasmaki (Marja); R.M. Dam (Rob Mvan); W.H. van Gilst (Wiek); D.J. van Veldhuisen (Dirk); J. Viikari (Jorma); M. Waldenberger (Melanie); Y. Wang (Yiqin); A. Wang (Aili); R. Wilson (Rory); T.-Y. Wong (Tien-Yin); Y.-B. Xiang (Yong-Bing); S. Yamaguchi (Shuhei); X. Ye (Xingwang); R. Young (Robin); T.L. Young (Terri); J.-M. Yuan (Jian-Min); X. Zhou (Xueya); F.W. Asselbergs (Folkert); M. Ciullo; R. Clarke (Robert); P. Deloukas (Panagiotis); A. Franke (Andre); W.F. Paul (W. Frank); S. Franks (Steve); Y. Friedlander (Yechiel); M.D. Gross (Myron D.); Z. Guo (Zhirong); T. Hansen (T.); M.-R. Jarvelin (Marjo-Riitta); T. Jørgensen (Torben); J.W. Jukema (Jan Wouter); M. Kähönen (Mika); H. Kajio (Hiroshi); M. Kivimaki (Mika); J.-Y. Lee (Jong-Young); T. Lehtimäki (Terho); A. Linneberg (Allan); T. Miki (Tetsuro); O. Pedersen (Oluf); N.J. Samani (Nilesh); T.I.A. Sørensen (Thorkild); R. Takayanagi (Ryoichi); D. Toniolo (Daniela); H. Ahsan (Habibul); H. Allayee (Hooman); Y.-T. Chen (Yuan-Tsong); J. Danesh (John); I.J. Deary (Ian J.); O.H. Franco (Oscar); L. Franke (Lude); B. THeijman (Bastiaan); J.D. Holbrook (Joanna D.); A.J. Isaacs (Aaron); B.-J. Kim (Bong-Jo); X. Lin (Xu); J. Liu (Jianjun); W. März (Winfried); A. Metspalu (Andres); K.L. Mohlke (Karen); K. Sangher; D. Harambir (Dharambir); X.-O. Shu (Xiao-Ou); J.B.J. van Meurs (Joyce); E.N. Vithana (Eranga); A.R. Wickremasinghe (Ananda); C. Wijmenga (Cisca); B.H.W. Wolffenbuttel (Bruce H.W.); M. Yokota (Mitsuhiro); W. Zheng (Wei); D. Zhu (Dingliang); P. Vineis (Paolo); S.A. Kyrtopoulos (Soterios A.); J.C.S. Kleinjans (Jos C.S.); M.I. McCarthy (Mark); R. Soong (Richie); C. Gieger (Christian); J. Scott (James); Y.Y. Teo (Yik Ying); J. He (Jiang); P. Elliott (Paul); E.S. Tai (Shyong); P. van der Harst (Pim); J.S. Kooner (Jaspal S.); J.C. Chambers (John)

    2015-01-01

    textabstractWe carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to 5

  4. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    DEFF Research Database (Denmark)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(...

  5. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    NARCIS (Netherlands)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N.; Saleheen, Danish; Lehne, Benjamin; Leach, Irene Mateo; Drong, Alexander W.; Abbott, James; Wahl, Simone; Tan, Sian-Tsung; Scott, William R.; Campanella, Gianluca; Chadeau-Hyam, Marc; Afzal, Uzma; Ahluwalia, Tarunveer S.; Bonder, Marc Jan; Chen, Peng; Dehghan, Abbas; Edwards, Todd L.; Esko, Tonu; Go, Min Jin; Harris, Sarah E.; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E.; Li, Huaixing; Mok, Zuan Yu; Nakatochi, Masahiro; Sapari, Nur Sabrina; Saxena, Richa; Stewart, Alexandre F. R.; Stolk, Lisette; Tabara, Yasuharu; Teh, Ai Ling; Wu, Ying; Wu, Jer-Yuarn; Zhang, Yi; Aits, Imke; Alves, Alexessander Da Silva Couto; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C.; Kim, Yun Kyoung; Koivula, Robert W.; Luan, Jian'an; Lyytikainen, Leo-Pekka; Nguyen, Quang N.; Pereira, Mark A.; Postmus, Iris; Raitakari, Olli T.; Bryan, Molly Scannell; Scott, Robert A.; Sorice, Rossella; Tragante, Vinicius; Traglia, Michela; White, Jon; Yamamoto, Ken; Zhang, Yonghong; Adair, Linda S.; Ahmed, Alauddin; Akiyama, Koichi; Asif, Rasheed; Aung, Tin; Barroso, Ines; Bjonnes, Andrew; Braun, Timothy R.; Cai, Hui; Chang, Li-Ching; Chen, Chien-Hsiun; Cheng, Ching-Yu; Chong, Yap-Seng; Collins, Rory; Courtney, Regina; Davies, Gail; Delgado, Graciela; Do, Loi D.; Doevendans, Pieter A.; Gansevoort, Ron T.; Gao, Yu-Tang; Grammer, Tanja B.; Grarup, Niels; Grewal, Jagvir; Gu, Dongfeng; Wander, Gurpreet S.; Hartikainen, Anna-Liisa; Hazen, Stanley L.; He, Jing; Heng, Chew-Kiat; Hixson, James E.; Hofman, Albert; Hsu, Chris; Huang, Wei; Husemoen, Lise L. N.; Hwang, Joo-Yeon; Ichihara, Sahoko; Igase, Michiya; Isono, Masato; Justesen, Johanne M.; Katsuy, Tomohiro; Kibriya, Muhammad G.; Kim, Young Jin; Kishimoto, Miyako; Koh, Woon-Puay; Kohara, Katsuhiko; Kumari, Meena; Kwek, Kenneth; Lee, Nanette R.; Lee, Jeannette; Liao, Jiemin; Lieb, Wolfgang; Liewald, David C. M.; Matsubara, Tatsuaki; Matsushita, Yumi; Meitinger, Thomas; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Mononen, Nina; Mueller-Nurasyid, Martina; Nabika, Toru; Nakashima, Eitaro; Ng, Hong Kiat; Nikus, Kjell; Nutile, Teresa; Ohkubo, Takayoshi; Ohnaka, Keizo; Parish, Sarah; Paternoster, Lavinia; Peng, Hao; Peters, Annette; Pham, Son T.; Pinidiyapathirage, Mohitha J.; Rahman, Mahfuzar; Rakugi, Hiromi; Rolandsson, Olov; Rozario, Michelle Ann; Ruggiero, Daniela; Sala, Cinzia F.; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparso, Thomas; Spiering, Wilko; Starr, John M.; Stott, David J.; Stram, Daniel O.; Sugiyama, Takao; Szymczak, Silke; Tang, W. H. Wilson; Tong, Lin; Trompet, Stella; Turjanmaa, Vaino; Ueshima, Hirotsugu; Uitterlinden, Andre G.; Umemura, Satoshi; Vaarasmaki, Marja; van Dam, Rob M.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; Viikari, Jorma S.; Waldenberger, Melanie; Wang, Yiqin; Wang, Aili; Wilson, Rory; Wong, Tien-Yin; Xiang, Yong-Bing; Yamaguchi, Shuhei; Ye, Xingwang; Young, Robin D.; Young, Terri L.; Yuan, Jian-Min; Zhou, Xueya; Asselbergs, Folkert W.; Ciullo, Marina; Clarke, Robert; Deloukas, Panos; Franke, Andre; Franks, Paul W.; Franks, Steve; Friedlander, Yechiel; Gross, Myron D.; Guo, Zhirong; Hansen, Torben; Jarvelin, Marjo-Riitta; Jorgensen, Torben; Jukema, J. Wouter; Kahonen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimaki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J.; Sorensen, Thorkild I. A.; Takayanagi, Ryoichi; Toniolo, Daniela; Ahsan, Habibul; Allayee, Hooman; Chen, Yuan-Tsong; Danesh, John; Deary, Ian J.; Franco, Oscar H.; Franke, Lude; Heijman, Bastiaan T.; Holbrook, Joanna D.; Isaacs, Aaron; Kim, Bong-Jo; Lin, Xu; Liu, Jianjun; Maerz, Winfried; Metspalu, Andres; Mohlke, Karen L.; Sanghera, Dharambir K.; Shu, Xiao-Ou; van Meurs, Joyce B. J.; Vithana, Eranga; Wickremasinghe, Ananda R.; Wijmenga, Cisca; Wolffenbuttel, Bruce H. W.; Yokota, Mitsuhiro; Zheng, Wei; Zhu, Dingliang; Vineis, Paolo; Kyrtopoulos, Soterios A.; Kleinjans, Jos C. S.; McCarthy, Mark I.; Soong, Richie; Gieger, Christian; Scott, James; Teo, Yik-Ying; He, Jiang; Elliott, Paul; Tai, E. Shyong; van der Harst, Pim; Kooner, Jaspal S.; Chambers, John C.; Doevendans, PAFM

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21

  6. Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.

    Science.gov (United States)

    Zhang, Feng; Wen, Yan; Guo, Xiong; Zhang, Yingang; Wang, Sen; Yang, Tielin; Shen, Hui; Chen, Xiangding; Tan, Lijun; Tian, Qing; Deng, Hong-Wen

    2015-02-01

    Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of KBD remains unknown. To identify relevant biological pathways for KBD, we conducted a genome-wide pathway-based association study (GWPAS) following by replication analysis, totally using 2743 Chinese Han adults. A modified gene set enrichment algorithm was used to detect association between KBD and 963 biological pathways. Cartilage gene expression analysis and serum complement measurement were performed to evaluate the functional relevance of identified pathway with KBD. We found that the Complement and Coagulation Cascades (CACC) pathway was significantly associated with KBD (P value=3.09×10(-5), false-discovery rate=0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value=1.97×10(-4)) of KNG1 gene. Further replication study observed that rs1656966 (P value=0.037) was significantly associated with KBD in an independent validation sample of 1026 subjects. Gene expression analysis observed that CFD (ratio=3.39±2.68), A2M (ratio=3.67±5.63), C5 (ratio=2.65±2.52) and CD46 (ratio=2.29±137) genes of the CACC pathway were up-regulated in KBD articular cartilage compared to healthy articular cartilage. The serum level of complement C5 in KBD patients were significantly higher than that in healthy controls (P value=0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD.

  7. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility.

    Science.gov (United States)

    Lascorz, Jesús; Försti, Asta; Chen, Bowang; Buch, Stephan; Steinke, Verena; Rahner, Nils; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Schulmann, Karsten; Goecke, Timm; Kloor, Matthias; Engel, Cristoph; Büttner, Reinhard; Kunkel, Nelli; Weires, Marianne; Hoffmeister, Michael; Pardini, Barbara; Naccarati, Alessio; Vodickova, Ludmila; Novotny, Jan; Schreiber, Stefan; Krawczak, Michael; Bröring, Clemens D; Völzke, Henry; Schafmayer, Clemens; Vodicka, Pavel; Chang-Claude, Jenny; Brenner, Hermann; Burwinkel, Barbara; Propping, Peter; Hampe, Jochen; Hemminki, Kari

    2010-09-01

    Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).

  8. Pain Symptoms Associated with Opioid Use among Vulnerable Persons with HIV: An exploratory study with implications for palliative care and opioid abuse prevention.

    Science.gov (United States)

    Knowlton, Amy R; Nguyen, Trang Q; Robinson, Allysha C; Harrell, Paul T; Mitchell, Mary M

    2015-01-01

    Current or former injection drug users with human immunodeficiency virus (HIV) are at high risk for pain, which adversely affects their quality of life and may increase their risk for illicit drug use or relapse. We explored associations between pain symptoms and substance use among injection-drug-using study participants with HIV who had histories of heroin use. Using generalized estimating equations and controlling for prior substance use, we found that pain in each six-month period was associated with the use of heroin and prescription opioids, but not the use of nonopioid drugs or alcohol. Routine clinical assessment and improved management of pain symptoms may be needed for persons with HIV and a history of injection drug use, particularly those with chronic pain, for whom there is increased risk for heroin use.

  9. Th17 response and autophagy - main pathways implicated in the development of inflammatory bowel disease by genome-wide association studies: new factors involved in inflammatory bowel disease susceptibility

    Directory of Open Access Journals (Sweden)

    Roberto Díaz-Peña

    2015-09-01

    Full Text Available Inflammatory bowel disease (IBD is an entity that mainly includes ulcerative colitis (UC and Crohn's disease (CD. Improved health care, diet changes, and higher industrialization are associated with an increase in IBD prevalence. This supports the central role of environmental factors in the pathology of this disease. However, IBD also shows a relevant genetic component as shown by high heritability. Classic genetic studies showed relevant associations between IBD susceptibility and genes involved in the immune response. This is consistent with prior theories about IBD development. According to these, contact of the immune system with a high number of harmless antigens from the diet and the bacterial flora should originate tolerance while preserving response against pathogens. Failure to achieve this balance may originate the typical inflammatory response associated with IBD. Recently, genome-wide association studies (GWASs have confirmed the implication of the immune system, particularly the Th17 immune response, previously associated to other autoimmune diseases, and of autophagy. In this paper, the mechanisms involved in these two relevant pathways and their potential role in the pathogenesis of IBD are reviewed.

  10. Genetic contribution for non-syndromic cleft lip with or without cleft palate (NS CL/P) in different regions of Brazil and implications for association studies.

    Science.gov (United States)

    Brito, Luciano A; Cruz, Lucas A; Rocha, Kátia M; Barbara, Ligia K; Silva, Camila B F; Bueno, Daniela F; Aguena, Meire; Bertola, Débora R; Franco, Diogo; Costa, André M; Alonso, Nivaldo; Otto, Paulo A; Passos-Bueno, Maria Rita

    2011-07-01

    Non-syndromic cleft lip with or without cleft palate (NS CL/P) is a complex disease in which heritability estimates vary widely depending on the population studied. To evaluate the importance of genetic contribution to NS CL/P in the Brazilian population, we conducted a study with 1,042 families from five different locations (Santarém, Fortaleza, Barbalha, Maceió, and Rio de Janeiro). We also evaluated the role of consanguinity and ethnic background. The proportion of familial cases varied significantly across locations, with the highest values found in Santarém (44%) and the lowest in Maceió (23%). Heritability estimates showed a higher genetic contribution to NS CL/P in Barbalha (85%), followed by Santarém (71%), Rio de Janeiro (70%), Fortaleza (64%), and Maceió (45%). Ancestry was not correlated with the occurrence of NS CL/P or with the variability in heritability. Only in Rio de Janeiro was the coefficient of inbreeding significantly larger in NS CL/P families than in the local population. Recurrence risk for the total sample was approximately 1.5-1.6%, varying according to the location studied (0.6-0.7% in Maceió to 2.2-2.8% in Barbalha). Our findings show that the degree of genetic contribution to NS CL/P varies according to the geographic region studied, and this difference cannot be attributed to consanguinity or ancestry. These findings suggest that Barbalha is a promising region for genetic studies. The data presented here will be useful in interpreting results from molecular analyses and show that care must be taken when pooling samples from different populations for association studies.

  11. A genetic association study of serum acute-phase C-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation.

    Directory of Open Access Journals (Sweden)

    Benjamin Rhodes

    2010-09-01

    Full Text Available BACKGROUND: The acute-phase increase in serum C-reactive protein (CRP is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation. METHODS AND FINDINGS: We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients. A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively, translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval concentration was 43.1 mg/l (32.1-50.0 for haplotype 1 and 14.2 mg/l (9.5-23.2 for haplotype 4. CONCLUSIONS: Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical

  12. Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies.

    Science.gov (United States)

    Xu, P; Wu, X; Wang, B; Luo, J; Liu, Y; Ehlers, J D; Close, T J; Roberts, P A; Lu, Z; Wang, S; Li, G

    2012-07-01

    Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.

  13. Association Between Cardiovascular and Intraocular Pressure Changes in a 14-Day 6 deg Head Down Tilt (HDT) Bed Rest Study: Possible Implications in Retinal Anatomy

    Science.gov (United States)

    Cromwell, Ronita; Zanello, Susana; Yarbough, Patrice; Ploutz-Snyder, Robert; Taibbi, Giovanni; Vizzeri, Gianmarco

    2013-01-01

    time points. There was no correlation between the largest change in IOP (BR-3 versus BR3) and cardiovascular measure changes between baseline (BR-5) and post bed rest (BR+2). While no clinically relevant visual changes were observed during the study, measurement of various retinal parameters was performed with optical coherence tomography (OCT). A decrease in central subfield retinal thickness was observed between BR+2 and baseline at BR-10, but no association was observed with IOP changes. This work investigates the time course of changes in IOP during 14-day HDT bed rest in an attempt to characterize HDT bed rest as a model of the VIIP syndrome and delve into its etiology.

  14. Comprehensive gene-based association study of a chromosome 20 linked region implicates novel risk loci for depressive symptoms in psychotic illness.

    Directory of Open Access Journals (Sweden)

    T Bernard Bigdeli

    Full Text Available BACKGROUND: Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants. METHODS: We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects. These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms. Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a the smallest observed P-value and b the threshold-truncated product of P-values for each locus. RESULTS: While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P(emp<2×10⁻⁵ based on the minimum P-value and truncated-product methods, respectively. CONCLUSIONS: Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.

  15. Dermatomyositis and myastenia gravis: An uncommon association with therapeutic implications.

    Science.gov (United States)

    Sangüesa Gómez, Clara; Flores Robles, Bryan Josué; Méndez Perles, Clara; Barbadillo, Carmen; Godoy, Hildegarda; Andréu, José Luis

    2015-01-01

    The association of dermatomyositis with myasthenia gravis (MG) is uncommon, having been reported so far in only 26 cases. We report the case of a 69 year-old man diagnosed with MG two years ago and currently treated with piridostigmyne. The patient developed acute proximal weakness, shoulder pain and elevated creatine-kinase (CK). He also developed generalized facial erythema and Gottron's papules. Laboratory tests showed positive antinuclear and anti-Mi2 antibodies. Further analysis confirmed CK levels above 1000 U/l. The clinical management of the patient and the therapeutic implications derived from the coexistence of both entities are discusssed.

  16. Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

    NARCIS (Netherlands)

    Huang, Jie; Huffman, Jennifer E.; Yamkauchi, Munekazu; Trompet, Stella; Asselbergs, Folkert W.; Sabater-Lleal, Maria; Tregouet, David-Alexandre; Chen, Wei-Min; Smith, Nicholas L.; Kleber, Marcus E.; Shin, So-Youn; Becker, Diane M.; Tang, Weihong; Dehghan, Abbas; Johnson, Andrew D.; Vinh Truong, [No Value; Folkersen, Lasse; Yang, Qiong; Oudot-Mellkah, Tiphaine; Buckley, Brendan M.; Moore, Jason H.; Williams, Frances M. K.; Campbell, Harry; Silbernagel, Guenther; Vitart, Veronique; Rudan, Igor; Tofler, Geoffrey H.; Navis, Gerjan J.; DeStefano, Anita; Wright, Alan F.; Chen, Ming-Huei; de Craen, Anton J. M.; Worrall, Bradford B.; Rudnicka, Alicja R.; Rumley, Ann; Bookman, Ebony B.; Psaty, Bruce M.; Chen, Fang; Keene, Keith L.; Franco, Oscar H.; Boehm, Bernhard O.; Uitterlinden, Andre G.; Carter, Angela M.; Jukema, J. Wouter; Sattar, Naveed; Bis, Joshua C.; Ikram, Mohammad A.; Sale, Michele M.; McKnight, Barbara; Fornage, Myriam; Ford, Ian; Taylor, Kent; Slagboom, P. Eline; McArdle, Wendy L.; Hsu, Fang-Chi; Franco-Cereceda, Anders; Goodall, Alison H.; Yanek, Lisa R.; Furie, Karen L.; Cushman, Mary; Hofman, Albert; Witteman, Jacqueline C. M.; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Wilson, James F.; Westendorp, Rudi G. J.; Kathiresan, Sekar; Reilly, Muredach P.; Tracy, Russell P.; Polasek, Ozren; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Cambien, Francois; Stott, David J.; Lowe, Gordon D.; Spector, Timothy D.; Meigs, James B.; Marz, Winfried; Eriksson, Per; Becker, Lewis C.; Morange, Pierre-Emmanuel; Soranzo, Nicole; Williams, Scott M.; Hayward, Caroline; van der Harst, Pim; Hamsten, Anders; Lowenstein, Charles J.; Strachan, David P.; O'Donnell, Christopher J.

    2014-01-01

    Objective Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular d

  17. Implications of immune dysfunction on endometriosis associated infertility.

    Science.gov (United States)

    Miller, Jessica E; Ahn, Soo Hyun; Monsanto, Stephany P; Khalaj, Kasra; Koti, Madhuri; Tayade, Chandrakant

    2017-01-24

    Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.

  18. Immune activation in HIV-infected aging women on antiretrovirals--implications for age-associated comorbidities: a cross-sectional pilot study.

    Directory of Open Access Journals (Sweden)

    Maria L Alcaide

    Full Text Available Persistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages.Twenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163, microbial translocation (LPS and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10 were evaluated.T cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation.HIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.

  19. Genome-wide association study implicates testis-sperm specific FKBP6 as a susceptibility locus for impaired acrosome reaction in stallions.

    Directory of Open Access Journals (Sweden)

    Terje Raudsepp

    Full Text Available Impaired acrosomal reaction (IAR of sperm causes male subfertility in humans and animals. Despite compelling evidence about the genetic control over acrosome biogenesis and function, the genomics of IAR is as yet poorly understood, providing no molecular tools for diagnostics. Here we conducted Equine SNP50 Beadchip genotyping and GWAS using 7 IAR-affected and 37 control Thoroughbred stallions. A significant (PA and g.11040379C>A (p.166H>N in exon 4 that were significantly associated with the IAR phenotype both in the GWAS cohort (n = 44 and in a large multi-breed cohort of 265 horses. All IAR stallions were homozygous for the A-alleles, while this genotype was found only in 2% of controls. The equine FKBP6 was exclusively expressed in testis and sperm and had 5 different transcripts, of which 4 were novel. The expression of this gene in AC/AG heterozygous controls was monoallelic, and we observed a tendency for FKBP6 up-regulation in IAR stallions compared to controls. Because exon 4 SNPs had no effect on the protein structure, it is likely that FKBP6 relates to the IAR phenotype via regulatory or modifying functions. In conclusion, FKBP6 was considered a susceptibility gene of incomplete penetrance for IAR in stallions and a candidate gene for male subfertility in mammals. FKBP6 genotyping is recommended for the detection of IAR-susceptible individuals among potential breeding stallions. Successful use of sperm as a source of DNA and RNA propagates non-invasive sample procurement for fertility genomics in animals and humans.

  20. An integrative study of Necremnus Thomson (Hymenoptera: Eulophidae) associated with invasive pests in Europe and North America: taxonomic and ecological implications.

    Science.gov (United States)

    Gebiola, Marco; Bernardo, Umberto; Ribes, Antoni; Gibson, Gary A P

    2015-02-01

    The species of Necremnus attacking two invasive pests of tomato and canola in Europe and North America, respectively, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) and Ceutorhynchus obstrictus (Marsham) (Coleoptera: Curculionidae), have been revised using an integrative taxonomy approach. Molecular data from the mitochondrial cytochrome oxidase c subunit I and the nuclear D2 expansion region of the 28S ribosomal subunit and internal transcribed spacer 2, the discovery of new morphological features, and study of type material resulted in the delineation of three species groups, the Necremnus artynes, Necremnus cosconius, and Necremnus tidius groups, the discovery of four new species, and the resurrection of three taxa from synonymy. Lectotypes have been designated for 13 species originally described in Eulophus by Walker. Although Necremnus has not been revised, an illustrated key is given to differentiate 23 recognized European species. The key, type images, and treatments of the three species groups will enable more accurate identification of the valid species of Necremnus in the future. They will also benefit biological control practitioners of pest species. The ecological consequences of the new taxonomic concepts are discussed.

  1. A Candidate Gene Association Study of 77 Polymorphisms in Migraine

    OpenAIRE

    Schürks, Markus; Kurth, Tobias; Buring, Julie E.; Zee, Robert Y.L.

    2009-01-01

    Population-based studies have established an association between migraine and cardiovascular disease (CVD). We sought to investigate whether genetic variants implicated in CVD are associated with migraine. We performed an association study among 25,713 women, participating in the Women’s Health Study, with information on 77 previously characterized polymorphisms. Migraine and migraine aura status were self-reported. We used logistic regression to investigate the genotype-migraine association....

  2. RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.

    Directory of Open Access Journals (Sweden)

    Steven Haney

    Full Text Available Genome-wide association (GWA studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D. In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.

  3. RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.

    Science.gov (United States)

    Haney, Steven; Zhao, Juan; Tiwari, Shiwani; Eng, Kurt; Guey, Lin T; Tien, Eric

    2013-01-01

    Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.

  4. Brain Structures Implicated in Inflammation-Associated Depression.

    Science.gov (United States)

    Harrison, Neil A

    2017-01-01

    Systemic inflammation rapidly impairs mood, motivation, and cognition inducing a stereotyped cluster of symptoms collectively known as "sickness behaviors." When inflammation is severe or chronic, these behavioral changes can appear indistinguishable from major depressive disorder (MDD). Human and rodent neuroimaging combined with experimental inflammatory challenges has clarified the neural circuitry associated with many of the key features of inflammation-induced-sickness behavior, and in so doing revealed often-remarkable commonalities with circuit abnormalities observed in MDD. This review aims to provide the first synthesis of this work illustrating areas of convergence and divergence with the MDD literature as well as highlighting areas for future study.

  5. Food Avoidance and Food Modification Practices of Older Rural Adults: Association with Oral Health Status and Implications for Service Provision

    Science.gov (United States)

    Quandt, Sara A.; Chen, Haiying; Bell, Ronny A.; Savoca, Margaret R.; Anderson, Andrea M.; Leng, Xiaoyan; Kohrman, Teresa; Gilbert, Gregg H.; Arcury, Thomas A.

    2010-01-01

    Purpose: Dietary variation is important for health maintenance and disease prevention among older adults. However, oral health deficits impair ability to bite and chew foods. This study examines the association between oral health and foods avoided or modified in a multiethnic rural population of older adults. It considers implications for…

  6. Persistent primitive hypoglossal artery associated with Chiari II malformation: Diagnosis and clinical implications

    Directory of Open Access Journals (Sweden)

    Gupta Mudit

    2010-01-01

    Full Text Available We present a case of persistent primitive hypoglossal artery (PPHA associated with Chiari II malformation and discuss the clinical implications. There has been one reported case of PPHA associated with Chiari 1 malformation, but none in association with Chiari II. Our patient also had a widened hypoglossal canal, with cerebrospinal fluid (CSF sac herniation through it.

  7. Genome-wide association study identifies four loci associated with eruption of permanent teeth

    DEFF Research Database (Denmark)

    Geller, Frank; Feenstra, Bjarke; Zhang, Hao

    2011-01-01

    The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years...

  8. Medication-wide association studies

    NARCIS (Netherlands)

    P.B. Ryan (Patrick); D. Madigan (David); P.E. Stang (Paul); M.J. Schuemie (Martijn); G. Hripcsak (G.)

    2013-01-01

    textabstractUndiscovered side effects of drugs can have a profound effect on the health of the nation, and electronic health-care databases offer opportunities to speed up the discovery of these side effects. We applied a "medication-wide association study" approach that combined multivariate analys

  9. Nutrition and age-associated inflammation: implications for disease prevention

    Science.gov (United States)

    Accumulating evidence suggests that aging is associated with dysregulated immune and inflammatory responses. Investigation into the cellular and molecular mechanisms underlying this phenomenon suggests that an up-regulated cyclooxygenase (COX)-2 expression, and resulting increase in production of pr...

  10. Implications of Berthlot`s descriptive of associative reactions

    Energy Technology Data Exchange (ETDEWEB)

    Hessler, J.P.

    1996-10-04

    Berthelot`s equation, k{sub {infinity}}(T) = A{sub {infinity}} exp (-Dk{sub B}T), provides a good description of the high-pressure rate coefficient for associative reactions such as CH{sub 3} + CH{sub 3}, CH{sub 3} + OH, and CH{sub 3} + H. The parameter D may be used to characterize an effective temperature-dependent barrier, {Delta}E{sub eff} = Dk{sub B}{sup 2}T{sup 2}, which is due to the internal energy, i.e. rotational and vibrational energy, or the centrifugal barrier of the associating species. The parameter A{sub {infinity}} may be identified as the rate coefficient for association when the species approach one another with zero translational and internal energy. A microcanonical rate expression is given which may be used to directly compare experimental results with theoretical calculations. In addition, this approach suggests that the Arrhenius expression for the high-pressure rate coefficient for dissociation should contain both the change of enthalpy of the reaction and this effective barrier.

  11. Geochemical Implications of CO2 Leakage Associated with Geologic Storage: A Review

    Energy Technology Data Exchange (ETDEWEB)

    Harvey, Omar R.; Qafoku, Nikolla; Cantrell, Kirk J.; Brown, Christopher F.

    2012-07-09

    Leakage from deep storage reservoirs is a major risk factor associated with geologic sequestration of carbon dioxide (CO2). Different scientific theories exist concerning the potential implications of such leakage for near-surface environments. The authors of this report reviewed the current literature on how CO2 leakage (from storage reservoirs) would likely impact the geochemistry of near surface environments such as potable water aquifers and the vadose zone. Experimental and modeling studies highlighted the potential for both beneficial (e.g., CO2 re sequestration or contaminant immobilization) and deleterious (e.g., contaminant mobilization) consequences of CO2 intrusion in these systems. Current knowledge gaps, including the role of CO2-induced changes in redox conditions, the influence of CO2 influx rate, gas composition, organic matter content and microorganisms are discussed in terms of their potential influence on pertinent geochemical processes and the potential for beneficial or deleterious outcomes. Geochemical modeling was used to systematically highlight why closing these knowledge gaps are pivotal. A framework for studying and assessing consequences associated with each factor is also presented in Section 5.6.

  12. Genome-wide association studies in pediatric endocrinology.

    Science.gov (United States)

    Dauber, Andrew; Hirschhorn, Joel N

    2011-01-01

    Genome-wide association (GWA) studies are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWA studies in type 1 diabetes, stature, pubertal timing, obesity, and vitamin D deficiency. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of novel therapeutic agents.

  13. Student Identity Considerations and Implications Associated with Socioscientific Issues Instruction

    Science.gov (United States)

    Ruzek, Mitchel James

    The purpose of this investigation was to explore how aspects of identity, perceived levels of controversy, and the strength of a student's attachment to their controversial identity relate to conceptual understanding and knowledge acquisition during socioscientific issues (SSI) based instruction in a biology classroom. The knowledge gained from this study will have the capacity to enhance our understanding of the role that attachment to identity plays during SSI negotiation. Additionally, insight was gained into the role played by aspects of identity in conceptual understanding of scientifically controversial topics during SSI based instruction. This study contributed to the existing knowledge base in science education by illuminating processes involved in socioscientific issue navigation among students of differing perceptions of controversy as well as students who held aspects of controversial identity that may or may not interact with the specific issues chosen. Students demonstrated evidence of variations of reasoning, justification, perception of controversy, and aspects of knowledge gain as they negotiated the issues of marijuana safety and fast food legality. Additionally, evidence was provided that showed general knowledge gain throughout the group during socioscientific issues instruction. It has been said that one of the appeals of the SSI instructional model is that is serves not only as a context for the delivery of content, but acts as a catalyst for various forms of epistemological beliefs and research into the development of conceptual and psychological knowledge structures (Zeidler, 2013). This investigation supports the deeper understanding of the contribution of controversy perception to epistemology as well as conceptual and psychological knowledge structures during SSI navigation.

  14. Implications of Error Analysis Studies for Academic Interventions

    Science.gov (United States)

    Mather, Nancy; Wendling, Barbara J.

    2017-01-01

    We reviewed 13 studies that focused on analyzing student errors on achievement tests from the Kaufman Test of Educational Achievement-Third edition (KTEA-3). The intent was to determine what instructional implications could be derived from in-depth error analysis. As we reviewed these studies, several themes emerged. We explain how a careful…

  15. Special Education Faculty Needs Assessment Study Implications

    Science.gov (United States)

    Smith, D.D.; Tyler, N.; Montrosse, B.E.; Young, C.; Robb, S.M.

    2011-01-01

    This paper presents the highlights of the Special Education Faculty Needs Assessment Study (SEFNA). Actions taken after the release of The 2001 Faculty Shortage Study demonstrate that supply-and-demand imbalances can be improved. The projected shortage of special education faculty will directly and negatively affect students with disabilities and…

  16. Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

    Science.gov (United States)

    Tafti, Mehdi; Lammers, Gert J.; Dauvilliers, Yves; Overeem, Sebastiaan; Mayer, Geert; Nowak, Jacek; Pfister, Corinne; Dubois, Valérie; Eliaou, Jean-François; Eberhard, Hans-Peter; Liblau, Roland; Wierzbicka, Aleksandra; Geisler, Peter; Bassetti, Claudio L.; Mathis, Johannes; Lecendreux, Michel; Khatami, Ramin; Heinzer, Raphaël; Haba-Rubio, José; Feketeova, Eva; Baumann, Christian R.; Kutalik, Zoltán; Tiercy, Jean-Marie

    2016-01-01

    Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18–1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10–1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13–1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15–1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15–1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Citation: Tafti M, Lammers GJ, Dauvilliers Y, Overeem S, Mayer G, Nowak J, Pfister C, Dubois V, Eliaou JF, Eberhard HP, Liblau R, Wierzbicka A, Geisler P, Bassetti CL, Mathis J, Lecendreux M, Khatami R, Heinzer R, Haba-Rubio J, Feketeova E, Baumann CR, Kutalik Z, Tiercy JM. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. SLEEP 2016;39(3):581–587. PMID:26518595

  17. Discursive Study of Religion : Approaches, Definitions, Implications

    NARCIS (Netherlands)

    von Stuckrad, Kocku

    2013-01-01

    The article explores recent approaches to historical analysis of discourse that have been developed in disciplines such as the sociology of knowledge and historical epistemology. These approaches have only sporadically been taken seriously in the academic study of religion, although they have a grea

  18. Associations between Gun Violence Exposure, Gang Associations, and Youth Aggression: Implications for Prevention and Intervention Programs

    Directory of Open Access Journals (Sweden)

    Myriam Forster

    2015-01-01

    Full Text Available Using cross-sectional data collected from three middle schools in Southeast Los Angeles, we assessed the association of neighborhood violence exposure, gang associations, and social self-control with past week aggression in a sample of minority youth (n=164. Results from Poisson and logistic regression models showed that direct exposure to gun violence, having friends in gangs, and low social self control were all positively associated with past week aggression. Among girls, having gang affiliated family members was positively associated with aggression, whereas among boys having friends in gangs was associated with past week aggression. Subjective expectations of engagement in future interpersonal violence were associated with being male, having friends in gangs, and fear of neighborhood gun violence. We recommend that youth violence prevention and intervention programs address the impact of family, peers, and gun violence on student coping and identify students with low social self-control who could benefit from social and emotional skills training.

  19. Association studies in consanguineous populations

    Energy Technology Data Exchange (ETDEWEB)

    Genin, E.; Clerget-Darpous, F. [Institut National d`Etudes Demographiques, Paris (France)

    1996-04-01

    To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients. 5 refs., 6 figs., 1 tab.

  20. ORNL-EPR study: results and implications

    Energy Technology Data Exchange (ETDEWEB)

    McAlees, D.G.

    1976-01-01

    A two-year preliminary design study of a tokamak experimental power reactor has been completed by the Oak Ridge National Laboratory. The major engineering features, plasma physics characteristics, and technological requirements of the device are discussed. Plasma confinement is provided in a toroidal chamber of major radius, R/sub o/ = 6.75 m and minor radius, a = 2.25 m. The toroidal magnetic field strength is 4.8 T. A unique poloidal magnetic field system creates the fields required for plasma equilibrium and stability. The power extraction system is centered around the blanket, which absorbs approximately 90 percent of the energy produced in the plasma. The operating characteristics and nuclear performance of the system are given. The results of the study indicate a low benefit-to-cost ratio for this design. Recent developments have suggested that some of the design constraints were too restrictive. The advisability of a large scale test of the ideas linked to these developments has become apparent. To this end, ORNL has started the design of a high-..beta.. tokamak. The basis for the high power density device is discussed.

  1. Factors associated with uterine endometrial hyperplasia and pyometra in wild canids: implications for fertility.

    Science.gov (United States)

    Asa, Cheryl S; Bauman, Karen L; Devery, Sarah; Zordan, Martín; Camilo, Gerardo R; Boutelle, Sally; Moresco, Anneke

    2014-01-01

    The ability to safely and effectively manage reproduction is central to the success of AZA captive-breeding programs. Although the AZA Wildlife Contraception Center routinely monitors contraceptive safety, there have been no studies that compare the effects of contraceptive use to separation of males from females, the other option for preventing reproduction. We used retrospective medical records and pathology reports submitted by AZA and related facilities for the seven AZA-managed canid species to assess rates of uterine pathology relative to female reproductive life histories. Our results showed that the prevalence of both pyometra and endometrial hyperplasia (EH) was associated not only with treatment with the two most common contraceptives (Suprelorin® and MGA implants) but also with the number of years barren (i.e., not producing a litter and not contracepted). Rates of pyometra and EH were especially high in African painted dogs and red wolves, but lowest in swift and fennec foxes. The number of years producing a litter had a low association, suggesting it could be protective against uterine pathology. A more recently developed Suprelorin® protocol using Ovaban® to prevent the initial stimulation phase, followed by implant removal when reversal is desired, may be a safer contraceptive option. These results concerning the relationship between reproductive management and uterine health have important implications for AZA-managed programs, since the unsustainability of many captive populations may be due at least in part to infertility. Managing a female's reproductive lifespan to optimize or maintain fertility will require a reconsideration of how breeding recommendations are formulated.

  2. Association between airborne PM2.5 chemical constituents and birth weight—implication of buffer exposure assignment

    Science.gov (United States)

    Ebisu, Keita; Belanger, Kathleen; Bell, Michelle L.

    2014-08-01

    Several papers reported associations between airborne fine particulate matter (PM2.5) and birth weight, though findings are inconsistent across studies. Conflicting results might be due to (1) different PM2.5 chemical structure across locations, and (2) various exposure assignment methods across studies even among the studies that use ambient monitors to assess exposure. We investigated associations between birth weight and PM2.5 chemical constituents, considering issues arising from choice of buffer size (i.e. distance between residence and pollution monitor). We estimated the association between each pollutant and term birth weight applying buffers of 5 to 30 km in Connecticut (2000-2006), in the New England region of the USA. We also investigated the implication of the choice of buffer size in relation to population characteristics, such as socioeconomic status. Results indicate that some PM2.5 chemical constituents, such as nitrate, are associated with lower birth weight and appear more harmful than other constituents. However, associations vary with buffer size and the implications of different buffer sizes may differ by pollutant. A homogeneous pollutant level within a certain distance is a common assumption in many environmental epidemiology studies, but the validity of this assumption may vary by pollutant. Furthermore, we found that areas close to monitors reflect more minority and lower socio-economic populations, which implies that different exposure approaches may result in different types of study populations. Our findings demonstrate that choosing an exposure method involves key tradeoffs of the impacts of exposure misclassification, sample size, and population characteristics.

  3. Understanding Driving Forces and Implications Associated with the Land Use and Land Cover Changes in Portugal

    Directory of Open Access Journals (Sweden)

    Bruno M. Meneses

    2017-02-01

    Full Text Available Understanding the processes of land use and land cover changes (LUCC and the associated driving forces is important for achieving sustainable development. This paper presents the LUCC in Portugal at the regional level (NUTS II from 1995 to 2010 and discusses the main driving forces and implications associated with these LUCC. The main objectives of this work are: (a to quantify the land use and land cover (LUC types (level I of LUC cartography by NUT II in Portugal for the years 1995, 2007 and 2010; (b to assess the spatio-temporal LUCC; and (c to identify and discuss the main driving forces of LUCC and corresponding implications based on correlations and Principal Components Analysis. The results revealed large regional and temporal LUCC and further highlighted the different and sometimes opposite time trends between neighboring regions. By associating driving forces to LUCC, different influences at the regional level were observed, namely LUCC into agriculture land derived from the construction of dams (Alentejo region, or the conversion of coniferous forest into eucalypt forest (Centre region associated with increased gross value added (GVA and employment in industry and forestry. Temporal differentiation was also observed, particularly in the settlements that expanded between 1995 and 2007 due to the construction of large infrastructures (e.g., highways, industrial complexes, or buildings, which is reflected on employment in industry and construction and respective GVA. However, certain LUCC have implications, particularly in energy consumption, for which different behavior between regions can be highlighted in this analysis, but also on land-use sustainability.

  4. Adenomyoepithelioma of the breast with associated atypical lobular hyperplasia: a previously unrecognized association with management implications.

    Science.gov (United States)

    Zhang, Shuang; Huo, Lei; Arribas, Elsa; Middleton, Lavinia P

    2015-02-01

    Adenomyoepitheliomas of breast are rare tumors. We report for the first time a case of an adenomyoepithelioma of the breast with associated lobular neoplasia. A 53-year-old woman had an annual screening mammogram, which identified areas of asymmetry in her left breast at 4-5-o'clock position. Resection of the masses revealed a well-circumscribed, gray-white, firm discrete nodule (0.8 × 0.4 × 0.3 cm). The tumor was composed of both adenomyoepithelial cell hyperplasia and focal atypical lobular hyperplasia. The 2 cell populations had some overlapping histologic features. Immunohistochemical analysis demonstrated a biphasic proliferation with approximately equal parts of luminal epithelial cells with clear and rounded appearance and myoepithelial cells. The myoepithelial component of the proliferation expressed myosin, p63, CK5/6, S-100, and dimly expressed E-cadherin. The epithelial component of the proliferation strongly expressed E-cadherin. In the areas of atypical lobular hyperplasia, there was distinct loss E-cadherin expression. Awareness of this association is highly important to provide these patients adequate follow-up and treatment.

  5. Implications of the Tentative Association between GW150914 and a Fermi-GBM Transient

    Science.gov (United States)

    Li, Xiang; Zhang, Fu-Wen; Yuan, Qiang; Jin, Zhi-Ping; Fan, Yi-Zhong; Liu, Si-Ming; Wei, Da-Ming

    2016-08-01

    The merger-driven gamma-ray bursts (GRBs) and their associated gravitational-wave (GW) radiation, if both are successfully detected, have some far-reaching implications, including, for instance: (i) the statistical comparison of the physical properties of the short/long-short GRBs with and without GW detection can test the general origin model; (ii) revealing the physical processes taking place at the central engine; (iii) measuring the velocity of the gravitational wave directly/accurately. In this work, we discuss these implications in the case of a possible association of GW150914/Gamma-ray Burst Monitor (GBM) transient 150914. We compared GBM transient 150914 with other SGRBs and found that such an event may be a distinct outlier in some statistical diagrams, possibly due to its specific binary black hole merger origin. However, the presence of a “new” group of SGRBs with “unusual” physical parameters is also possible. If the outflow of GBM transient 150914 was launched by the accretion onto the nascent black hole, the magnetic activity rather than the neutrino process is likely responsible for the energy extraction, and the accretion disk mass is estimated to be ˜10-5 M ⊙. The GW150914/GBM transient 150914 association, if confirmed, would provide the first opportunity to directly measure the GW velocity, and its departure from the speed of the light should be within a factor of ˜10-17.

  6. Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications.

    Science.gov (United States)

    Pei, Yue; Asif-Malik, Aman; Canales, Juan J

    2016-01-01

    Biogenic amines are a collection of endogenous molecules that play pivotal roles as neurotransmitters and hormones. In addition to the "classical" biogenic amines resulting from decarboxylation of aromatic acids, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much lower concentrations in the central nervous system (CNS), and hence referred to as "trace" amines (TAs), are now recognized to play significant neurophysiological and behavioral functions. At the turn of the century, the discovery of the trace amine-associated receptor 1 (TAAR1), a phylogenetically conserved G protein-coupled receptor that is responsive to both TAs, such as β-phenylethylamine, octopamine, and tyramine, and structurally-related amphetamines, unveiled mechanisms of action for TAs other than interference with aminergic pathways, laying the foundations for deciphering the functional significance of TAs and its mammalian CNS receptor, TAAR1. Although, its molecular interactions and downstream targets have not been fully elucidated, TAAR1 activation triggers accumulation of intracellular cAMP, modulates PKA and PKC signaling and interferes with the β-arrestin2-dependent pathway via G protein-independent mechanisms. TAAR1 is uniquely positioned to exert direct control over DA and 5-HT neuronal firing and release, which has profound implications for understanding the pathophysiology of, and therefore designing more efficacious therapeutic interventions for, a range of neuropsychiatric disorders that involve aminergic dysregulation, including Parkinson's disease, schizophrenia, mood disorders, and addiction. Indeed, the recent development of novel pharmacological tools targeting TAAR1 has uncovered the remarkable potential of TAAR1-based medications as new generation pharmacotherapies in neuropsychiatry. This review summarizes recent developments in the study of TAs and TAAR1, their intricate neurochemistry and

  7. Association of bacteria with marine invertebrates: Implications for ballast water management

    Digital Repository Service at National Institute of Oceanography (India)

    Khandeparker, L.; Anil, A.C.

    Bacteria associated with plankton are of importance in marine bioinvasions and the implementation of ship’s ballast water treatment technologies. In this study, epibiotic and endobiotic bacteria associated with zooplankton, including barnacle...

  8. Genome-wide association implicates numerous genes underlying ecological trait variation in natural populations of Populus trichocarpa.

    Science.gov (United States)

    McKown, Athena D; Klápště, Jaroslav; Guy, Robert D; Geraldes, Armando; Porth, Ilga; Hannemann, Jan; Friedmann, Michael; Muchero, Wellington; Tuskan, Gerald A; Ehlting, Jürgen; Cronk, Quentin C B; El-Kassaby, Yousry A; Mansfield, Shawn D; Douglas, Carl J

    2014-07-01

    In order to uncover the genetic basis of phenotypic trait variation, we used 448 unrelated wild accessions of black cottonwood (Populus trichocarpa) from much of its range in western North America. Extensive data from large-scale trait phenotyping (with spatial and temporal replications within a common garden) and genotyping (with a 34 K Populus single nucleotide polymorphism (SNP) array) of all accessions were used for gene discovery in a genome-wide association study (GWAS). We performed GWAS with 40 biomass, ecophysiology and phenology traits and 29,355 filtered SNPs representing 3518 genes. The association analyses were carried out using a Unified Mixed Model accounting for population structure effects among accessions. We uncovered 410 significant SNPs using a Bonferroni-corrected threshold (P<1.7×10(-6)). Markers were found across 19 chromosomes, explained 1-13% of trait variation, and implicated 275 unique genes in trait associations. Phenology had the largest number of associated genes (240 genes), followed by biomass (53 genes) and ecophysiology traits (25 genes). The GWAS results propose numerous loci for further investigation. Many traits had significant associations with multiple genes, underscoring their genetic complexity. Genes were also identified with multiple trait associations within and/or across trait categories. In some cases, traits were genetically correlated while in others they were not.

  9. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility

    NARCIS (Netherlands)

    Maestrini, E.; Pagnamenta, A. T.; Lamb, J. A.; Bacchelli, E.; Sykes, N. H.; Sousa, I.; Toma, C.; Barnby, G.; Butler, H.; Winchester, L.; Scerri, T. S.; Minopoli, F.; Reichert, J.; Cai, G.; Buxbaum, J. D.; Korvatska, O.; Schellenberg, G. D.; Dawson, G.; de Bildt, A.; Minderaa, R. B.; Mulder, E. J.; Morris, A. P.; Bailey, A. J.; Monaco, A. P.

    2010-01-01

    Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we pe

  10. Association of CHMP4B and Autophagy with Micronuclei: Implications for Cataract Formation

    Directory of Open Access Journals (Sweden)

    Antonia P. Sagona

    2014-01-01

    Full Text Available Autophagy is a mechanism of cellular self-degradation that is very important for cellular homeostasis and differentiation. Components of the endosomal sorting complex required for transport (ESCRT machinery are required for endosomal sorting and also for autophagy and the completion of cytokinesis. Here we show that the ESCRT-III subunit CHMP4B not only localizes to normal cytokinetic bridges but also to chromosome bridges and micronuclei, the latter surrounded by lysosomes and autophagosomes. Moreover, CHMP4B can be co-immunoprecipitated with chromatin. Interestingly, a CHMP4B mutation associated with autosomal dominant posterior polar cataract abolishes the ability of CHMP4B to localize to micronuclei. We propose that CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. This may have implications for DNA degradation during lens cell differentiation, thus potentially protecting lens cells from cataract development.

  11. Age-associated epigenetic drift: implications, and a case of epigenetic thrift?

    Science.gov (United States)

    Teschendorff, Andrew E; West, James; Beck, Stephan

    2013-10-15

    It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.

  12. Ventilator associated pneumonia and transfusion, is there really an association? (the NAVTRA study

    Directory of Open Access Journals (Sweden)

    Gonzalez Marco

    2006-07-01

    Full Text Available Abstract Background Anemic syndrome is a frequent problem in intensive care units. The most probable etiology is the suppression of the erythropoietin response due to the direct effects of cytokines, as well as frequent blood sampling. Transfusions are not free of complications, therefore transfusion reactions are estimated to occur in 2% of the total packed red blood cells (pRBCs transfused. In the past several years, several trials had tried to compare the restrictive with the more liberal use of transfusions, and they were found to be equally effective. Nosocomial pneumonia is the most common nosocomial infection in intensive care units; the prevalence is 47% with an attributive mortality of 33%. There are multiple risk factors for the development of nosocomial pneumonia. Colonization of the upper airways is the most important pathophysiological factor but there are other factors implicated like, sedation techniques, inappropriate use of antibiotics and recumbent positioning. A secondary analysis of the CRIT study describes transfusion therapy and its practices in the United States. They found that transfusion practice is an independent risk factor for the development of nosocomial pneumonia. Methods This is a multicenter, prospective cohort study in different intensive care units in Colombia. A total of 474 patients were selected who had more than 48 hours of mechanical ventilation. The primary objective is to try to demonstrate the hypothetical relationship between the use of transfusions and nosocomial pneumonia. Secondly, we will try to determine which other factors are implicated in the development of pneumonia in intensive care units and describe the incidence of pneumonia and transfusion practices. Discussion Ventilator associated pneumonia is a primary problem in the intensive care unit, multiple factors have been associated with its presence in this study we try to explore the possible association between pneumonia and transfusion

  13. Genetic association studies in lumbar disc degeneration

    DEFF Research Database (Denmark)

    Eskola, Pasi J; Lemmelä, Susanna; Kjaer, Per;

    2012-01-01

    Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans....

  14. Cross-sectional study of morbidity, morbidity-associated factors and cost of treatment in Ngaoundere, Cameroon, with implications for health policy in developing countries and development assistance policy

    Directory of Open Access Journals (Sweden)

    Holtedahl Knut

    2002-04-01

    Full Text Available Abstract Background In a population-based epidemiological study in Ngaoundere, Cameroon, we studied cross-sectional child morbidity and the cost of necessary investigation and treatment. Methods Three teams of two to three health workers visited haphazardly selected households in all major housing quarters. We asked permission to enter for a health survey. Children with cough, fever or weight loss as well as sick adults were offered free-of-charge local hospital examination and treatment. Results From 177 households with 1777 persons, 51 (2.9% persons were referred. Thirty-five of them had an undiagnosed disease threatening individual health and in many cases also public health. Seven were hospitalised, including three adults with tuberculosis. Malnutrition was diagnosed in nine small children. Four patients had AIDS, seven had malaria. Average total cost for ambulant patients was 15 USD, for hospitalised patients 110 USD. In the households, almost half of the women 16–50 years of age had no schooling. Two per cent of women and nine per cent of men were daily smokers. Coughing children were more likely than non-coughing children to live in a household with at least one smoker (OR = 3.58, 95% CI 1.72 to 7.46, and they generally lived in more poor households (P = 0.018. Twelve of 16 children with weight loss were referred from households with a high poverty score. Conclusions Adult smoking and poverty affect children's health. The cost of hospitalisation or long-lasting therapy is beyond the means of most ordinary families. Diseases with severe consequences for public health, like tuberculosis, AIDS and malaria should have national programs with free, decentralised examination and treatment. Access to generic drugs is important. A major educational effort is needed to improve public health.

  15. [Food addiction: Definition, measurement and limits of the concept, associated factors, therapeutic and clinical implications].

    Science.gov (United States)

    Cathelain, Sarah; Brunault, Paul; Ballon, Nicolas; Réveillère, Christian; Courtois, Robert

    2016-12-01

    Addictions, which are characterized by the inability to control a behavior despite existence of physical or psychological consequences, have biological, psychological and social determinants. Although the possibility of developing an addiction to some psychoactive substances (e.g. alcohol, tobacco, cannabis) and to gambling (i.e., gambling disorder) is now well demonstrated, the possibility to develop a non-drug addiction (i.e., behavioral addiction) to certain behaviors which provide pleasure (e.g. eating, having sex, buying things) is still in debate. The concept of food addiction, which refers to people who exhibit substance dependence criteria in relation to some high-fat and high-sugar foods, was recently proposed by applying substance dependence DSM criteria to eating behavior. To assess food addiction, the Yale Food Addiction Scale is now the only self-administered questionnaire (diagnosis and estimate of the number of symptoms of food addiction). Prevalence for food addiction is higher in overweight and obese patients, and in patients with certain psychopathological characteristics (i.e., depression, Attention Deficit Hyperactivity Disorder, high impulsivity), in patients who are single and in patients with neurobiological alterations in the reward system. However, it is still unclear whether food addiction is necessary associated with subsequent increase in body weight and/or obesity. An increasing number of studies demonstrated that drug addiction and food addiction shares some similar clinical, neurobiological and psychopathological and sociocultural risk factors. To test the pertinence to include food addiction as an addiction, it would be interesting to conduct future studies in patients who may experience harms related to their food addiction, including not only patients with obesity, but also patients with metabolic syndrome, type 2 diabetes, hypertension, dyslipidemia, atherosclerosis, stroke, or coronary heart disease. Food addiction is a clinical

  16. A network based method for analysis of lncRNA-disease associations and prediction of lncRNAs implicated in diseases.

    Science.gov (United States)

    Yang, Xiaofei; Gao, Lin; Guo, Xingli; Shi, Xinghua; Wu, Hao; Song, Fei; Wang, Bingbo

    2014-01-01

    Increasing evidence has indicated that long non-coding RNAs (lncRNAs) are implicated in and associated with many complex human diseases. Despite of the accumulation of lncRNA-disease associations, only a few studies had studied the roles of these associations in pathogenesis. In this paper, we investigated lncRNA-disease associations from a network view to understand the contribution of these lncRNAs to complex diseases. Specifically, we studied both the properties of the diseases in which the lncRNAs were implicated, and that of the lncRNAs associated with complex diseases. Regarding the fact that protein coding genes and lncRNAs are involved in human diseases, we constructed a coding-non-coding gene-disease bipartite network based on known associations between diseases and disease-causing genes. We then applied a propagation algorithm to uncover the hidden lncRNA-disease associations in this network. The algorithm was evaluated by leave-one-out cross validation on 103 diseases in which at least two genes were known to be involved, and achieved an AUC of 0.7881. Our algorithm successfully predicted 768 potential lncRNA-disease associations between 66 lncRNAs and 193 diseases. Furthermore, our results for Alzheimer's disease, pancreatic cancer, and gastric cancer were verified by other independent studies.

  17. Associations between Sleep, Cortisol Regulation, and Diet: Possible Implications for the Risk of Alzheimer Disease.

    Science.gov (United States)

    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-07-01

    Accumulation of proteinaceous amyloid β plaques and tau oligomers may occur several years before the onset of Alzheimer disease (AD). Under normal circumstances, misfolded proteins get cleared by proteasome degradation, autophagy, and the recently discovered brain glymphatic system, an astroglial-mediated interstitial fluid bulk flow. It has been shown that the activity of the glymphatic system is higher during sleep and disengaged or low during wakefulness. As a consequence, poor sleep quality, which is associated with dementia, might negatively affect glymphatic system activity, thus contributing to amyloid accumulation. The diet is another important factor to consider in the regulation of this complex network. Diets characterized by high intakes of refined sugars, salt, animal-derived proteins and fats and by low intakes of fruit and vegetables are associated with a higher risk of AD and can perturb the circadian modulation of cortisol secretion, which is associated with poor sleep quality. For this reason, diets and nutritional interventions aimed at restoring cortisol concentrations may ease sleep disorders and may facilitate brain clearance, consequentially reducing the risk of cognitive impairment and dementia. Here, we describe the associations that exist between sleep, cortisol regulation, and diet and their possible implications for the risk of cognitive impairment and AD.

  18. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism.

    Science.gov (United States)

    Wang, Zhi-Qiang; Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Guillemette, Chantal; Gobeil, Stéphane; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2015-10-13

    Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.

  19. Practical and Scholarly Implications of Information Behaviour Research: A Pilot Study of Research Literature

    Science.gov (United States)

    Koh, Kyungwon; Rubenstein, Ellen; White, Kelvin

    2015-01-01

    Introduction: This pilot study examined how current information behaviour research addresses the implications and potential impacts of its findings. The goal was to understand what implications and contributions the field has made and how effectively authors communicate implications of their findings. Methods: We conducted a content analysis of 30…

  20. The sequence, and its evolutionary implications, of a Thermococcus celer protein associated with transcription

    Science.gov (United States)

    Kaine, B. P.; Mehr, I. J.; Woese, C. R.

    1994-01-01

    Through random search, a gene from Thermococcus celer has been identified and sequenced that appears to encode a transcription-associated protein (110 amino acid residues). The sequence has clear homology to approximately the last half of an open reading frame reported previously for Sulfolobus acidocaldarius [Langer, D. & Zillig, W. (1993) Nucleic Acids Res. 21, 2251]. The protein translations of these two archaeal genes in turn are homologs of a small subunit found in eukaryotic RNA polymerase I (A12.2) and the counterpart of this from RNA polymerase II (B12.6). Homology is also seen with the eukaryotic transcription factor TFIIS, but it involves only the terminal 45 amino acids of the archaeal proteins. Evolutionary implications of these homologies are discussed.

  1. Migraine Associated with Gastrointestinal Disorders: Review of the Literature and Clinical Implications

    NARCIS (Netherlands)

    Hemert, van S.; Breedveld, A.C.; Rovers, J.M.P.; Vermeiden, J.P.W.; Witteman, B.J.M.; Smits, M.; Roos, de N.M.

    2014-01-01

    Recent studies suggest that migraine may be associated with gastrointestinal (GI) disorders, including irritable bowel syndrome (IBS), inflammatory bowel syndrome, and celiac disease. Here, an overview of the associations between migraine and GI disorders is presented, as well as possible mechanisti

  2. Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

    NARCIS (Netherlands)

    Tafti, M.; Lammers, G.J.; Dauvilliers, Y.; Overeem, S.; Mayer, G.; Nowak, J.; Pfister, C.; Dubois, V.; Eliaou, J.F.; Eberhard, H.P.; Liblau, R.; Wierzbicka, A.; Geisler, P.; Bassetti, C.L.; Mathis, J.; Lecendreux, M.; Khatami, R.; Heinzer, R.; Haba-Rubio, J.; Feketeova, E.; Baumann, C.R.; Kutalik, Z.; Tiercy, J.M.

    2016-01-01

    STUDY OBJECTIVES: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoi

  3. Preliminary evidence of association between EFHC2, a gene implicated in fear recognition, and harm avoidance.

    Science.gov (United States)

    Blaya, Carolina; Moorjani, Priya; Salum, Giovanni Abrahão; Gonçalves, Leonardo; Weiss, Lauren A; Leistner-Segal, Sandra; Manfro, Gisele G; Smoller, Jordan W

    2009-03-06

    Genetic variation at the EF-hand domain containing 2 gene (EFHC2) locus has been associated with fear recognition in Turner syndrome. The aim of this study was to examine whether EFHC2 variants are associated with non-syndromic anxiety-related traits [harm avoidance (HA) and behavioral inhibition (BI)] and with panic disorder (PD). Our sample comprised 127 PD patients and 132 controls without psychiatric disorder. We genotyped nine SNPs within the EFHC2 locus and used PLINK to perform association analyses. An intronic SNP (rs1562875) was associated with HA (permuted p=0.031) accounting alone for over 3% of variance in this trait. This same SNP was nominally, but not empirically, associated with BI (r(2)=0.022; nominal p=0.022) and PD (OR=2.64; nominal p=0.009). The same association was found in a subsample of only females. In sum, we observed evidence of association between a variant in EFHC2, a gene previously associated with the processing of fear and social threat, and HA. Larger studies are warranted to confirm this association.

  4. Survival Implications Associated with Variation in Mastectomy Rates for Early-Staged Breast Cancer

    Directory of Open Access Journals (Sweden)

    John M. Brooks

    2012-01-01

    Full Text Available Despite a 20-year-old guideline from the National Institutes of Health (NIH Consensus Development Conference recommending breast conserving surgery with radiation (BCSR over mastectomy for woman with early-stage breast cancer (ESBC because it preserves the breast, recent evidence shows mastectomy rates increasing and higher-staged ESBC patients are more likely to receive mastectomy. These observations suggest that some patients and their providers believe that mastectomy has advantages over BCSR and these advantages increase with stage. These beliefs may persist because the randomized controlled trials (RCTs that served as the basis for the NIH guideline were populated mainly with lower-staged patients. Our objective is to assess the survival implications associated with mastectomy choice by patient alignment with the RCT populations. We used instrumental variable methods to estimate the relationship between surgery choice and survival for ESBC patients based on variation in local area surgery styles. We find results consistent with the RCTs for patients closely aligned to the RCT populations. However, for patients unlike those in the RCTs, our results suggest that higher mastectomy rates are associated with reduced survival. We are careful to interpret our estimates in terms of limitations of our estimation approach.

  5. A literature review of neck pain associated with computer use: public health implications

    OpenAIRE

    2008-01-01

    Prolonged use of computers during daily work activities and recreation is often cited as a cause of neck pain. This review of the literature identifies public health aspects of neck pain as associated with computer use. While some retrospective studies support the hypothesis that frequent computer operation is associated with neck pain, few prospective studies reveal causal relationships. Many risk factors are identified in the literature. Primary prevention strategies have largely been confi...

  6. Periodontal Systemic Connections-Novel Associations-A Review of the Evidence with Implications for Medical Practitioners.

    Science.gov (United States)

    Kalakonda, Butchibabu; Koppolu, Pradeep; Baroudi, Kusai; Mishra, Ashank

    2016-04-01

    Periodontal diseases, considered as inflammatory diseases have proved to have a spectrum of systemic implications. Earliest research has associated periodontal disease with common systemic aliments such as hypertension, diabetes, osteoporosis, rheumatoid arthritis to name a few. The evolution of advanced diagnostic aids let researchers make vast inroads in linking periodontal diseases to systemic diseases like Alzheimer's disease (AD) and even Schizophrenia. Our aim was to review and critically evaluate comprehensive literature and provide knowledge to medical practitioners on these associations so as to pave way for closer interactions between medical and dental practitioners in implementing better health care. Electronic databases such as PubMed, Google Scholar and Cochrane databases were used as source of the data for relevant studies published from 2005 up to 2015 with the following keywords, "'Periodontal disease", "systemic conditions", "periodontal disease and Alzheimer's", "Periodontal disease and Schizophrenia", "Periodontal disease and Psoriasis" and "Periodontal disease and erectile dysfunction". The evidence presented ascertains that a reasonable and modest association does exist between Periodontal disease and Alzheimer's, Schizophrenia, Erectile dysfunction, as well as Psoriasis and thus establishes periodontal disease as a potential risk factor.

  7. Genome-wide association study identifies four loci associated with eruption of permanent teeth.

    Directory of Open Access Journals (Sweden)

    Frank Geller

    2011-09-01

    Full Text Available The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years, analyzed as age-adjusted standard deviation score averaged over multiple time points, based on childhood records for 5,104 women from the Danish National Birth Cohort. Four loci showed association at P<5×10(-8 and were replicated in four independent study groups from the United States and Denmark with a total of 3,762 individuals; all combined P-values were below 10(-11. Two loci agreed with previous findings in primary tooth eruption and were also known to influence height and breast cancer, respectively. The two other loci pointed to genomic regions without any previous significant genome-wide association study results. The intronic SNP rs7924176 in ADK could be linked to gene expression in monocytes. The combined effect of the four genetic variants was most pronounced between age 10 and 12 years, where children with 6 to 8 delayed tooth eruption alleles had on average 3.5 (95% confidence interval: 2.9-4.1 fewer permanent teeth than children with 0 or 1 of these alleles.

  8. Genome-wide association studies in asthma: progress and pitfalls

    Directory of Open Access Journals (Sweden)

    March ME

    2015-01-01

    Full Text Available Michael E March,1 Patrick MA Sleiman,1,2 Hakon Hakonarson1,2 1Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine. Keywords: asthma, genetics, GWAS, pharmacogenetics, biomarkers

  9. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

    Science.gov (United States)

    Easton, Douglas F; Lesueur, Fabienne; Decker, Brennan; Michailidou, Kyriaki; Li, Jun; Allen, Jamie; Luccarini, Craig; Pooley, Karen A; Shah, Mitul; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Ahmad, Jamil; Thompson, Ella R; Damiola, Francesca; Pertesi, Maroulio; Voegele, Catherine; Mebirouk, Noura; Robinot, Nivonirina; Durand, Geoffroy; Forey, Nathalie; Luben, Robert N; Ahmed, Shahana; Aittomäki, Kristiina; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Beckman, Matthias W; Benitez, Javier; Van Den Berg, David; Blot, William J; Bogdanova, Natalia V; Bojesen, Stig E; Brenner, Hermann; Chang-Claude, Jenny; Chia, Kee Seng; Choi, Ji-Yeob; Conroy, Don M; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Fostira, Florentia; García-Closas, Montserrat; Giles, Graham G; Glendon, Gord; González-Neira, Anna; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hart, Steven N; Hartman, Mikael; Hooning, Maartje J; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; James, Paul A; John, Esther M; Johnson, Nichola; Jones, Michael; Kabisch, Maria; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lambrechts, Diether; Li, Na; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Meindl, Alfons; Mitchell, Gillian; Muir, Kenneth; Nevelsteen, Ines; van den Ouweland, Ans; Peterlongo, Paolo; Phuah, Sze Yee; Pylkäs, Katri; Rowley, Simone M; Sangrajrang, Suleeporn; Schmutzler, Rita K; Shen, Chen-Yang; Shu, Xiao-Ou; Southey, Melissa C; Surowy, Harald; Swerdlow, Anthony; Teo, Soo H; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Verhoef, Senno; Wong-Brown, Michelle; Zheng, Wei; Zheng, Ying; Nevanlinna, Heli; Scott, Rodney J; Andrulis, Irene L; Wu, Anna H; Hopper, John L; Couch, Fergus J; Winqvist, Robert; Burwinkel, Barbara; Sawyer, Elinor J; Schmidt, Marjanka K; Rudolph, Anja; Dörk, Thilo; Brauch, Hiltrud; Hamann, Ute; Neuhausen, Susan L; Milne, Roger L; Fletcher, Olivia; Pharoah, Paul D P; Campbell, Ian G; Dunning, Alison M; Le Calvez-Kelm, Florence; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia

    2016-01-01

    Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels. PMID:26921362

  10. Insights into kidney diseases from genome-wide association studies.

    Science.gov (United States)

    Wuttke, Matthias; Köttgen, Anna

    2016-09-01

    Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin-to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD-defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology.

  11. Depression and Apathy Among People Living with HIV: Implications for Treatment of HIV Associated Neurocognitive Disorders

    Science.gov (United States)

    Whitehead, Nicole E.; Burrell, Larry E.; Dotson, Vonetta M.; Cook, Robert L.; Malloy, Paul; Devlin, Kathryn; Cohen, Ronald A.

    2015-01-01

    Depression and apathy are common among people living with HIV (PLWH). However, in PLWH, it is unclear whether depression and apathy are distinct conditions, which contribute to different patterns of disruption to cognitive processing and brain systems. Understanding these conditions may enable the development of prognostic indicators for HIV associated neurocognitive disorders (HAND). The present study examined substance use behavior and cognitive deficits, associated with depression and apathy, in 120 PLWH, using hierarchical regression analyses. Higher levels of depression were associated with a history of alcohol dependence and greater deficits in processing speed, motor and global cognitive functioning. Higher levels of apathy were associated with a history of cocaine dependence. It is recommended that PLWH get screened appropriately for apathy and depression, in order to receive the appropriate treatment, considering the comorbidities associated with each condition. Future research should examine the neurological correlates of apathy and depression in PLWH. PMID:25533921

  12. Factors associated with female genital mutilation in Burkina Faso and its policy implications

    Directory of Open Access Journals (Sweden)

    Chung Donna

    2011-05-01

    Full Text Available Abstract Background Female genital mutilation (FGM usually undertaken between the ages of 1-9 years and is widely practised in some part of Africa and by migrants from African countries in other parts of the world. Laws prohibit FGM in almost every country. FGM can cause immediate complications (pain, bleeding and infection and delayed complications (sexual, obstetric, psychological problems. Several factors have been associated with an increased likelihood of FGM. In Burkina Faso, the prevalence of FGM appears to have increased in recent years. Methods We investigated social, demographic and economic factors associated with FGM in Burkina Faso using the 2003 Demographic Health Survey (DHS. The DHS is a nationally representative cross-sectional survey (multistage stratified random sampling of households of women of reproductive age (15-49 years. Associations between potential risk factors and the prevalence of FGM were explored using χ2 and t-tests and Mann Whitney U-test as appropriate. Logistic regression modelling was used to investigate social, demographic and economic risk factors associated with FGM. Main outcome measures i whether a woman herself had had FGM; ii whether she had one or more daughters with FGM. Results Data were available on 12,049 women. Response rates by region were at least 90%. Women interviewed were representative of the underlying populations of the different regions of Burkina Faso. Seventy seven percent (9267 of the women interviewed had had FGM. 7336 women had a daughter of whom 2216 (30.2% had a daughter with FGM and 334 (4.5% said that they intended that their daughter should have it. Univariate analysis showed that age, religion, wealth, ethnicity, literacy, years of education, household affluence, region and who had responsibility for health care decisions in the household had (RHCD were all significantly related to the two outcomes (p Conclusions and Policy implications Factors associated with FGM are varied

  13. Molecular basis of ALS and FTD: implications for translational studies.

    Science.gov (United States)

    Liščić, Rajka M

    2015-12-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options.

  14. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Directory of Open Access Journals (Sweden)

    Varun Warrier

    Full Text Available Asperger Syndrome (AS is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC, which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448 were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448 lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  15. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Science.gov (United States)

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Peltonen, Leena; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  16. Epidemiology of Epilepsy in Older Adults with an Intellectual Disability in Ireland: Associations and Service Implications

    Science.gov (United States)

    McCarron, Mary; O'Dwyer, Marie; Burke, Eilish; McGlinchey, Eimear; McCallion, Philip

    2014-01-01

    There are limited studies on the prevalence of epilepsy and co-morbid conditions in older adults with an ID. To begin to address this prevalence of epilepsy was estimated for participants in the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing. Associations with demographic variables and co morbid health conditions were…

  17. Associative visual agnosia: a case study.

    Science.gov (United States)

    Charnallet, A; Carbonnel, S; David, D; Moreaud, O

    2008-01-01

    We report a case of massive associative visual agnosia. In the light of current theories of identification and semantic knowledge organization, a deficit involving both levels of structural description system and visual semantics must be assumed to explain the case. We suggest, in line with a previous case study, an alternative account in the framework of (non abstractive) episodic models of memory.

  18. Associative Visual Agnosia: A Case Study

    OpenAIRE

    A. Charnallet; S. Carbonnel; David, D.; Moreaud, O.

    2008-01-01

    We report a case of massive associative visual agnosia. In the light of current theories of identification and semantic knowledge organization, a deficit involving both levels of structural description system and visual semantics must be assumed to explain the case. We suggest, in line with a previous case study [1], an alternative account in the framework of (non abstractive) episodic models of memory [4].

  19. Understanding Salesforce Behavior using Genetic Association Studies

    NARCIS (Netherlands)

    W.E. van den Berg (Wouter)

    2014-01-01

    markdownabstract__Abstract__ Using genetic association studies, this thesis aims to investigate the drivers of successful customer-salesperson interactions in a context where knowledge development has become crucial to the value creation process. Central to this thesis is the developing role of the

  20. A Comparative Study of Sparse Associative Memories

    Science.gov (United States)

    Gripon, Vincent; Heusel, Judith; Löwe, Matthias; Vermet, Franck

    2016-07-01

    We study various models of associative memories with sparse information, i.e. a pattern to be stored is a random string of 0s and 1s with about log N 1s, only. We compare different synaptic weights, architectures and retrieval mechanisms to shed light on the influence of the various parameters on the storage capacity.

  1. Functional analysis of variance for association studies.

    Directory of Open Access Journals (Sweden)

    Olga A Vsevolozhskaya

    Full Text Available While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1 it tests for a joint effect of gene variants, including both common and rare; (2 it fully utilizes linkage disequilibrium and genetic position information; and (3 allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods - SKAT and a previously proposed method based on functional linear models (FLM, - especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

  2. Physiological Effects Associated with Quinoa Consumption and Implications for Research Involving Humans: a Review.

    Science.gov (United States)

    Simnadis, Thomas George; Tapsell, Linda C; Beck, Eleanor J

    2015-09-01

    Quinoa is a pseudo-grain consumed as a dietary staple in South America. In recent years, consumer demand for quinoa in the developed world has grown steadily. Its perceived health benefits have been cited as a driving force behind this trend, but there are very few human studies investigating the impact of quinoa consumption. The aim of this review was to identify physiological effects of quinoa consumption with potential for human health. A critical evaluation of animal model studies was conducted. The quality of identified studies was assessed using a methodological quality assessment tool and summative conclusions were drawn to guide the direction of future human research. The majority of studies were of fair quality. Purported physiological effects of quinoa consumption included decreased weight gain, improved lipid profile and improved capacity to respond to oxidative stress. These physiological effects were attributed to the presence of saponins, protein and 20-hydroxyecdysone in the quinoa seed. The implications of these findings are that human studies should investigate the impact of quinoa consumption on weight gain and lipid levels. The role of quinoa as an antioxidant is still unclear and requires further elucidation in animal models.

  3. Quantum-holographic and classical Hopfield-like associative nnets: implications for modeling two cognitive modes of consciousness

    Science.gov (United States)

    Rakovic, D.; Dugic, M.

    2005-05-01

    Quantum bases of consciousness are considered with psychosomatic implications of three front lines of psychosomatic medicine (hesychastic spirituality, holistic Eastern medicine, and symptomatic Western medicine), as well as cognitive implications of two modes of individual consciousness (quantum-coherent transitional and altered states, and classically reduced normal states) alongside with conditions of transformations of one mode into another (considering consciousness quantum-coherence/classical-decoherence acupuncture system/nervous system interaction, direct and reverse, with and without threshold limits, respectively) - by using theoretical methods of associative neural networks and quantum neural holography combined with quantum decoherence theory.

  4. Study of Implications of FDI on Indian Economy

    Directory of Open Access Journals (Sweden)

    Srikant MISRA

    2012-12-01

    Full Text Available Foreign direct investment (FDI is always contributing in the positive growth toward the economy of one country due to the investment by another country or country’s personnel’s. The effectiveness and efficiency of Global economy depends upon the investor’s perception, if investment seen with the purpose of long terms investment in the social-economical development then it is said that the investment contributes positively towards global economy, if it is short term for the purpose of making profit then it may be less significant than that long term and disinvestment leads negative effect. The FDI may also be affected due to the governmental trade barriers and policies for the foreign investments and leads to less or more effective toward contribution in economy as well as GDP and GNP of the country.In this paper, our aim is to point out the negative and positive implications which affect the economic scenario and also measure the level of predominance by the factors for economic contribution of particular country with special reference to India. FDI seen as an important catalyst for economic growth in the developing countries, The main purpose of the study is to investigate the impact of FDI on economic growth in India, from the period of 1990 to 2010.This article will also be examined current international investment regime and their relation with Indian economy. This article hopes to find a new position for effectiveness and efficiency of Indian economy through integrated global market by FDI.

  5. Abdominal fat mass is associated with adaptive immune activation: the CODAM study

    NARCIS (Netherlands)

    Thewissen, M.M.; Damoiseaux, J.G.; Duijvestijn, A.M.; Greevenbroek, M.M.; Kallen, van der C.J.H.; Feskens, E.J.M.; Blaak, E.E.; Schalkwijk, C.G.; Stehouwer, C.D.A.; Cohen Tervaert, J.W.; Ferreira, I.

    2011-01-01

    Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist circumferen

  6. Associates of an Elevated Natriuretic Peptide Level in Stable Heart Failure Patients: Implications for Targeted Management

    Directory of Open Access Journals (Sweden)

    Aftab Jan

    2013-01-01

    Full Text Available Background. Persistently elevated natriuretic peptide (NP levels in heart failure (HF patients are associated with impaired prognosis. Recent work suggests that NP-guided therapy can improve outcome, but the mechanisms behind an elevated BNP remain unclear. Among the potential stimuli for NP in clinically stable patients are persistent occult fluid overload, wall stress, inflammation, fibrosis, and ischemia. The purpose of this study was to identify associates of B-type natriuretic peptide (BNP in a stable HF population. Methods. In a prospective observational study of 179 stable HF patients, the association between BNP and markers of collagen metabolism, inflammation, and Doppler-echocardiographic parameters including left ventricular ejection fraction (LVEF, left atrial volume index (LAVI, and E/e prime (E/e′ was measured. Results. Univariable associates of elevated BNP were age, LVEF, LAVI, E/e′, creatinine, and markers of collagen turnover. In a multiple linear regression model, age, creatinine, and LVEF remained significant associates of BNP. E/e′ and markers of collagen turnover had a persistent impact on BNP independent of these covariates. Conclusion. Multiple variables are associated with persistently elevated BNP levels in stable HF patients. Clarification of the relative importance of NP stimuli may help refine NP-guided therapy, potentially improving outcome for this at-risk population.

  7. DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

    Science.gov (United States)

    Searles Quick, V B; Davis, J M; Olincy, A; Sikela, J M

    2015-12-15

    The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms. We therefore also examined DUF1220 copy number in schizophrenia subgroups defined by negative and positive symptom features, versus autistic individuals and controls. In the schizophrenic population (N=609), decreased DUF1220 copy number was linearly associated with increasing positive symptom severity (CON1 P=0.013, HLS1 P=0.0227), an association greatest in adult-onset schizophrenia (CON1 P=0.00155, HLS1 P=0.00361). In schizophrenic males, DUF1220 CON1 subtype copy number increase was associated with increased negative symptom severity (P=0.0327), a finding similar to that seen in autistic populations. Subgroup analyses demonstrated that schizophrenic individuals with predominantly positive symptoms exhibited reduced CON1 copy number compared with both controls (P=0.0237) and schizophrenic individuals with predominantly negative symptoms (P=0.0068). These findings support the view that (1) autism and schizophrenia exhibit both opposing and partially overlapping phenotypes and may represent a disease continuum, (2) variation in DUF1220 copy number contributes to schizophrenia disease risk and to the severity of both disorders, and (3) schizophrenia and autism may be, in part, a harmful by-product of the rapid and extreme evolutionary increase in DUF1220 copy number in the human species.

  8. A genome-wide association study of female sexual dysfunction.

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    Andrea Burri

    Full Text Available BACKGROUND: Female sexual dysfunction (FSD is an important but controversial problem with serious negative impact on women's quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD. METHODOLOGY/PRINCIPAL FINDINGS: We performed a genome-wide association study (GWAS on 2.5 million single-nucleotide polymorphisms (SNPs in 1,104 female twins (25-81 years of age in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10 × -8, we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2 × 10(-7; rs1876525, P = 1.2 × 10(-7; and rs13209281 P = 8.3 × 10(-7 on chromosome 6, around 500 kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci. CONCLUSIONS/SIGNIFICANCE: We report the first GWAS of FSD symptoms in humans. This has pointed to several "risk alleles" and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology.

  9. Fluid retention associated with imatinib treatment in patients with gastroenterol stromal: Quantitative radiologic assessment and implications for management

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Won; Shinagare, Atul B.; Krajewski, Katherine M.; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikihil H. [Dept. of Imaging, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Harvard Medical School, Boston (United States); Pyo, Jun Hee [The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston (United States)

    2015-04-15

    We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

  10. Factors associated to duration of hepatitis a outbreaks: implications for control.

    Directory of Open Access Journals (Sweden)

    Nuria Torner

    Full Text Available Even though hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. The aim of this study was to investigate the association between duration and characteristics of hepatitis A outbreaks. Hepatitis A (HA outbreaks reported between 1991 and 2007 were studied. An outbreak was defined as ≥2 epidemiologically-linked cases with ≥1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM antibodies. Relationships between explanatory variables and outbreak duration were assessed by logistic regression. During the study period, 268 outbreaks (rate 2.45 per million persons-year and 1396 cases (rate 1.28 per 10(5 persons-year were reported. Factors associated with shorter duration were time to intervention (OR = 0.96; 95% CI: 0.94-0.98 and school setting (OR = 0.39; 95% CI: 0.16-0.92. In person-to-person transmission outbreaks only time to intervention was associated with shorter outbreak duration (OR = 0.96; 95% CI: 0.95-0.98. The only variables associated with shorter outbreak duration were early administration of IG or vaccine and a school setting. Timely reporting HA outbreaks was associated with outbreak duration. Making confirmed HA infections statutory reportable for clinical laboratories could diminish outbreak duration.

  11. Factors Associated to Duration of Hepatitis A Outbreaks: Implications for Control

    Science.gov (United States)

    Torner, Nuria; Broner, Sonia; Martinez, Ana; Tortajada, Cecilia; Garcia de Olalla, Patricia; Barrabeig, Irene; Sala, MariaRosa; Camps, Neus; Minguell, Sofia; Alvarez, Josep; Ferrús, Gloria; Torra, Roser; Godoy, Pere; Dominguez, Angela

    2012-01-01

    Even though hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. The aim of this study was to investigate the association between duration and characteristics of hepatitis A outbreaks. Hepatitis A (HA) outbreaks reported between 1991 and 2007 were studied. An outbreak was defined as ≥2 epidemiologically-linked cases with ≥1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM) antibodies. Relationships between explanatory variables and outbreak duration were assessed by logistic regression. During the study period, 268 outbreaks (rate 2.45 per million persons-year) and 1396 cases (rate 1.28 per 105 persons-year) were reported. Factors associated with shorter duration were time to intervention (OR = 0.96; 95% CI: 0.94–0.98) and school setting (OR = 0.39; 95% CI: 0.16–0.92). In person-to-person transmission outbreaks only time to intervention was associated with shorter outbreak duration (OR = 0.96; 95% CI: 0.95–0.98). The only variables associated with shorter outbreak duration were early administration of IG or vaccine and a school setting. Timely reporting HA outbreaks was associated with outbreak duration. Making confirmed HA infections statutory reportable for clinical laboratories could diminish outbreak duration. PMID:22355358

  12. Pollution and skin: from epidemiological and mechanistic studies to clinical implications.

    Science.gov (United States)

    Krutmann, Jean; Liu, Wei; Li, Li; Pan, Xiaochuan; Crawford, Martha; Sore, Gabrielle; Seite, Sophie

    2014-12-01

    In recent years, the health effects associated with air pollution have been intensively studied. Most studies focus on air pollution effects on the lung and the cardiovascular system. More recently, however, epidemiological and mechanistic studies suggest that air pollution is also affecting skin integrity. This state-of-the-art review focuses on this latter aspect; it was developed with the collaboration of European and Chinese board of experts with specific interests in environmental health, clinical and basic research in dermatology and cosmetic dermatology. A literature review limited to pollution and health effects and (sensitive) skin was performed using PubMed. Review and original articles were chosen. We summarize the existing scientific evidence that air pollution exerts detrimental effects on human skin, discuss potential clinical implications and suggest specific and unspecific cosmetic protective measures.

  13. Impact of associated injuries in the Floating knee: A retrospective study

    Directory of Open Access Journals (Sweden)

    Yesupalan Rajam S

    2009-01-01

    Full Text Available Abstract Background Floating knee injuries are usually associated with other significant injuries. Do these injuries have implications on the management of the floating knee and the final outcome of patients? Our study aims to assess the implications of associated injuries in the management and final outcome of floating knee. Methods 29 patients with floating knees were assessed in our institution. A retrospective analysis of medical records and radiographs were done and all associated injuries were identified. The impact of associated injuries on delay in initial surgical management, delay in rehabilitation & final outcome of the floating knee were assessed. Results 38 associated injuries were noted. 7 were associated with ipsilateral knee injuries. Lower limb injuries were most commonly associated with the floating knee. Patients with some associated injuries had a delay in surgical management and others a delay in post-operative rehabilitation. Knee ligament and vascular injuries were associated with poor outcome. Conclusion The associated injuries were quite frequent with the floating knee. Some of the associated injuries caused a delay in surgical management and post-operative rehabilitation. In assessment of the final outcome, patients with associated knee and vascular injuries had a poor prognosis. Majority of the patients with associated injuries had a good or excellent outcome.

  14. Longitudinal associations between BMI, waist circumference, and cardiometabolic risk in US youth: Monitoring implications

    Science.gov (United States)

    This study examined whether change in body mass index (BMI) or waist circumference (WC)is associated with change in cardiometabolic risk factors and differences between cardiovascular disease specific and diabetes specific risk factors among adolescents. We also sought to examine any differences by ...

  15. Paleomagnetic Study of Azores Archipelago: Volcano-Tectonic Implications

    Science.gov (United States)

    Silva, P. F.; Henry, B.; Marques, F. O.; Madureira, P.; Miranda, J. M. A.; Lourenco, N. V.; Madeira, J.; Hildenbrand, A.; Nunes, J. C.; Roxerová, Z.

    2014-12-01

    ., Madureira, P., Mériaux, C; Kratinová, Z. Palaeomagnetic study of a sub-aerial volcanic ridge (São Jorge Island, Azores) for the past 1.3 Myr: evidence for the Cobb Mountain Subchron, volcano flank instability and tectono-magmatic implications. Geophysical Journal International, 188, 3, 959-978, 2012

  16. Associative Visual Agnosia: A Case Study

    Directory of Open Access Journals (Sweden)

    A. Charnallet

    2008-01-01

    Full Text Available We report a case of massive associative visual agnosia. In the light of current theories of identification and semantic knowledge organization, a deficit involving both levels of structural description system and visual semantics must be assumed to explain the case. We suggest, in line with a previous case study [1], an alternative account in the framework of (non abstractive episodic models of memory [4].

  17. Factors associated to duration of hepatitis A outbreaks: implications for control

    OpenAIRE

    Torner Gràcia, Núria; Broner, Sonia; Martinez, Ana; Tortajada, Cecilia; Garcia de Olalla, Patricia; Barrabeig i Fabregat, Irene; Sala, Maria Rosa; Camps, Neus; Minguell, Sofia; Álvarez, Josep; Ferrús, Gloria; Torra, Roser; Godoy i García, Pere; Domínguez García, Àngela

    2012-01-01

    Even though hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. The aim of this study was to investigate the association between duration and characteristics of hepatitis A outbreaks. Hepatitis A (HA) outbreaks reported between 1991 and 2007 were studied. An outbreak was defined as $2 epidemiologically-linked cases with $1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM) antibodies. Relationships between explanatory variables and out...

  18. Factors Associated to Duration of Hepatitis A Outbreaks: Implications for Control

    OpenAIRE

    Torner Gràcia, Núria; Broner, Sonia Judith; Martinez, Ana; Tortajada, Cecilia; García de Olalla, Patricia; Barrabeig i Fabregat, Irene; Sala, Maria Rosa; Camps, Neus; Minguell, Sofia; Alvarez, Josep; Ferrús, Gloria; Torra, Roser; Godoy i García, Pere; Domínguez García, Àngela; Hepatitis A Surveillance Group of Catalonia

    2012-01-01

    Even though hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. The aim of this study was to investigate the association between duration and characteristics of hepatitis A outbreaks. Hepatitis A (HA) outbreaks reported between 1991 and 2007 were studied. An outbreak was defined as ≥2 epidemiologically-linked cases with ≥1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM) antibodies. Relationships between explanatory variables and outbreak durati...

  19. Multiple Intelligences (MI of Associate in Hotel and Restaurant Management Students & Its Implication to the Teaching of Oral Communication

    Directory of Open Access Journals (Sweden)

    Juvy G. Mojares

    2015-11-01

    Full Text Available A number of educators argue that MI helps students build positive attitudes toward learning in English class. A study says that “Students who are using their areas of strength to learn feel more competent and confident and enjoy the challenge of acquiring new information”. This study sought to find out the MI of selected Associate in Hotel and Restaurant Management (AHRMstudents. It also delved on the implication of MI to the teaching of the subject. The research design used was basically a descriptive method employing an adopted MI survey form administered to Oral Communication students. There were five sections of second year AHRM students. Out of 196 students, 111 were selected to answer the survey questions by the use of the combination of stratified random sampling and the Slovin’s formula. Results showed that the top three intelligences the respondents have based on their scores are intrapersonal, followed by bodily/kinesthetic and logical/mathematical intelligences; least of the intelligences are verbal/linguistic and visual/spatial.This implied that teaching of Oral Communication should nurture the intrapersonal intelligence and more importantly should enhance and develop the verbal strength of the AHRM students. Teaching should focus more on improving communication skills with others, and not just within themselves.

  20. Genome-wide association study identifies genetic loci associated with iron deficiency.

    Directory of Open Access Journals (Sweden)

    Christine E McLaren

    Full Text Available The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS Study with serum ferritin (SF≤12 µg/L (cases and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women. Regression analysis was used to examine the association between case-control status (336 cases, 343 controls and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7 for all. An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9, corrected P=0.012 was replicated within the VA samples (observed P=0.012. Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.

  1. Gastroschisis and associated defects: an international study.

    LENUS (Irish Health Repository)

    Mastroiacovo, Pierpaolo

    2007-04-01

    Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

  2. Direct association of Mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance.

    Science.gov (United States)

    Garzón, Javier; Rodríguez-Muñoz, María; Sánchez-Blázquez, Pilar

    2012-09-01

    In the nervous system, the interaction of opioids like morphine and its derivatives, with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of analgesic tolerance, as well as physical dependence. Tolerance implies that increasing doses of the drug are required to achieve the same effect, a phenomenon that contributes significantly to the social problems surrounding recreational opioid abuse. In recent years, our understanding of the mechanisms that control MOR function in the nervous system, and that eventually produce opioid tolerance, has increased greatly. Pharmacological studies have identified a number of signaling proteins involved in morphine-induced tolerance, including the N-methyl-D-aspartate acid glutamate receptor (NMDAR), nitric oxide synthase (NOS), protein kinase C (PKC), protein kinase A (PKA), calcium (Ca²⁺)/calmodulin (CaM)-dependent kinase II (CaMKII), delta-opioid receptor (DOR) and the regulators of G-protein signaling (RGS) proteins. There is general agreement on the critical role of the NMDAR/nNOS/CaMKII pathway in this process, which is supported by the recent demonstration of a physical association between MORs and NMDARs in post-synaptic structures. Indeed, it is feasible that treatments that diminish morphine tolerance may target distinct elements within the same regulatory MOR-NMDAR pathway. Accordingly, we propose a model that incorporates the most relevant signaling components implicated in opioid tolerance in which, certain signals originating from the activated MOR are perceived by the associated NMDAR, which in turn exerts a negative feedback effect on MOR signaling. MOR- and NMDAR-mediated signals work together in a sequential and interconnected manner to ultimately induce MOR desensitization. Future studies of these phenomena should focus on adding further components to this signaling pathway in order to better define the mechanism underlying MOR desensitization in neural cells.

  3. The implications of trade liberalization for diet and health: a case study from Central America

    Directory of Open Access Journals (Sweden)

    Hawkes Corinna

    2009-07-01

    Full Text Available Abstract Background Central America has undergone extensive trade liberalization over the past two decades, and has recently signed a Free Trade Agreement with the United States. The region is also experiencing a dual burden of malnutrition with the growth of dietary patterns associated with the global 'nutrition transition'. This study describes the relationship between trade liberalization policies and food imports and availability, and draws implications for diet and health, using Central America as a case study region. Methods Changes in tariff and non-tariff barriers for each country were documented, and compared with time-series graphs of import, production and availability data to show the outcome of changes in trade policy in relation to food imports and food availability. Results Changes in trade policy in Central America have directly affected food imports and availability via three avenues. First, the lowering of trade barriers has promoted availability by facilitating higher imports of a wide range of foods. Second, trade liberalization has affected food availability through promoting domestic meat production. Third, reductions in barriers to investment appear to be critical in expansion of processed food markets. This suggests that changes in trade policies have facilitated rising availability and consumption of meat, dairy products, processed foods and temperate (imported fruits in Central America. Conclusion This study indicates that the policies of trade liberalization in Central American countries over the past two decades, particularly in relation to the United States, have implications for health in the region. Specifically, they have been a factor in facilitating the "nutrition transition", which is associated with rising rates of obesity and chronic diseases such as cardiovascular disease and cancer. Given the significant cost of chronic disease for the health care system, individuals and the wider community, it is critical

  4. A Study on Associative Neural Memories

    OpenAIRE

    B.D.C.N.Prasad; P. E. S. N. Krishna Prasad; Sagar Yeruva; P Sita Rama Murty

    2011-01-01

    Memory plays a major role in Artificial Neural Networks. Without memory, Neural Network can not be learned itself. One of the primary concepts of memory in neural networks is Associative neural memories. A survey has been made on associative neural memories such as Simple associative memories (SAM), Dynamic associative memories (DAM), Bidirectional Associative memories (BAM), Hopfield memories, Context Sensitive Auto-associative memories (CSAM) and so on. These memories can be applied in vari...

  5. Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders

    Directory of Open Access Journals (Sweden)

    Cai Y

    2015-07-01

    Full Text Available Yan Cai,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, 2Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea Abstract: Alzheimer’s disease (AD is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1, presenilin 2 (PSEN2, and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson’s disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders. Keywords: mutations in presenilin 2, Alzheimer’s disease

  6. Implications of flexible work systems for work studies.

    Science.gov (United States)

    Kogi, K

    1997-12-01

    The relationship between changing work systems and work study methods is discussed by focusing on a recent trend toward more flexible work systems in different countries. These systems are commonly characterized by (a) uncoupling of working hours from business hours, (b) combining different atypical work forms and (c) individualized work patterns. Increased flexibility in working patterns is demanded because business hours may be covered by different workers and because special arrangements become necessary for unpopular shifts or linking separate jobs. Changes in work systems seem more successful when they are associated with (a) multiskilled work, (b) independent task implementation, (c) networked communication, (d) balanced or adjusted workload, and (e) accommodation of workers' preferences. Special attention is drawn to safety and health concerns and work-life effects. Many intervention studies done for work improvement are paying attention to multifaceted work aspects, locally available options, and participation by people. All these elements are important because prepackaged solutions do not exist. The following three views seem especially useful for action-oriented work studies: 1) Look at multiple aspects of the work, including work content and atypical work forms; 2) Know worker preferences and available options; and 3) Take into account work elements that may not be well defined, but important from local points of view. It is envisioned that these studies can provide support for a well-informed participatory process of work system changes in each local context.

  7. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications.

    Science.gov (United States)

    Reymann, Klaus G; Frey, Julietta U

    2007-01-01

    Our review focuses on the mechanisms which enable the late maintenance of hippocampal long-term potentiation (LTP; >3h), a phenomenon which is thought to underlie prolonged memory. About 20 years ago we showed for the first time that the maintenance of LTP - like memory storage--depends on intact protein synthesis and thus, consists of at least two temporal phases. Here we concentrate on mechanisms required for the induction of the transient early-LTP and of the protein synthesis-dependent late-LTP. Our group has shown that the induction of late-LTP requires the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory, reinforcing inputs within specific, effective time windows. The induction of late-LTP is characterized by novel, late-associative properties such as 'synaptic tagging' and 'late-associative reinforcement'. Both phenomena require the associative setting of synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. 'Synaptic tagging' guarantees input specificity and thus the specific processing of afferent signals for the establishment of late-LTP. 'Late-associative reinforcement' describes a process where early-LTP by the co-activation of modulatory inputs can be transformed into late-LTP in activated synapses where a tag is set. Recent evidence from behavioral experiments, which studied processes of emotional and cognitive reinforcement of LTP, point to the physiological relevance of the above mechanisms during cellular and system's memory formation.

  8. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

    NARCIS (Netherlands)

    Huang, Jie; Sabater-Lleal, Maria; Asselbergs, Folkert W.; Tregouet, David; Shin, So-Youn; Ding, Jingzhong; Baumert, Jens; Oudot-Mellakh, Tiphaine; Folkersen, Lasse; Johnson, Andrew D.; Smith, Nicholas L.; Williams, Scott M.; Ikram, Mohammad A.; Kleber, Marcus E.; Becker, Diane M.; Vinh Truong, [No Value; Mychaleckyj, Josyf C.; Tang, Weihong; Yang, Qiong; Sennblad, Bengt; Moore, Jason H.; Williams, Frances M. K.; Dehghan, Abbas; Silbernagel, Guenther; Schrijvers, Elisabeth M. C.; Smith, Shelly; Karakas, Mahir; Tofler, Geoffrey H.; Silveira, Angela; Navis, Gerjan J.; Lohman, Kurt; Chen, Ming-Huei; Peters, Annette; Goel, Anuj; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Lundmark, Per; Psaty, Bruce M.; Strawbridge, Rona J.; Boehm, Bernhard O.; Carter, Angela M.; Meisinger, Christa; Peden, John F.; Bis, Joshua C.; McKnight, Barbara; Ohrvik, John; Taylor, Kent; Franzosi, Maria Grazia; Seedorf, Udo; Collins, Rory; Franco-Cereceda, Anders; Syvaenen, Ann-Christine; Goodall, Alison H.; Yanek, Lisa R.; Cushman, Mary; Mueller-Nurasyid, Martina; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Kooner, Jaspal S.; Hofman, Albert; Danesh, John; Clarke, Robert; Meigs, James B.; Kathiresan, Sekar; Reilly, Muredach P.; Klopp, Norman; Harris, Tamara B.; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Watkins, Hugh; Spector, Timothy D.; Becker, Lewis C.; Tracy, Russell P.; Maerz, Winfried; Uitterlinden, Andre G.; Eriksson, Per; Cambien, Francois; Morange, Pierre-Emmanuel; Koenig, Wolfgang; Soranzo, Nicole; van der Harst, Pim; Liu, Yongmei; O'Donnell, Christopher J.; Hamsten, Anders

    2012-01-01

    We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19

  9. The Association between Dietary Energy Density and Type 2 Diabetes in Europe : Results from the EPIC-InterAct Study

    NARCIS (Netherlands)

    van den Berg, Saskia W.; van der A, Daphne L.; Spijkerman, Annemieke M. W.; van Woudenbergh, Geertruida J.; Tijhuis, Mariken J.; Amiano, Pilar; Ardanaz, Eva; Beulens, Joline W. J.; Boeing, Heiner; Clavel-Chapelon, Francoise; Crowe, Francesca L.; de Lauzon-Guillain, Blandine; Fagherazzi, Guy; Franks, Paul W.; Freisling, Heinz; Gonzalez, Carlos; Grioni, Sara; Halkjaer, Jytte; Maria Huerta, Jose; Huybrechts, Inge; Kaaks, Rudolf; Khaw, Kay Tee; Masala, Giovanna; Nilsson, Peter M.; Overvad, Kim; Panico, Salvatore; Ramon Quiros, J.; Rolandsson, Olov; Sacerdote, Carlotta; Sanchez, Maria-Jose; Schulze, Matthias B.; Slimani, Nadia; Struijk, Ellen A.; Tjonneland, Anne; Tumino, Rosario; Sharp, Stephen J.; Langenberg, Claudia; Forouhi, Nita G.; Feskens, Edith J. M.; Riboli, Elio; Wareham, Nicholas J.

    2013-01-01

    Background: Observational studies implicate higher dietary energy density (DED) as a potential risk factor for weight gain and obesity. It has been hypothesized that DED may also be associated with risk of type 2 diabetes (T2D), but limited evidence exists. Therefore, we investigated the association

  10. Genome-wide association study identifies five new schizophrenia loci.

    LENUS (Irish Health Repository)

    Ripke, Stephan

    2011-10-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

  11. Fluid Retention Associated with Imatinib Treatment in Patients with Gastrointestinal Stromal Tumor: Quantitative Radiologic Assessment and Implications for Management

    Science.gov (United States)

    Shinagare, Atul B.; Krajewski, Katherine M.; Pyo, Junhee; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.

    2015-01-01

    Objective We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. Materials and Methods In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. Results The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Conclusion Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management. PMID:25741192

  12. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Timothy G Jenkins

    2014-07-01

    Full Text Available Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc., trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc. and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9-19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body. Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.

  13. Urban river restoration: implications on channel sedimentation patterns and associated ecosystem and human health

    Science.gov (United States)

    Gibbs, H.; Gurnell, A.; Heppell, K.; Spencer, K.

    2012-04-01

    the restored as opposed to the unrestored stretch at both sites, and this difference persisted after standardisation to loading/m2 of channel to account for differing channel dimensions. Metal concentrations at the two sites were analysed using sediment quality guidelines to assess the potential impact upon both the aquatic ecosystem (Environment Agency draft freshwater quality guidelines, 2008) and human health (Dutch Intervention Values for human, plant and/or animal life, 2009). Greater exceedances occurred for the ecological rather than the human health guidelines. Cu, Ni, Pb and Zn were of greatest concern in terms of ecological sediment quality at Sutcliffe Park and Pb and Zn at Chinbrook Meadows. At Sutcliffe Park a greater proportion of samples exceeded the Predicted Effects Level (PEL) in the restored as opposed to the unrestored stretch; conversely at Chinbrook Meadows a greater proportion of samples in the unrestored stretch as opposed to the restored stretch exceeded the PEL. In terms of human health, exceedances only occurred for Cu and Zn at Sutcliffe Park, with the greater proportion being in the restored stretch. The results from this research will have implications for the design, management and maintenance of restored urban rivers in terms of fine sediment accumulation assessment, its quality and the associated potential impact upon ecosystem and human health.

  14. A NOS1 variant implicated in cognitive performance influences evoked neural responses during a high density EEG study of early visual perception.

    LENUS (Irish Health Repository)

    O'Donoghue, Therese

    2012-05-01

    The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear.

  15. Quantifying shark distribution patterns and species-habitat associations: implications of marine park zoning.

    Directory of Open Access Journals (Sweden)

    Mario Espinoza

    Full Text Available Quantifying shark distribution patterns and species-specific habitat associations in response to geographic and environmental drivers is critical to assessing risk of exposure to fishing, habitat degradation, and the effects of climate change. The present study examined shark distribution patterns, species-habitat associations, and marine reserve use with baited remote underwater video stations (BRUVS along the entire Great Barrier Reef Marine Park (GBRMP over a ten year period. Overall, 21 species of sharks from five families and two orders were recorded. Grey reef Carcharhinus amblyrhynchos, silvertip C. albimarginatus, tiger Galeocerdo cuvier, and sliteye Loxodon macrorhinus sharks were the most abundant species (>64% of shark abundances. Multivariate regression trees showed that hard coral cover produced the primary split separating shark assemblages. Four indicator species had consistently higher abundances and contributed to explaining most of the differences in shark assemblages: C. amblyrhynchos, C. albimarginatus, G. cuvier, and whitetip reef Triaenodon obesus sharks. Relative distance along the GBRMP had the greatest influence on shark occurrence and species richness, which increased at both ends of the sampling range (southern and northern sites relative to intermediate latitudes. Hard coral cover and distance across the shelf were also important predictors of shark distribution. The relative abundance of sharks was significantly higher in non-fished sites, highlighting the conservation value and benefits of the GBRMP zoning. However, our results also showed that hard coral cover had a large effect on the abundance of reef-associated shark species, indicating that coral reef health may be important for the success of marine protected areas. Therefore, understanding shark distribution patterns, species-habitat associations, and the drivers responsible for those patterns is essential for developing sound management and conservation

  16. Quantifying shark distribution patterns and species-habitat associations: implications of marine park zoning.

    Science.gov (United States)

    Espinoza, Mario; Cappo, Mike; Heupel, Michelle R; Tobin, Andrew J; Simpfendorfer, Colin A

    2014-01-01

    Quantifying shark distribution patterns and species-specific habitat associations in response to geographic and environmental drivers is critical to assessing risk of exposure to fishing, habitat degradation, and the effects of climate change. The present study examined shark distribution patterns, species-habitat associations, and marine reserve use with baited remote underwater video stations (BRUVS) along the entire Great Barrier Reef Marine Park (GBRMP) over a ten year period. Overall, 21 species of sharks from five families and two orders were recorded. Grey reef Carcharhinus amblyrhynchos, silvertip C. albimarginatus, tiger Galeocerdo cuvier, and sliteye Loxodon macrorhinus sharks were the most abundant species (>64% of shark abundances). Multivariate regression trees showed that hard coral cover produced the primary split separating shark assemblages. Four indicator species had consistently higher abundances and contributed to explaining most of the differences in shark assemblages: C. amblyrhynchos, C. albimarginatus, G. cuvier, and whitetip reef Triaenodon obesus sharks. Relative distance along the GBRMP had the greatest influence on shark occurrence and species richness, which increased at both ends of the sampling range (southern and northern sites) relative to intermediate latitudes. Hard coral cover and distance across the shelf were also important predictors of shark distribution. The relative abundance of sharks was significantly higher in non-fished sites, highlighting the conservation value and benefits of the GBRMP zoning. However, our results also showed that hard coral cover had a large effect on the abundance of reef-associated shark species, indicating that coral reef health may be important for the success of marine protected areas. Therefore, understanding shark distribution patterns, species-habitat associations, and the drivers responsible for those patterns is essential for developing sound management and conservation approaches.

  17. The implications of sex role identity and psychological capital for organisations: A South African study

    OpenAIRE

    Colleen Bernstein; Sara Volpe

    2016-01-01

    Orientation: A large body of research evidence indicates that both sex role identity (SRI) and psychological capital (PsyCap) may have critical implications for individual and organisational well-being. As SRI is constituted of sex-based personality traits it is possible that SRI may have implications for individuals’ PsyCap.Research purpose: The purpose of this study was to investigate the relationship between SRI and the positive psychological construct of PsyCap.Motivation for the study: R...

  18. Arsenic toxicity to cladocerans isolated and associated with iron: implications for aquatic environments

    Directory of Open Access Journals (Sweden)

    SUELLEN C.M. SALES

    2016-01-01

    Full Text Available ABSTRACT Arsenic is an ametal ubiquitous in nature and known by its high toxicity. Many studies have tried to elucidate the arsenic metabolism in the cell and its impact to plants, animals and human health. In aqueous phase, inorganic arsenic is more common and its oxidation state (As III and As V depends on physical and chemical environmental conditions. The aim of this study was to evaluate toxicity of arsenic to Daphnia similis and Ceriodaphnia silvestrii, isolated and associated with iron. The results showed differences in toxicity of As III and As V to both species. Effective concentration (EC50 mean values were 0.45 mg L-1 (As III and 0.54 mg L-1 (As V for D. similis, and 0.44 mg L-1 (As III and 0.69 mg L-1 (As V for C. silvestrii. However, As V IC25 mean value was 0.59 mg L-1, indicating that C. silvestrii has mechanisms to reduce arsenic toxicity. On the other hand, when associated with iron at 0.02 and 2.00 mg L-1, EC50 values decreased for D. similis (0.34 and 0.38 mg L-1 as well as C. silvestrii (0.37 and 0.37 mg L-1, showing synergistic effect of these substances.

  19. Studying risk factors associated with Human Leptospirosis

    Directory of Open Access Journals (Sweden)

    Ramachandra Kamath

    2014-01-01

    Full Text Available Background: Leptospirosis is one of the most under diagnosed and underreported disease in both developed and developing countries including India. It is established that environmental conditions and occupational habit of the individuals put them at risk of acquiring disease, which varies from community to community. Various seroprevalence studies across the world have documented emerging situation of this neglected tropical disease, but limited have probed to identify the risk factors, especially in India. Objectives: The objective of this study was to identify the environmental and occupational risk factors associated with the disease in Udupi District. Materials and Methods: This population-based case-control study was carried out in Udupi, a District in Southern India from April 2012 until August 2012. Udupi is considered to be endemic for Leptospirosis and reported 116 confirmed cases in the year 2011. Seventy of 116 laboratory confirmed cases and 140 sex matched neighborhood healthy controls participated in the study. A predesigned, semi-structured and validated questionnaire was used for data collection through house to house visit and observations were noted about environmental conditions. Univariate analysis followed by multivariate analysis (back ward conditional logistic regression was performed by using STATA version 9.2 (StataCorp, College Station, TX, USA to identify potential risk factors. Results: Occupational factors such as outdoor activities (matched odds ratio [OR] of 3.95, 95% confidence interval [CI]: 1.19-13.0, presence of cut or wound at body parts during work (matched OR: 4.88, CI: 1.83-13.02 and environmental factors such as contact with rodents through using the food materials ate by rat (matched OR: 4.29, CI: 1.45-12.73 and contact with soil or water contaminated with urine of rat (matched OR: 4.58, CI: 1.43-14.67 were the risk factors identified to be associated with disease. Conclusion: Leptospirosis is still

  20. Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Caroline Perronnet

    2010-01-01

    Full Text Available Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD, which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.

  1. SYSTEMIC INFLAMMATION IMPAIRS ATTENTION AND COGNITIVE FLEXIBILITY BUT NOT ASSOCIATIVE LEARNING IN AGED RATS: Possible Implications for Delirium

    Directory of Open Access Journals (Sweden)

    Deborah J Culley

    2014-06-01

    Full Text Available Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 ug/kg or saline and were tested on the attentional shifting task (AST, an index of integrity of the prefrontal cortex, on days 1-3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24-48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly 3-fold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.

  2. Medicine possession ratio as proxy for adherence to antiepileptic drugs: prevalence, associations, and cost implications

    Directory of Open Access Journals (Sweden)

    Jacobs K

    2016-04-01

    Full Text Available Karen Jacobs,1 Marlene Julyan,2 Martie S Lubbe,1 Johanita R Burger,1 Marike Cockeran1 1Medicine Usage in South Africa, Faculty of Health Sciences, 2Clinical Pharmacy, School of Pharmacy, North-West University (Potchefstroom Campus, Potchefstroom, South Africa Objective: To determine the adherence status to antiepileptic drugs (AEDs among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods: A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168, who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low or >110% (unacceptably high was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results: Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208 but were independent of sex (P<0.182; Cramer’s V=0.009. Age group (P<0.0001; Cramer’s V=0.067, active ingredient (P<0.0001; Cramer’s V=0.071, and number of comorbidities (P<0.0001; Cramer’s V=0.050 were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US$736,376.23 of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US

  3. Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia.

    Science.gov (United States)

    Rosenthal, Elisabeth A; Ranchalis, Jane; Crosslin, David R; Burt, Amber; Brunzell, John D; Motulsky, Arno G; Nickerson, Deborah A; Wijsman, Ellen M; Jarvik, Gail P

    2013-12-01

    Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

  4. Entrepreneurship Education at Tertiary Education Level: Implication to Historical Studies

    Directory of Open Access Journals (Sweden)

    Salahu Mohammed Lawal

    2012-07-01

    Full Text Available Nigeria is richly endowed with both human and material resources that when well utilized can make her one of the richest and developed nation in the world.  But poor utilization of the resources, corruption and dwindling fortune in her education system made her among the first twenty five poorest nations in the world.  Similarly, report shows that 26% of the employable population remained unemployed.  This called for the need for entrepreneurship education most especially at tertiary level where high level manpower is supposed to be trained.  It is on this premise that the paper attempts to examine entrepreneurship education and its implication to history students and graduates.

  5. Associations between Mycobacterium ulcerans and aquatic plant communities of West Africa: implications for Buruli ulcer disease.

    Science.gov (United States)

    McIntosh, Mollie; Williamson, Heather; Benbow, M Eric; Kimbirauskas, Ryan; Quaye, Charles; Boakye, Daniel; Small, Pamela; Merritt, Richard

    2014-06-01

    Numerous studies have associated Buruli ulcer (BU) disease with disturbed aquatic habitats; however, the natural reservoir, distribution, and transmission of the pathogen, Mycobacterium ulcerans, remain unknown. To better understand the role of aquatic plants in the ecology of this disease, a large-scale survey was conducted in waterbodies of variable flow throughout three regions of Ghana, Africa. Our objectives were to characterize plant communities and identify potential relationships with M. ulcerans and other mycolactone-producing mycobacteria (MPM). Waterbodies with M. ulcerans had significantly different aquatic plant communities, with submerged terrestrial plants identified as indicators of M. ulcerans presence. Mycobacterium ulcerans and MPM were detected on 14 plant taxa in emergent zones from both lotic and lentic waterbodies in endemic regions; however, M. ulcerans was not detected in the non-endemic Volta region. These findings support the hypothesis that plants provide substrate for M. ulcerans colonization and could act as potential indicators for disease risk. These findings also suggest that M. ulcerans is a widespread environmental bacteria species, but that it is absent or reduced in regions of low disease incidence. A better understanding is needed regarding the mechanistic associations among aquatic plants and M. ulcerans for identifying the mode of transmission of BU disease.

  6. Contrasting movements and connectivity of reef-associated sharks using acoustic telemetry: implications for management.

    Science.gov (United States)

    Espinoza, Mario; Lédée, Elodie J I; Simpfendorfer, Colin A; Tobin, Andrew J; Heupel, Michelle R

    2015-12-01

    Understanding the efficacy of marine protected areas (MPAs) for wide-ranging predators is essential to designing effective management and conservation approaches. The use of acoustic monitoring and network analysis can improve our understanding of the spatial ecology and functional connectivity of reef-associated species, providing a useful approach for reef-based conservation planning. This study compared and contrasted the movement and connectivity of sharks with different degrees of reef association. We examined the residency, dispersal, degree of reef connectivity, and MPA use of grey reef (Carcharhinus amblyrhynchos), silvertip (C. albimarginatus), and bull (C. leucas) sharks monitored in the central Great Barrier Reef (GBR). An array of 56 acoustic receivers was used to monitor shark movements on 17 semi-isolated reefs. Carcharhinus amblyrhynchos and C. albimarginatus were detected most days at or near their tagging reef. However, while C. amblyrhynchos spent 80% of monitoring days in the array, C. albimarginatus was only detected 50% of the time. Despite both species moving similar distances (sharks like C. leucas, a combination of spatial planning and other alternative measures is critical. Our findings demonstrate that acoustic monitoring can serve as a useful platform for designing more effective MPA networks for reef predators displaying a range of movement patterns.

  7. Lateralized free-association priming: implications for the hemispheric organization of semantic memory.

    Science.gov (United States)

    Koivisto, M; Laine, M

    1995-01-01

    The organization of semantic memory in intact cerebral hemispheres was examined by a free-association priming task. Normal subjects studied a list of word pairs where the semantic relations were either coordinate (e.g. saw-axe) or locative (e.g. bear-forest). Priming of the word pairs was tested by presenting test cues (initial words of the pairs) to the left or to the right visual field. Results showed an interaction between visual field and word pair type, suggesting a qualitative difference in the semantic organization of the hemispheres. Specifically, the results support the view that coordinate relations are represented in both hemispheres whereas locative relations are represented mainly in the right hemisphere.

  8. 'Smoking genes': a genetic association study.

    Directory of Open Access Journals (Sweden)

    Zoraida Verde

    Full Text Available Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A [rs1801272], CYP2A6*9 (-48T>G [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T [rs8192789], CYP2A13*3 (7520C>G, CYP2A13*4 (579G>A, CYP2A13*7 (578C>T [rs72552266], CYP2B6*4 (785A>G, CYP2B6*9 (516G>T, CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A [rs1800497], 5HTT LPR, HTR2A -1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126 and ethnically matched never smokers (controls, N = 80. The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both PA (Taq1A polymorphisms was 3.60 (95%CI: 1.75, 7.44 and 2.63 (95%CI: 1.41, 4.89 respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65. We found a significant genotype effect (all P≤0.017 for the following smoking-related phenotypes: (i cigarettes smoked per day and CYP2A13*3; (ii pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A; (iii nicotine dependence (assessed with the Fagestrom test and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5, serotoninergic (HTR2A, opioid (OPRM1 or cannabinoid receptors (CNR1.

  9. Crystal structure of the conserved domain of the DC lysosomal associated membrane protein: implications for the lysosomal glycocalyx

    OpenAIRE

    Wilke Sonja; Krausze Joern; Büssow Konrad

    2012-01-01

    Abstract Background The family of lysosome-associated membrane proteins (LAMP) comprises the multifunctional, ubiquitous LAMP-1 and LAMP-2, and the cell type-specific proteins DC-LAMP (LAMP-3), BAD-LAMP (UNC-46, C20orf103) and macrosialin (CD68). LAMPs have been implicated in a multitude of cellular processes, including phagocytosis, autophagy, lipid transport and aging. LAMP-2 isoform A acts as a receptor in chaperone-mediated autophagy. LAMP-2 deficiency causes the fatal Danon disease. The ...

  10. Prevalence and associated factors of Schistosomiasis among children in Yemen: implications for an effective control programme.

    Directory of Open Access Journals (Sweden)

    Hany Sady

    Full Text Available BACKGROUND: Schistosomiasis, one of the most prevalent neglected tropical diseases, is a life-threatening public health problem in Yemen especially in rural communities. This cross-sectional study aims to determine the prevalence and associated risk factors of schistosomiasis among children in rural Yemen. METHODS/FINDINGS: Urine and faecal samples were collected from 400 children. Urine samples were examined using filtration technique for the presence of Schistosoma haematobium eggs while faecal samples were examined using formalin-ether concentration and Kato Katz techniques for the presence of S. mansoni. Demographic, socioeconomic and environmental information were collected via a validated questionnaire. Overall, 31.8% of the participants were found to be positive for schistosomiasis; 23.8% were infected with S. haematobium and 9.3% were infected with S. mansoni. Moreover, 39.5% of the participants were anaemic whereas 9.5% had hepatosplenomegaly. The prevalence of schistosomiasis was significantly higher among children aged >10 years compared to those aged ≤ 10 years (P<0.05. Multivariate analysis confirmed that presence of other infected family member (P<0.001, low household monthly income (P = 0.003, using unsafe sources for drinking water (P = 0.003, living nearby stream/spring (P = 0.006 and living nearby pool/pond (P = 0.002 were the key factors significantly associated with schistosomiasis among these children. CONCLUSIONS/SIGNIFICANCE: This study reveals that schistosomiasis is still highly prevalent in Yemen. These findings support an urgent need to start an integrated, targeted and effective schistosomiasis control programme with a mission to move towards the elimination phase. Besides periodic drug distribution, health education and community mobilisation, provision of clean and safe drinking water, introduction of proper sanitation are imperative among these communities in order to curtail the transmission and morbidity caused

  11. Position of the American Dietetic Association: health implications of dietary fiber.

    Science.gov (United States)

    Slavin, Joanne L

    2008-10-01

    It is the position of the American Dietetic Association that the public should consume adequate amounts of dietary fiber from a variety of plant foods. Populations that consume more dietary fiber have less chronic disease. In addition, intake of dietary fiber has beneficial effects on risk factors for developing several chronic diseases. Dietary Reference Intakes recommend consumption of 14 g dietary fiber per 1,000 kcal, or 25 g for adult women and 38 g for adult men, based on epidemiologic studies showing protection against cardiovascular disease. Appropriate kinds and amounts of dietary fiber for children, the critically ill, and the very old are unknown. The Dietary Reference Intakes for fiber are based on recommended energy intake, not clinical fiber studies. Usual intake of dietary fiber in the United States is only 15 g/day. Although solubility of fiber was thought to determine physiological effect, more recent studies suggest other properties of fiber, perhaps fermentability or viscosity are important parameters. High-fiber diets provide bulk, are more satiating, and have been linked to lower body weights. Evidence that fiber decreases cancer is mixed and further research is needed. Healthy children and adults can achieve adequate dietary fiber intakes by increasing variety in daily food patterns. Dietary messages to increase consumption of high-fiber foods such as whole grains, legumes, fruits, and vegetables should be broadly supported by food and nutrition professionals. Consumers are also turning to fiber supplements and bulk laxatives as additional fiber sources. Few fiber supplements have been studied for physiological effectiveness, so the best advice is to consume fiber in foods. Look for physiological studies of effectiveness before selecting functional fibers in dietetics practice.

  12. Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion) Echocardiographic Study

    DEFF Research Database (Denmark)

    Verma, Anil; Meris, Alessandra; Skali, Hicham;

    2008-01-01

    OBJECTIVES: This study sought to understand prognostic implications of increased baseline left ventricular (LV) mass and geometric patterns in a high risk acute myocardial infarction. BACKGROUND: The LV hypertrophy and alterations in LV geometry are associated with an increased risk of adverse ca...

  13. Incidence and clinical implication of nosocomial infections associated with implantable biomaterials - catheters, ventilator-associated pneumonia, urinary tract infections.

    Science.gov (United States)

    Guggenbichler, Josef Peter; Assadian, Ojan; Boeswald, Michael; Kramer, Axel

    2011-01-01

    Health care associated infections, the fourth leading cause of disease in industrialised countries, are a major health issue. One part of this condition is based on the increasing insertion and implantation of prosthetic medical devices, since presence of a foreign body significantly reduces the number of bacteria required to produce infection. The most significant hospital-acquired infections, based on frequency and potential severity, are those related to procedures e.g. surgical site infections and medical devices, including urinary tract infection in catheterized patients, pneumonia in patients intubated on a ventilator and bacteraemia related to intravascular catheter use. At least half of all cases of nosocomial infections are associated with medical devices.Modern medical and surgical practices have increasingly utilized implantable medical devices of various kinds. Such devices may be utilized only short-time or intermittently, for months, years or permanently. They improve the therapeutic outcome, save human lives and greatly enhance the quality of life of these patients. However, plastic devices are easily colonized with bacteria and fungi, able to be colonized by microorganisms at a rate of 0.5 cm per hour. A thick biofilm is formed within 24 hours on the entire surface of these plastic devices once inoculated even with a small initial number of bacteria.The aim of the present work is to review the current literature on causes, frequency and preventive measures against infections associated with intravascular devices, catheter-related urinary tract infection, ventilator-associated infection, and infections of other implantable medical devices. Raising awareness for infection associated with implanted medical devices, teaching and training skills of staff, and establishment of surveillance systems monitoring device-related infection seem to be the principal strategies used to achieve reduction and prevention of such infections. The intelligent use of

  14. Comparative biological potency of acidic sulfate aerosols: implications for the interpretation of laboratory and field studies.

    Science.gov (United States)

    Schlesinger, R B; Chen, L C

    1994-04-01

    Biological responses to inhaled acid sulfates result from the deposition of hydrogen ion (H+) on airway surfaces. Thus, effects from sulfuric acid and ammonium bisulfate, the two major ambient species, have been assumed to be the same for a given H+ concentration within the exposure atmosphere, assuming similar respiratory tract deposition patterns. However, recent inhalation studies have indicated that sulfuric acid is disproportionately potent compared to ammonium bisulfate when the H+ content of the exposure atmosphere is considered, suggesting that some factors following inhalation affect the amount of H+ contacting airway surfaces. This study assessed a mechanism potentially underlying this phenomenon, namely, the extent of neutralization by respiratory tract ammonia. This was evaluated using a physical model system designed to mimic transit of these aerosols in the upper respiratory tract of the animal model used in this laboratory, the rabbit. The results suggest that for equal exposure quantities of H+, more acid would be deposited when sulfuric acid is inhaled than when ammonium bisulfate is inhaled. Furthermore, results from a series of in vitro exposures of tracheal epithelial cells to sulfuric acid and ammonium bisulfate aerosols indicated that the biological response is a function of the total mass (ionic) concentration of H+ deliverable to the cells or the total extractable H+ per particle. The results of this study have possible implications for ambient monitoring of particulate-associated strong acidity, suggesting that it may be necessary to specilate such measures into the relative amounts of H+ as sulfuric acid or ammonium bisulfate in order to most accurately relate atmospheric acid levels to observed health effects. In addition, since much of the ambient particulate-associated H+ exists as sulfuric acid/ammonium bisulfate mixtures rather than pure compounds, H(+)-associated health effects from controlled exposure studies of sulfuric acid may

  15. Interpretation of illness in patients with chronic diseases from Shanghai and their associations with life satisfaction, escape from illness, and ability to reflect the implications of illness

    Institute of Scientific and Technical Information of China (English)

    Arndt Bssing; Ariane von Bergh; Xiao-feng Zhai; Chang-quan Ling

    2014-01-01

    OBJECTIVE:The aim of this study is to analyze how patients with chronic diseases from Shanghai interpret their disease, and how these interpretations inlfuence patients’ life satisfaction, intention to escape from their illness and their ability to relfect on the implications of their illness. METHODS:A cross-sectional study enrolling 142 patients (mean age (50 ± 16) years;63%men, 37%women) with chronic diseases (60%cancer) was recruited in the Changhai Hospital of Traditional Chinese Medicine, Shanghai, China and surveyed using standardized questionnaires. RESULTS: Patients with chronic diseases from Shanghai interpreted their illness mostly as an Adverse Interruption of Life (55%), as a Threat/Enemy (50%), but also as a Challenge (49%), and only rarely as a Call for Help (18%) or as a Punishment (13%). Particularly fatalistic negative (i.e., Threat/Enemy, Adverse Interruption of Life) and strategy-associated disease interpretations (i.e., Relieving Break, Call for Help) were moderately associated with patients’ intention to escape from illness. In contrast, positive interpretations (i.e., something of Value, Challenge) and also the guilt-associated negative interpretation Failure were moderately related with patients’ ability to relfect on their illness. However, life satisfaction was weakly associated only with the view that il ness might be a Chal enge. Interestingly, 58%of those who would see their il ness as an Adverse Interruption (AI+) could see it also as a Challenge (Ch+). Detailed analyses showed that AI+Ch+patients differ from their AI+Ch- counterparts signiifcantly with respect to their ability to relfect life and implications of illness (F=9.1;P=0.004). CONCLUSION: The observed interpretations of illness, particularly the negative perceptions, could be used as indicators that patients require further psychological assistance to cope with their burden. Helping AI+patients see their illness also as a Challenge, and thus develop a higher

  16. Examining the association between childhood asthma and parent and grandparent asthma status: Implications for Practice

    OpenAIRE

    Valerio, Melissa A.; Andreski, Patricia M.; Schoeni, Robert F.; McGonagle, Katherine A.

    2010-01-01

    Examination of intergenerational asthma beyond maternal asthma has been limited. The association between childhood asthma and intergenerational asthma status among a national cohort of children was examined.

  17. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    Science.gov (United States)

    Law, Philip J.; Berndt, Sonja I.; Speedy, Helen E.; Camp, Nicola J.; Sava, Georgina P.; Skibola, Christine F.; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J.; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R.; Clot, Guillem; Teras, Lauren R.; Quintela, Inés; Birmann, Brenda M.; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E.; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R.; Hall, Andrew G.; Purdue, Mark P.; Mainou-Fowler, Tryfonia; Vajdic, Claire M.; Jackson, Graham H.; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G.; Lawrence, Charles; Call, Timothy G.; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K.; Conde, Lucia; Bracci, Paige M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C. H.; Southey, Melissa C.; Milne, Roger L.; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J.; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M.; Harris, Robert J.; Miligi, Lucia; Pettitt, Andrew R.; North, Kari E.; Allsup, David J.; Fraumeni, Joseph F.; Bailey, James R.; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J.; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J. S.; Catovsky, Daniel; Campo, Elias; Cerhan, James R.; Allan, James M.; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. PMID:28165464

  18. Health implications associated with exposure to farmed and wild sea turtles.

    Science.gov (United States)

    Warwick, Clifford; Arena, Phillip C; Steedman, Catrina

    2013-01-01

    Exposure to sea turtles may be increasing with expanding tourism, although reports of problems arising from interaction with free-living animals appear of negligible human health and safety concern. Exposure both to wild-caught and captive-housed sea turtles, including consumption of turtle products, raises several health concerns for the public, including: microbiological (bacteria, viruses, parasites and fungi), macrobiological (macroparasites), and organic and inorganic toxic contaminants (biotoxins, organochlorines and heavy metals). We conducted a review of sea turtle associated human disease and its causative agents as well as a case study of the commercial sea turtle facility known as the Cayman Turtle Farm (which receives approximately 240,000 visitors annually) including the use of water sampling and laboratory microbial analysis which identified Pseudomonas aeruginosa, Aeromonas spp., Vibrio spp. and Salmonella spp. Our assessment is that pathogens and toxic contaminants may be loosely categorized to represent the following levels of potential risk: viruses and fungi = very low; protozoan parasites = very low to low; metazoan parasites, bacteria and environmental toxic contaminants = low or moderate to high; and biotoxin contaminant = moderate to very high. Farmed turtles and their consumable products may constitute a significant reservoir of potential human pathogen and toxin contamination. Greater awareness among health-care professionals regarding both potential pathogens and toxic contaminants from sea turtles, as well as key signs and symptoms of sea turtle-related human disease, is important for the prevention and control of salient disease.

  19. Factors associated with job satisfaction among commune health workers: implications for human resource policies

    Directory of Open Access Journals (Sweden)

    Bach Xuan Tran

    2013-01-01

    Full Text Available Background: Job satisfaction among health workers is an important indicator in assessing the performance and efficiency of health services. Objective: This study measured job satisfaction and determined associated factors among health workers in 38 commune health stations in an urban district and a rural district of Hanoi, Vietnam. A total of 252 health workers (36 medical doctors and 216 nurses and technicians; 74% female were interviewed. A job satisfaction measure was developed using factor analysis, from which four dimensions emerged, namely ‘benefits and prospects,’ ‘facility and equipment,’ ‘performance,’ and ‘professionals.’ Results: The results demonstrate that respondents were least satisfied with the following categories: salary and incentives (24.0%, benefit packages (25.1%, equipment (35.7%, and environment (41.8%. The average satisfaction score was moderate across four domains; it was the highest for ‘performance’ (66.6/100 and lowest for ‘facility and equipment’ (50.4/100. Tobit-censored regression models, constructed using stepwise selection, determined significant predictors of job satisfaction including age, areas of work and expertise, professional education, urban versus rural setting, and sufficient number of staff. Conclusion: The findings highlight the need to implement health policies that focus on incentives, working conditions, workloads, and personnel management at grassroots level.

  20. Restoring Wisconsin Art Therapy Association in Art Therapy History: Implications for Professional Definition and Inclusivity

    Science.gov (United States)

    Potash, Jordan; Burnie, Michele; Pearson, Rosemary; Ramirez, Wayne

    2016-01-01

    The Wisconsin Art Therapy Association (WATA), formally established in 1969, was the first incorporated organization of art therapists in the United States. Under the leadership of Wayne Ramirez, WATA lobbied the national association for an inclusive definition of art therapy that aimed to foster respect for psychiatric, educational, and community…

  1. Post-transplant lymphoproliferative disorders: implications for acquired immunodeficiency syndrome-associated malignancies.

    Science.gov (United States)

    Swinnen, L J

    2001-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may coexist, each representing a discrete lymphomagenic event, a situation that is unique to immunodeficiency states. The incidence varies from 1% in renal recipients to 5% in heart recipients, but can be markedly increased by the use of anti-T-cell therapies or by T-cell depletion in bone marrow transplantation. PTLD continues to arise, even many years after transplantation, and late T-cell lymphomas have recently been recognized. Pretransplant Epstein-Barr virus (EBV) seronegativity increases risk to as high as 30%-50%. PTLD has a highly variable clinical picture; certain patterns are, however, seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of bcl-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long-term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported for interferon alfa and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to associate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency-related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to the acquired immunodeficiency syndrome setting.

  2. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  3. CLINICAL IMPLICATION OF FATTY ACID CHANGES IN PATIENTS WITH PRIMARY GOUT ASSOCIATED WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    N. N. Kushnarenko

    2015-12-01

    Full Text Available Aim. To study blood levels of non-esterified fatty acids (NEFAs and adenyl nucleotides, and fatty acids levels in lipids of erythrocyte membranes in patients with primary gout associated with arterial hypertension (HT. Material and methods. 175 male patients with primary gout were included in the study. According to 24-hour blood pressure (BP monitoring results patients were split into two groups: 74 patients with normal BP (group 1 and 101 patients with HT (group 2. 29 healthy age-comparable subjects were included into control group. Uric acid, total NEFAs and glycerol blood levels were studied in all patients. Adenyl nucleotides (ATP , ADP and AMP levels were determined in erythrocytes. Higher fatty acid levels were specified in lipids of erythrocyte membranes, including the following acids: myristinic (С14:0, palmitinic (С16:0, stearic (С18:0, pentadecanic (С15:0, heptadecanic (С17:0, pentadecenic (С15:1, heptadecenic (С17:1, palmitooleic (С16:1, oleic (С18:1, linoleic (С18:2ω6, α-linolenic (С18:3ω3, γ-linolenic (С18:3ω6, dihomo-γ-linolenic (С20:3ω6, arachidonic (С20:4ω6, eicosapentaenoic (С20:5ω3, and docosapentaenoic (С22:5ω3. Results and discussion. Hypertensive patients with gout demonstrated higher NEFAs blood level and greater changes in ATP-ADP-AMP system than normotensive gout patients and healthy subjects as well as 2.2 and 3.7 times higher NEFAs/ATP ratio, respectively. In hypertensive patients with primary gout the composition of fatty acids in erythrocyte membranes lipids changed due to increase in saturated fatty acids amount and decrease in unsaturated fatty acids amount, at that monoenic acid levels increased while polyenic acid levels decreased in unsaturated acids composition. Hypertensive patients with gout shown 1.3 and 2.5 times less levels of ω-3 poly-unsaturated fatty acids (PUFA than normotensive gout patients and healthy subjects, respectively. At the same time ω-6 PUFA levels changed in

  4. Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia

    DEFF Research Database (Denmark)

    Carrera, Noa; Arrojo, Manuel; Sanjuán, Julio

    2012-01-01

    Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, ...

  5. The Danish Association for Science and Technology Studies

    DEFF Research Database (Denmark)

    A presentation of the Danish Association for Science and Technology Studies (DASTS). Organization, experiences, challenges and future developments.......A presentation of the Danish Association for Science and Technology Studies (DASTS). Organization, experiences, challenges and future developments....

  6. Hospital IT adoption strategies associated with implementation success: implications for achieving meaningful use.

    Science.gov (United States)

    Ford, Eric W; Menachemi, Nir; Huerta, Timothy R; Yu, Feliciano

    2010-01-01

    Health systems are facing significant pressure to either implement health information technology (HIT) systems that have "certified" electronic health record applications and that fulfill the federal government's definition of "meaningful use" or risk substantial financial penalties in the near future. To this end, hospitals have adopted one of three strategies, described as "best of breed," "best of suite," and "single vendor," to meet organizational and regulatory demands. The single-vendor strategy is used by the simple majority of U.S. hospitals, but is it the most effective mode for achieving full implementation? Moreover, what are the implications of adopting this strategy for achieving meaningful use? The simple answer to the first question is that the hospitals using the hybrid best of suite strategy had fully implemented HIT systems in significantly greater proportions than did hospitals employing either of the other strategies. Nonprofit and system-affiliated hospitals were more likely to have fully implemented their HIT systems. In addition, increased health maintenance organization market penetration rates were positively correlated with complete implementation rates. These results have ongoing implications for achieving meaningful use in the near term. The federal government's rewards and incentives program related to the meaningful use of HIT in hospitals has created an organizational imperative to implement such systems. For hospitals that have not begun systemwide implementation, pursuing a best of suite strategy may provide the greatest chance for achieving all or some of the meaningful use targets in the near term or at least avoiding future penalties scheduled to begin in 2015.

  7. Community College Study Abroad: Implications for Student Success

    Science.gov (United States)

    Raby, Rosalind Latiner; Rhodes, Gary M.; Biscarra, Albert

    2014-01-01

    The aim of this research is to explore whether participation in study abroad by community college students impacts levels of engagement and if there is a connection between studying abroad and academic achievement. While university-level studies have a history in exploring these questions, the same is not true for community colleges. The…

  8. Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Bo Gun Jang

    Full Text Available Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates that Lgr5(+ cells may not only be the cells responsible for the origin of tumors; they may also be the so-called cancer stem cells. In the present study, we investigated the presence of Lgr5(+ cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled Lgr5(+ cells at the basal glands of the gastric antrum. Notably, the number of Lgr5(+ cells was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas and 43% of early gastric carcinomas were positive for LGR5. Lgr5(+ cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, Lgr5(+ cells were often restricted to the base of the tumor glands, and such Lgr5(+ restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2. Thus, our findings show that Lgr5(+ cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5(+ cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5(+ cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis.

  9. Replication of association between ELAVL4 and Parkinson disease: the GenePD study

    Science.gov (United States)

    DeStefano, Anita L.; Latourelle, Jeanne; Lew, Mark F.; Suchowersky, Oksana; Klein, Christine; Golbe, Lawrence I.; Mark, Margery H.; Growdon, John H.; Wooten, G. Fredrick; Watts, Ray; Guttman, Mark; Racette, Brad A.; Perlmutter, Joel S.; Marlor, Lynn; Shill, Holly A.; Singer, Carlos; Goldwurm, Stefano; Pezzoli, Gianni; Saint-Hilaire, Marie H.; Hendricks, Audrey E.; Gower, Adam; Williamson, Sally; Nagle, Michael W.; Wilk, Jemma B.; Massood, Tiffany; Huskey, Karen W.; Baker, Kenneth B.; Itin, Ilia; Litvan, Irene; Nicholson, Garth; Corbett, Alastair; Nance, Martha; Drasby, Edward; Isaacson, Stuart; Burn, David J.; Chinnery, Patrick F.; Pramstaller, Peter P.; Al-hinti, Jomana; Moller, Anette T.; Ostergaard, Karen; Sherman, Scott J.; Roxburgh, Richard; Snow, Barry; Slevin, John T.; Cambi, Franca; Gusella, James F.; Myers, Richard H.

    2009-01-01

    Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene. PMID:18587682

  10. Research domain criteria and the study of trauma in children: Implications for assessment and treatment research.

    Science.gov (United States)

    Stover, Carla Smith; Keeshin, Brooks

    2016-11-09

    By definition, the Diagnostic and Statistical Manual (DSM) diagnosis of posttraumatic stress disorder (PTSD) requires exposure to a traumatic event. Yet, the DSM diagnostic requirements for children and adolescents for PTSD may fail to capture traumatized youth with significant distress and functional impairment. Many important studies have utilized PTSD diagnosis as a mechanism for grouping individuals for comparative studies examining brain functioning, neuroendocrinology, genetics, attachment, and cognition; however, focusing only on those with the diagnosis of PTSD can miss the spectrum of symptoms and difficulties that impact children who experience trauma and subsequent impairment. Some studying child trauma have focused on examining brain and biology of those with exposure and potential impairment rather than only those with PTSD. This line of inquiry, complementary to PTSD specific studies, has aided our understanding of some of the changes in brain structure and neuroregulatory systems at different developmental periods following traumatic exposure. Application of the Research Domain Criteria (RDoC) framework proposed by NIMH to the study of child trauma exposure and subsequent impairment is an opportunity to examine domains of function and how they are impacted by trauma. Research to date has focused largely in the areas of negative valence, regulatory, and cognitive systems, however those studying complex or developmental trauma have identified an array of domains that are impacted which map onto many of the RDoC categories. This paper will review the relevant literature associated with child trauma as it relates to the RDoC domains, outline areas of needed research, and describe their implications for treatment and the advancement of the field.

  11. Studies of Beliefs about EFL Teaching and Learning and Its Significance and Implications

    Institute of Scientific and Technical Information of China (English)

    周小惠; 徐汝舟

    2013-01-01

    This paper gives a brief review of teacher and learner beliefs, so as to highlight the important roles these beliefs play in EFL teaching and learning. Based on it, the paper goes deeper into the significance of the studies of beliefs for EFL teaching, learning, teacher education, etc. Furthermore, some implications emerging from the studies are discussed.

  12. Recent advances in the study of HPV-associated carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Liyan; Jin; Zhi-Xiang; Xu

    2015-01-01

    Human papillomaviruses(HPVs) cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women, who develop cervical cancer die from it. Despite the optimism that has accompanied the introduction of prophylactic vaccines to prevent some HPV infections, the relatively modest uptake of the vaccine, especially in the developing world, and the very high fraction of men and women who are already infected, means that HPV-associated disease will remain as a significant public health problem for decades. In this review, we summarize some recent findings on HPV-associated carcinogenesis, such as mi RNAs in HPV-associated cancers, implication of stem cells in the biology and therapy of HPV-positive cancers, HPV vaccines, targeted therapy of cervical cancer, and drug treatment for HPV-induced intraepithelial neoplasias.

  13. Implications of Queer Theory for the Study of Religion and Gender: Entering the Third Decade

    Directory of Open Access Journals (Sweden)

    Claudia Schippert

    2011-08-01

    Full Text Available This essay explores the conceptual and contextual shifts in queer theoretical work as it is entering into its third decade of articulation. The essay reviews important recent themes in, and examines implications of, queer theoretical scholarship for the study of religion and gender. I suggest that among the implications are a (more undisciplined study of religion (and secularism that takes seriously shifts resulting from transnational and diasporic queer scholarship, shifts in conceptions of agency and resistance resulting from analyses  and critique of homonormative positions, and can critically intervene in homonationalism and Islamophobia.

  14. Risk factors associated with pulmonary arterial hypertension in patients with systemic sclerosis and implications for screening

    Directory of Open Access Journals (Sweden)

    C.P. Denton

    2011-12-01

    Full Text Available Pulmonary arterial hypertension (PAH is a relatively common complication of systemic sclerosis (SSc affecting 5–12% of patients, and its development is associated with significant morbidity and a particularly poor prognosis. Deaths associated with other complications of SSc, such as renal crisis, have fallen significantly in recent years in line with improvements in their treatment and management. However, mortality due to PAH in this population, although improved, has shown a less dramatic decline. The early diagnosis of PAH in SSc would allow for earlier treatment, before functional and haemodynamic impairment becomes severe; this may further improve outcome, and evidence suggests that screening of SSc patients for PAH is associated with improved survival. In addition, patients with PAH associated with SSc are not a homogeneous population and they differ in terms of disease haemodynamic severity, functional capacity and rate of disease progression. Likewise, management strategies may differ, and the ability to stratify patients may help optimise screening and treatment. A number of patient-, clinical- and disease-specific risk factors associated with the development and prognosis of PAH in SSc have been identified, but their optimal use, alone or in combination, in screening and stratification of patients remains to be established.

  15. Coaches' implicit associations between size and giftedness: implications for the relative age effect.

    Science.gov (United States)

    Furley, Philip; Memmert, Daniel

    2016-01-01

    The relative age effect (RAE) is a well-established phenomenon in education and sports. Coaches have been assumed to be important social agents of RAE via biased selection decisions in favour of children with maturation advantages. In the present research, we used the Implicit Association Test to investigate automatic associations between body size and a player's domain-specific giftedness amongst youth baseball (N = 18) and youth soccer coaches (N = 34). We found medium to strong automatic associations between body size and player giftedness (baseball: MD = 0.62; soccer: MD = 0.51). Specifically, taller players were associated with positive performance-related attributes, whereas smaller players were associated with negative attributes. The results are in line with theories of grounded cognition by showing that the abstract concept of "sport giftedness" is partly grounded in the perception of physical height amongst youth sports coaches. We argue that this grounded cognition has the potential to influence coaches' selection decisions and in turn account for RAE as coaches are biased towards physically more matured players, even when no apparent performance advantage is evident.

  16. Implications of Common Core State Standards on the Social Studies

    Science.gov (United States)

    Kenna, Joshua L.; Russell, William B., III.

    2014-01-01

    Social studies teachers have often been on the outside looking in during much of the era billed as the standards-based educational reform (SBER), but with the adoption and implementation of the Common Core State Standards (CCSS), social studies teachers seem to have been invited back inside. Yet, how will the standards impact social studies…

  17. Submergence and Uplift Associated to Paleoearthquakes in the Northern Sunda Subduction System: Implications for Future Earthquakes.

    Science.gov (United States)

    Mondal, D. R.; McHugh, C. M.; Mortlock, R. A.; Steckler, M. S.; Seeber, L.; Goodbred, S. L., Jr.; Akhter, S. H.; Mustaque, S.

    2015-12-01

    Recent studies documented that the northern part of the Sunda subduction zone ruptured several times in the past 1500 years including one in 1762. To better understand megathrust surface ruptures and the hazards associated to them, we surveyed the SE coast of Bangladesh along the Teknaf peninsula and the Saint Martin anticline by dating coral microatolls of Porites lutea species by the U-Th dating method. Porites luteagrows a few centimeters below the low tide level creating a 5-12 mm thick skeletal band per year, which makes them a good indicator of relative sea level change that might be caused during tectonic submergence and uplift. U-Th ages were obtained from coral slabs and their growth bands interpreted from x-rays. The corals and marine terraces uplift were measured with high precision RTK GPS and modeled with high resolution DEM. The coral microatolls along the St. Martin anticline were dated to be ~ 250, 800 and 1300 years old. Since storm and other climatic phenomenon cannot cause uplift, we interpret that 2.5 m uplift was caused by 1762 earthquake that killed the coral microatolls. The coral slabs show three growth interruptions, where skeletal growth bands continued to grow onlapping the older growth bands. These growth onlaps could be the result of smaller uplift events after 1762 that did not result in coral mortality. The subsidence history extracted from vertical growth of the slabs suggests that the island is submerging at a rate of 11 mm/year. Corals growing 250 m from the dead coral colony post date the 1762 earthquake. Today living Porites lutea can be found 2.5 m below the dead coral heads and 9 cm above the spring low tide. The elevation of marine terraces (T1, T2 and T3) along the Teknaf coast is 2.5 m, 5-7 m and 11-13 m above sea level, respectively. A shell bed on top of T1 was dated at 1763 (dated by C14). This and the other two terraces could have been uplifted during the three earthquakes dated from coral microatolls. Considering the

  18. Detection of noroviruses in foods: a study on virus extraction procedures in foods implicated in outbreaks of human gastroenteritis.

    Science.gov (United States)

    Rutjes, Saskia A; Lodder-Verschoor, Froukje; van der Poel, Wim H M; van Duijnhoven, Yvonne T H P; de Roda Husman, Ana Maria

    2006-08-01

    Disease outbreaks in which foods are epidemiologically implicated as the common source are frequently reported. Noroviruses and enteric hepatitis A viruses are among the most prevalent causative agents of foodborne diseases. However, the detection of these viruses in foods other than shellfish is often time-consuming and unsuccessful. In this study, three virus concentration methods were compared: polyethylene glycol (PEG) plus NaCl, ultracentrifugation, and ultrafiltration. Two RNA extraction methods, TRIzol and RNeasy Mini Kit (Qiagen), were compared for detection of viruses in whipped cream and lettuce (as representatives of the dairy and vegetable-fruit food groups, respectively). A seeding experiment with canine calicivirus was conducted to determine the efficiency of each virus extraction procedure. The PEG-NaCl-TRIzol method was most efficient for the detection of viruses in whipped cream and the ultracentrifugation-RNeasy-Mini Kit procedure was best for detection on lettuce. Based on the seeding experiments, food items implicated in norovirus-associated gastroenteritis outbreaks were subjected to the optimal procedure for a specific composition and matrix. No noroviruses were detected in the implicated food items, possibly because the concentration of virus on the food item was too low or because of the presence of inhibitory factors. For each food group, a specific procedure is optimal. Inhibitory factors should be controlled in these procedures because they influence virus detection in food.

  19. American Bar Association Supplementary Guidelines for the Mitigation Function of Defense Teams in Death Penalty Cases: implications for social work.

    Science.gov (United States)

    Andrews, Arlene Bowers

    2012-04-01

    When a client faces a penalty of death, defense attorneys may call on social workers in many capacities: mitigation specialist, expert witness, consulting specialist, direct witness, or defense-initiated victim outreach worker. The American Bar Association set forth standards for capital defense attorneys, which led an interdisciplinary team to produce the "Supplementary Guidelines for the Mitigation Function of Defense Teams in Death Penalty Cases" to promote the exceptional competence and diligence required when the consequence is life or death. This article summarizes the "Supplementary Guidelines," with implications for social work practice--that is, professional responsibility, competence, interviewing skill, knowledge of behavioral and mental impairment, records review, life history compilation, data interpretation, witness support, law-related knowledge, and testimony. The social work, which is scrutinized in a court of law, requires cultural competence, diverse oral and written communication skills, diligence, and the highest ethical standards.

  20. Microscale physiological and ecological studies of aquatic cyanobacteria: macroscale implications.

    Science.gov (United States)

    Paerl, H W

    1996-01-01

    Cyanobacteria have had a profound and unparalleled biogeochemical impact on the earth's biosphere. As the first oxygenic phototrophs, cyanobacteria were responsible for the transition from anaerobic to aerobic life. Ironically, molecular oxygen (O2) is inhibitory to critical components of cyanobacterial metabolism, including photosynthesis and nitrogen fixation. Cyanobacteria have developed a great variety of biochemical, structural, and biotic adaptations ensuring optimal growth and proliferation in diverse oxic environments to counter this difficult situation. Structurally, cyanobacteria reveal remarkable diversity, including the formation of highly differentiated, O2-deplete cells (heterocysts), multicellularity as trichomes, and aggregates, that, among N2-fixing genera, facilitate division of labor between aerobic and anaerobic processes. Cyanobacteria enjoy unique consortial and symbiotic associations with other microorganisms, higher plants, and animals, in which O2 consumption is closely coupled in time and space to its production. Because as prokaryotes they are devoid of O2-consuming organelles (e.g., mitochondria), cyanobacteria have developed alternative strategies for locally protecting O2-sensitive processes, including consortial relationships with other microorganisms. Specific organic compounds released by cyanobacteria are capable of chemotactically attracting bacterial consorts, which in turn attach to the host cyanobacteria, consume O2, and recycle inorganic nutrients within the cyanobacterial "phycosphere." Multicellularity and aggregation lead to localized O2 gradients and hypoxic/anoxic microzones in which O2-sensitive processes can coexist. Microscale partitioning of O2-producing and O2-inhibited processes promotes contiguous and effective metabolite and nutrient exchange between these processes in oxygenated waters, representing a bulk of the world's oceanic and freshwater ecosystems.

  1. Biomechanical factors associated with shoe/pedal interfaces. Implications for injury.

    Science.gov (United States)

    Gregor, R J; Wheeler, J B

    1994-02-01

    The principal demand on the body during cycling is on the lower extremities as they are responsible for producing a majority of the energy imparted to the bike. As a result the legs, due to high reactive forces between the foot and pedal, experience high loads on the joints. These loads may adversely affect joint tissues and contribute to overuse injuries, e.g. knee pain. The mechanical link between the leg and the bike is the shoe/pedal interface. This transmission site, by design, can either create smooth transfer of energy or abnormally high repetitive loads which are potentially injurious to the body. Incidence of lower extremity injury in cycling is high, and historically biomechanical analyses of this activity have focused their attention on either the rider or the bike, but not the link between the two. Recently, pedal designs have changed in response to complaints of sore knees with the development of pedals allowing varying degrees of float. This form of transmission is intended to enhance power transfer from rider to bike as well as minimise trauma to the legs by permitting the foot to rotate during the pedalling cycle in a toe-in/heel-out or heel-in/toe-out movement pattern. Recent evidence suggests this type of pedal design does reduce trauma and maintains power output. This article reviews common lower extremity overuse injuries and biomechanical factors during the pedalling cycle with the primary focus on the shoe/pedal interface. We will summarise information available on lower extremity kinematics and kinetics as well as recent data specifically related to shoe/pedal interface kinetics, evaluation of different pedal types-specifically comparison between clipless 'fixed' and clipless 'float' systems-and discuss their resultant effect on lower extremity dynamics and their implications for injury.

  2. Association between depression and development of coronary artery disease: pathophysiologic and diagnostic implications

    Directory of Open Access Journals (Sweden)

    Sakamoto

    2011-03-01

    Full Text Available Carlos V Serrano Jr1, Karina Tiemi Setani2, Erica Sakamoto2, Anna Maria Andrei3, Renério Fraguas41Heart Institute (InCor, 2Medical School, University of São Paulo, Brazil; 3Albert Einstein Hospital, São Paulo, Brazil; 4Department and Institute of Psychiatry, Medical School, University of São Paulo, BrazilAbstract: Depression and coronary artery disease (CAD are both extremely prevalent diseases. In addition, compromised quality of life and life expectancy are characteristics of both situations. There are several conditions that aggravate depression and facilitate the development of CAD, as well as provoke a worse prognosis in patients with already established CAD: inferior adherence to medical orientations (medications and life style modifications, greater platelet activation and aggregation, endothelial dysfunction, and impaired autonomic dysfunction (lowered heart rate variability. Recent literature has shown that depression alone is becoming an independent risk factor for cardiac events both in primary and secondary prevention. As the diagnosis of depression in patients with heart disease is difficult, due to similarities of symptoms, the health professional should perform a careful evaluation to differentiate the clinical signs of depression from those related with general heart diseases. After a myocardial infarction, depression is an independent risk factor for mortality. Successful therapy of depression has been shown to improve patients’ quality of life and cardiovascular outcome. However, multicentric clinical trials are needed to support this inference. A practical liaison between qualified professionals is necessary for the better management of depressed patients with excess risk in developing CAD. Accordingly, pathophysiological and clinical implications between depression and CAD are discussed in this article.Keywords: depression, coronary artery disease, behavioral disorders, prognosis

  3. Savant Syndrome: Case Studies, Hypotheses, and Implications for Special Education.

    Science.gov (United States)

    Cheatham, Susan Klug; And Others

    1995-01-01

    The concept of savant syndrome, encompassing those individuals historically known as "idiot savants," is reviewed. Case studies demonstrating special abilities in the areas of calendar calculating, musical ability, artistic talent, memorization, mathematical skills, mechanical achievement, and fine sensory discrimination are discussed, as well as…

  4. Savant Syndrome: Case Studies, Hypotheses, and Implications for Special Education.

    Science.gov (United States)

    Cheatham, Susan Klug; And Others

    1995-01-01

    The concept of savant syndrome, encompassing those individuals historically known as "idiot savants," is reviewed. Case studies demonstrating special abilities in the areas of calendar calculating, musical ability, artistic talent, memorization, mathematical skills, mechanical achievement, and fine sensory discrimination are discussed,…

  5. Sensitivity studies associated with dosimetry experiment interpretation

    Energy Technology Data Exchange (ETDEWEB)

    Bourganel, S.; Soldevila, M. [CEA/DANS/DM2S/SERMA, CEA Saclay, 91191, Gif sur Yvette (France); Ferrer, A.; Gregoire, G.; Destouches, C.; Beretz, D. [CEA/DEN-CAD/DER/SPEX, CEA Cadarache, F13108, Saint Paul lez Durance (France)

    2011-07-01

    Document available in abstract form only, full text of document follows: Interpretation of reactor dosimetry experiments with C/E comparison requires precise knowledge of parameters involved in modeling. Some parameters have more weight than others on the calculated values. So, sensitivity studies should be conducted to verify the importance of these parameters. The conclusions of these studies are used to refine the experiment modeling, or to correct uncertainty calculations. The results of these sensitivity studies allow a post-irradiation analysis, which can justify the discarding of some atypical C/M values. Derived uncertainties may be improved by the sensitivity analyses. Beyond classical parameters as geometry or composition, this paper describes some specific sensitivity studies conducted for dosimetry irradiation in reactor, and presents conclusions. These studies are based on dosimeters irradiated in the EOLE reactor facility at Cadarache CEA center. Conclusions drawn from these studies are generic and can be applied to any dosimetry study. Calculations performed for these studies were realized using TRIPOLI-4 Monte Carlo code. (authors)

  6. Genome-wide association study of multiplex schizophrenia pedigrees

    DEFF Research Database (Denmark)

    Levinson, Douglas F; Shi, Jianxin; Wang, Kai;

    2012-01-01

    The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).......The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs)....

  7. Associated disease risk from the introduced generalist pathogen Sphaerothecum destruens: management and policy implications.

    Science.gov (United States)

    Andreou, Demetra; Gozlan, Rodolphe Elie

    2016-08-01

    The rosette agent Sphaerothecum destruens is a novel pathogen, which is currently believed to have been introduced into Europe along with the introduction of the invasive fish topmouth gudgeon Pseudorasbora parva (Temminck & Schlegel, 1846). Its close association with P. parva and its wide host species range and associated host mortalities, highlight this parasite as a potential source of disease emergence in European fish species. Here, using a meta-analysis of the reported S. destruens prevalence across all reported susceptible hosts species; we calculated host-specificity providing support that S. destruens is a true generalist. We have applied all the available information on S. destruens and host-range to an established framework for risk-assessing non-native parasites to evaluate the risks posed by S. destruens and discuss the next steps to manage and prevent disease emergence of this generalist parasite.

  8. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications.

    Science.gov (United States)

    Sudhyadhom, Atchar; Bova, Frank J; Foote, Kelly D; Rosado, Christian A; Kirsch-Darrow, Lindsey; Okun, Michael S

    2007-07-01

    The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

  9. Explosive volcanism and associated pressures - Implications for models of endogenically shocked quartz

    Science.gov (United States)

    De Silva, S. L.; Wolff, J. A.; Sharpton, V. L.

    1990-01-01

    The nature of explosive volcanic phenomena and associated pressures, both from field and theoretical perspectives, is discussed. An endogenic origin for shocked quartz at the K/T boundary requires impulsive pressures greater than 60 kbars to be generated during explosive volcanism. Explosive volcanic eruptions which are events of sustained decompression may be initiated by impulsive explosions while the magnitudes of the overpressures are small. These maximum overpressures can be controlled mainly by the tensile strength of the rock surrounding the magma chamber-conduit system. Thus maximum overpressures in the volcanic environment are limited to less than 500 bars which are orders of magnitude less than those required for shock quartz (greater than 60 kbars). This observation is found to be consistent with the complete lack of field or petrographic evidence in support of shock metamorphism associated with volcanic eruptions and their products.

  10. Erythrophore cell response to food-associated pathogenic bacteria: implications for detection.

    Science.gov (United States)

    Hutchison, Janine R; Dukovcic, Stephanie R; Dierksen, Karen P; Carlyle, Calvin A; Caldwell, Bruce A; Trempy, Janine E

    2008-09-01

    Cell-based biosensors have been proposed for use as function-based detectors of toxic agents. We report the use of Betta splendens chromatophore cells, specifically erythrophore cells, for detection of food-associated pathogenic bacteria. Evaluation of erythrophore cell response, using Bacillus spp., has revealed that this response can distinguish pathogenic Bacillus cereus from a non-pathogenic B. cereus ΔplcR deletion mutant and a non-pathogenic Bacillus subtilis. Erythrophore cells were exposed to Salmonella enteritidis, Clostridium perfringens and Clostridium botulinum. Each bacterial pathogen elicited a response from erythrophore cells that was distinguished from the corresponding bacterial growth medium, and this observed response was unique for each bacterial pathogen. These findings suggest that erythrophore cell response has potential for use as a biosensor in the detection and toxicity assessment for food-associated pathogenic bacteria.

  11. Erythrophore cell response to food‐associated pathogenic bacteria: implications for detection

    Science.gov (United States)

    Hutchison, Janine R.; Dukovcic, Stephanie R.; Dierksen, Karen P.; Carlyle, Calvin A.; Caldwell, Bruce A.; Trempy, Janine E.

    2008-01-01

    Summary Cell‐based biosensors have been proposed for use as function‐based detectors of toxic agents. We report the use of Betta splendens chromatophore cells, specifically erythrophore cells, for detection of food‐associated pathogenic bacteria. Evaluation of erythrophore cell response, using Bacillus spp., has revealed that this response can distinguish pathogenic Bacillus cereus from a non‐pathogenic B. cereus ΔplcR deletion mutant and a non‐pathogenic Bacillus subtilis. Erythrophore cells were exposed to Salmonella enteritidis, Clostridium perfringens and Clostridium botulinum. Each bacterial pathogen elicited a response from erythrophore cells that was distinguished from the corresponding bacterial growth medium, and this observed response was unique for each bacterial pathogen. These findings suggest that erythrophore cell response has potential for use as a biosensor in the detection and toxicity assessment for food‐associated pathogenic bacteria. PMID:21261862

  12. Arab Teens Lifestyle Study (ATLS): objectives, design, methodology and implications

    OpenAIRE

    Musaiger AO; ATLS Research Group; Al-Hazzaa HM

    2011-01-01

    Hazzaa M Al-Hazzaa1,2, Abdulrahman O Musaiger3, ATLS Research Group1Exercise Physiology Laboratory, Department of Physical Education and Movement Sciences, College of Education, King Saud University, 2Scientific Board, Obesity Research Chair, King Saud University, Riyadh, Saudi Arabia; 3Arab Center for Nutrition, Manama, Bahrain, and Nutrition and Health Studies Unit, Deanship of Scientific Research, University of Bahrain, BahrainBackground: There is a lack of comparable data on physical acti...

  13. A retrospective study of phonetic inventory complexity in acquisition of Spanish: implications for phonological universals.

    Science.gov (United States)

    Cataño, Lorena; Barlow, Jessica A; Moyna, María Irene

    2009-06-01

    This study evaluates 39 different phonetic inventories of 16 Spanish-speaking children (ages 0;11 to 5;1) in terms of hierarchical complexity. Phonetic featural differences are considered in order to evaluate the proposed implicational hierarchy of Dinnsen et al.'s phonetic inventory typology for English. The children's phonetic inventories are examined independently and in relation to one another. Five hierarchical complexity levels are proposed, similar to those of English and other languages, although with some language-specific differences. These findings have implications for theoretical assumptions about the universality of phonetic inventory development, and for remediation of Spanish-speaking children with phonological impairments.

  14. Identification of parathyroid glands: anatomical study and surgical implications.

    Science.gov (United States)

    Melo, Catarina; Pinheiro, Susana; Carvalho, Lina; Bernardes, António

    2015-03-01

    While performing thyroid surgery, the unintentional lesion of parathyroid glands and laryngeal nerves results in a profound alteration in patient's quality of life. To minimize thyroid surgery morbidity, the surgeon must have an in-depth knowledge of the thyroid gland morphology and its anatomical relations in the anterior compartment of the neck. This work intended to simulate total thyroidectomies using cadaver parts and isolate fragments that may correspond to parathyroid glands. The thyroid glands and "eventual" parathyroid glands were then submitted to histological study. Ninety-two cadaver parts were used for macroscopic dissection. A total of 242 fragments were isolated, 154 of which were confirmed through histological study to be parathyroid glands. In 36 cases, all "eventual" parathyroid glands isolated during dissection were confirmed through histological verification. In 40 cases, some glands were confirmed. In 16 cases, none of the "eventual" parathyroid glands was confirmed. The 92 thyroid glands isolated during dissection were also submitted to histological study. In 21 thyroid glands, 16 parathyroid glands were identified in the histological cuts: 8 sub-capsular, 8 extra-capsular, 6 intra-thyroidal. There was no statistical difference between the dimensions of the parathyroid glands. Parathyroid gland identification and preservation are sometimes a challenge during thyroid surgery, difficulty that has been demonstrated during dissection of cadaver parts.

  15. HCV and Oxidative Stress: Implications for HCV Life Cycle and HCV-Associated Pathogenesis

    OpenAIRE

    Regina Medvedev; Daniela Ploen; Eberhard Hildt

    2016-01-01

    HCV (hepatitis C virus) is a member of the Flaviviridae family that contains a single-stranded positive-sense RNA genome of approximately 9600 bases. HCV is a major causative agent for chronic liver diseases such as steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma which are caused by multifactorial processes. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. This review summarizes the mechanisms involved ...

  16. Vertical Cities of the Future: Implications for the Study and Teaching of Urban Geography

    Science.gov (United States)

    Berger, Michael L.

    1974-01-01

    The implications of a vertical city, of which the John Hancock Center in Chicago is a prototype, should be considered by teachers of urban studies. Questions clustering around nine discussion areas indicate the kinds of expanded, critical, and interdisciplinary thinking that planning and teaching for the future require. (JH)

  17. Implications of Using Case Study Instruction in a Foreign/Second Language Methods Course

    Science.gov (United States)

    Haley, Marjorie Hall

    2004-01-01

    To date, very little has been written about what kind of experiences foreign and second language teachers had during their preservice teaching internships and the implications of these experiences on the quality of foreign and second language instruction in the United States in K-12 settings. This article presents the case study of one student…

  18. Comparative Study of University and Polytechnic Graduates in Finland: Implications of Higher Education on Earnings

    Science.gov (United States)

    Xia, Belle Selene; Liitiainen, Elia; Rekola, Mika

    2012-01-01

    This study explores the implications of higher education on earnings in Finland. The challenges as well as opportunities of obtaining a university degree as compared to graduating from polytechnics are evaluated using the REFLEX (The Flexible Professional in the Knowledge Society) data. As a Nordic country, Finland is known for its educated…

  19. Implications of China’s Growing Demand for Oil: A Case Study in Venezuela

    Science.gov (United States)

    2007-12-01

    24 Naughton, The Chinese Economy, 92. 25 Justin Yifu Lin, “The Household Responsibility System Reform in China: A Peasant’s Institutional Choice...its implications,” Journal of Strategic Studies 30, No. 4 (2007), 833-862. Lin, Justin Yifu . “The Household Responsibility System Reform in China

  20. A Retrospective Study of Phonetic Inventory Complexity in Acquisition of Spanish: Implications for Phonological Universals

    Science.gov (United States)

    Catano, Lorena; Barlow, Jessica A.; Moyna, Maria Irene

    2009-01-01

    This study evaluates 39 different phonetic inventories of 16 Spanish-speaking children (ages 0;11 to 5;1) in terms of hierarchical complexity. Phonetic featural differences are considered in order to evaluate the proposed implicational hierarchy of Dinnsen et al.'s phonetic inventory typology for English. The children's phonetic inventories are…

  1. A genome-wide association study of emotion dysregulation: Evidence for interleukin 2 receptor alpha.

    Science.gov (United States)

    Powers, Abigail; Almli, Lynn; Smith, Alicia; Lori, Adriana; Leveille, Jen; Ressler, Kerry J; Jovanovic, Tanja; Bradley, Bekh

    2016-12-01

    Emotion dysregulation has been implicated as a risk factor for many psychiatric conditions. Therefore, examining genetic risk associated with emotion dysregulation could help inform cross-disorder risk more generally. A genome-wide association study (GWAS) of emotion dysregulation using single nucleotide polymorphism (SNP) array technology was conducted in a highly traumatized, minority, urban sample (N = 2600, males = 774). Post-hoc analyses examined associations between SNPs identified in the GWAS and current depression, posttraumatic stress disorder (PTSD), and history of suicide attempt. Methylation quantitative trait loci were identified and gene set enrichment analyses were used to broadly determine biological processes involved with these SNPs. Among males, SNP rs6602398, located within the interleukin receptor 2A gene, IL2RA, was significantly associated with emotion dysregulation (p = 1.1 × 10(-8)). Logistic regression analyses revealed this SNP was significantly associated with depression (Exp(B) = 2.67, p < 0.001) and PTSD (Exp(B) = 2.07, p < 0.01). This SNP was associated with differential DNA methylation (p < 0.05) suggesting it may be functionally active. Finally, through gene set enrichment analyses, ten psychiatric disease pathways (adjusted p < 0.01) and the calcium signaling pathway (adjusted p = 0.008) were significantly associated with emotion dysregulation. We found initial evidence for an association between emotion dysregulation and genetic risk loci that have already been implicated in medical disorders that have high comorbidity with psychiatric disorders. Our results provide further evidence that emotion dysregulation can be understood as a potential psychiatric cross-disorder risk factor, and that sex differences across these phenotypes may be critical. Continued research into genetic and biological risk associated with emotion dysregulation is needed.

  2. The role of associative and non-associative learning in the training of horses and implications for the welfare (a review

    Directory of Open Access Journals (Sweden)

    Paolo Baragli

    2015-03-01

    Full Text Available Horses were domesticated 6000 years ago and since then different types of approaches have been developed to enhance the horse's wellbeing and the human-horse relationship. Even though horse training is an increasingly important research area and many articles have been published on the subject, equitation is still the sport with the highest rate of human injuries, and a significant percentage of horses are sold or slaughtered due to behavioral problems. One explanation for this data is that the human-horse relationship is complex and the communication between humans and horses has not yet been accurately developed. Thus, this review addresses correct horse training based on scientific knowledge in animal learning and psychology. Specifically, it starts from the basic communication between humans and horses and then focuses on associative and non-associative learning, with many practical outcomes in horse management from the ground and under saddle. Finally, it highlights the common mistakes in the use of negative reinforcement, as well as all the implications that improper training could have on horse welfare. Increased levels of competence in horse training could be useful for equine technicians, owners, breeders, veterinarians, and scientists, in order to safeguard horse welfare, and also to reduce the number of human injuries and economic loss for civil society and the public health system.

  3. Ethical implications of using the minipig in regulatory toxicology studies

    DEFF Research Database (Denmark)

    Webster, John; Bollen, Peter; Grimm, Herwig

    2010-01-01

    Two key questions are addressed in this article. What are the potential harms to minipigs relative to the harms for dogs and non-human primates and can these harms be reduced more easily in minipigs than in other species? Are there potential benefits resulting from the use of minipigs relative...... in studies designed for safety assessment. On this basis we rejected the argument that minipigs are more acceptable experimental animals than dogs or monkeys despite the fact that their use may prove less offensive to some groups within society at large. Species selection must be made on a case-by-case basis...... where the benefits are assessed by weighing the scientific evidence relating to the predictivity of the animal model, against the harm that may accrue to the animals both from the test procedures and their lifetime experience within the laboratory environment. Within this context we recognise...

  4. Social constructivism and its implications for critical media studies

    Directory of Open Access Journals (Sweden)

    Wilhelm Kempf

    2006-04-01

    Full Text Available While media critics maintain that war coverage has a strong bias toward promoting conflict escalation, their opponents claim that the concept of distorted reality cannot be upheld. What seems to be a media-political dispute results from an epistemological issue that tangles the very roots of cultural studies in general: the question of whether the social construction of reality implies the arbitrariness of opinions. The present paper discusses this proposition from a constructivist point of view and shows that it is based on an inadequate and logically incorrect understanding of truth and reality, and on a lack of differentiation between facts and meanings, between truth and beliefs and between objective and subjective realities. Defining a third path between cultural imperialism and a naïve understanding of cultural relativism, the paper finally discusses the methodological basis on which media criticism can build.

  5. Genome-wide association study of autistic-like traits in a general population study of young adults

    Directory of Open Access Journals (Sweden)

    Rachel Maree Jones

    2013-10-01

    Full Text Available Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A genome-wide association study using 2,462,046 single nucleotide polymorphisms (SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine Study. No SNP associations reached genome-wide significance (p < 5.0 x 10-8. However, investigations into nominal observed SNP associations (p < 1.0 x 10-5 add support to two positional candidate genes previously implicated in ASD aetiology, PRKCB1 and CBLN1.The rs198198 SNP (p = 9.587 x 10-6, is located within an intron of the protein kinase C, beta 1 (PRKCB1 gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 x 10-6 is located in a region flanking the Cerebellin 1 (CBLN1 gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.

  6. Generic information can retrieve known biological associations: implications for biomedical knowledge discovery.

    Directory of Open Access Journals (Sweden)

    Herman H H B M van Haagen

    Full Text Available MOTIVATION: Weighted semantic networks built from text-mined literature can be used to retrieve known protein-protein or gene-disease associations, and have been shown to anticipate associations years before they are explicitly stated in the literature. Our text-mining system recognizes over 640,000 biomedical concepts: some are specific (i.e., names of genes or proteins others generic (e.g., 'Homo sapiens'. Generic concepts may play important roles in automated information retrieval, extraction, and inference but may also result in concept overload and confound retrieval and reasoning with low-relevance or even spurious links. Here, we attempted to optimize the retrieval performance for protein-protein interactions (PPI by filtering generic concepts (node filtering or links to generic concepts (edge filtering from a weighted semantic network. First, we defined metrics based on network properties that quantify the specificity of concepts. Then using these metrics, we systematically filtered generic information from the network while monitoring retrieval performance of known protein-protein interactions. We also systematically filtered specific information from the network (inverse filtering, and assessed the retrieval performance of networks composed of generic information alone. RESULTS: Filtering generic or specific information induced a two-phase response in retrieval performance: initially the effects of filtering were minimal but beyond a critical threshold network performance suddenly drops. Contrary to expectations, networks composed exclusively of generic information demonstrated retrieval performance comparable to unfiltered networks that also contain specific concepts. Furthermore, an analysis using individual generic concepts demonstrated that they can effectively support the retrieval of known protein-protein interactions. For instance the concept "binding" is indicative for PPI retrieval and the concept "mutation abnormality" is

  7. Geo hazard studies and their policy implications in Nicaragua

    Science.gov (United States)

    Strauch, W.

    2007-05-01

    Nicaragua, situated at the Central American Subduction zone and placed in the trajectory of tropical storms and hurricanes, is a frequent showplace of natural disasters which have multiplied the negative effects of a long term socioeconomic crisis leaving Nicaragua currently as the second poorest country of the Americas. In the last years, multiple efforts were undertaken to prevent or mitigate the affectation of the natural phenomena to the country. National and local authorities have become more involved in disaster prevention policy and international cooperation boosted funding for disaster prevention and mitigation measures in the country. The National Geosciences Institution (INETER) in cooperation with foreign partners developed a national monitoring and early warning system on geological and hydro-meteorological phenomena. Geological and risk mapping projects were conducted by INETER and international partners. Universities, NGO´s, International Technical Assistance, and foreign scientific groups cooperated to capacitate Nicaraguan geoscientists and to improve higher education on disaster prevention up to the master degree. Funded by a World Bank loan, coordinated by the National System for Disaster Prevention, Mitigation and Attention (SINAPRED) and scientifically supervised by INETER, multidisciplinary hazard and vulnerability studies were carried out between 2003 and 2005 with emphasis on seismic hazard. These GIS based works provided proposals for land use policies on a local level in 30 municipalities and seismic vulnerability and risk information for each single building in Managua, Capital of Nicaragua. Another large multidisciplinary project produced high resolution air photos, elaborated 1:50,000 vectorized topographic maps, and a digital elevation model for Western Nicaragua. These data, integrated in GIS, were used to assess: 1) Seismic Hazard for Metropolitan Managua; 2) Tsunami hazard for the Pacific coast; 3) Volcano hazard for Telica

  8. Air pollution and health studies in China--policy implications.

    Science.gov (United States)

    Chen, Bingheng; Kan, Haidong; Chen, Renjie; Jiang, Songhui; Hong, Chuanjie

    2011-11-01

    During the rapid economic development in China, ambient air pollutants in major cities, including PM10 (particulate matter with aerodynamic diameter air pollution levels in China are still at the higher end of the world level. Less information is available regarding changes in national levels of other pollutants such as PM2.5 and ozone. The Chinese Ministry of Environmental Protection (MOEP) set an index for "controlling/reducing total SO2 emissions" to evaluate the efficacy of air pollution control strategy in the country. Total SO2 emissions declined for the first time in 2007. Chinese epidemiologic studies evidenced adverse health effects of ambient air pollution similar to those reported from developed countries, though risk estimates on mortality/morbidity per unit increase of air pollutant are somewhat smaller than those reported in developed countries. Disease burden on health attributable to air pollution is relatively greater in China because of higher pollution levels. Improving ambient air quality has substantial and measurable public health benefits in China. It is recommended that the current Chinese air quality standards be updated/revised and the target for "controlling/reducing total SO2 emissions" be maintained and another target for "reducing total NO2 emissions" be added in view of rapid increase in motor vehicles. Continuous and persistent efforts should be taken to improve ambient air quality.

  9. Hierarchical modularity in ERα transcriptional network is associated with distinct functions and implicates clinical outcomes.

    Science.gov (United States)

    Tang, Binhua; Hsu, Hang-Kai; Hsu, Pei-Yin; Bonneville, Russell; Chen, Su-Shing; Huang, Tim H-M; Jin, Victor X

    2012-01-01

    Recent genome-wide profiling reveals highly complex regulation networks among ERα and its targets. We integrated estrogen (E2)-stimulated time-series ERα ChIP-seq and gene expression data to identify the ERα-centered transcription factor (TF) hubs and their target genes, and inferred the time-variant hierarchical network structures using a Bayesian multivariate modeling approach. With its recurrent motif patterns, we determined three embedded regulatory modules from the ERα core transcriptional network. The GO analyses revealed the distinct biological function associated with each of three embedded modules. The survival analysis showed the genes in each module were able to render a significant survival correlation in breast cancer patient cohorts. In summary, our Bayesian statistical modeling and modularity analysis not only reveals the dynamic properties of the ERα-centered regulatory network and associated distinct biological functions, but also provides a reliable and effective genomic analytical approach for the analysis of dynamic regulatory network for any given TF.

  10. Size distribution of particle-associated polybrominated diphenyl ethers (PBDEs) and their implications for health

    Science.gov (United States)

    Lyu, Yan; Xu, Tingting; Li, Xiang; Cheng, Tiantao; Yang, Xin; Sun, Xiaomin; Chen, Jianmin

    2016-03-01

    In order to better understand the size distribution of particle-associated PBDEs and their deposition pattern in the human respiratory tract, we carried out a 1-year campaign during 2012-2013 for the measurement of size-resolved particles at the urban site of Shanghai. The results showed that particulate PBDEs exhibited a bimodal distribution with a mode peak in the accumulation particle size range and the second mode peak in the coarse particle size ranges. As the number of bromine atoms in the molecule increases, accumulation-mode peak intensity increased while coarse-mode peak intensity decreased. This change was consistent with the variation of PBDEs' subcooled vapor pressure. Absorption and adsorption processes dominated the distribution of PBDEs among the different size particles. The evaluated deposition flux of Σ13 PBDEs was 26.8 pg h-1, in which coarse particles contributed most PBDEs in head and tracheobronchial regions, while fine-mode particles contributed major PBDEs in the alveoli region. In association with the fact that fine particles can penetrate deeper into the respiratory system, fine-particle-bound highly brominated PBDEs can be inhaled more deeply into human lungs and cause a greater risk to human health.

  11. Foraging Strategies of Laysan Albatross Inferred from Stable Isotopes: Implications for Association with Fisheries.

    Science.gov (United States)

    Edwards, Ann E; Fitzgerald, Shannon M; Parrish, Julia K; Klavitter, John L; Romano, Marc D

    2015-01-01

    Fatal entanglement in fishing gear is the leading cause of population decline for albatross globally, a consequence of attraction to bait and fishery discards of commercial fishing operations. We investigated foraging strategies of Laysan albatross (Phoebastria immutabilis), as inferred from nitrogen and carbon isotope values of primary feathers, to determine breeding-related, seasonal, and historic factors that may affect the likelihood of association with Alaskan or Hawaiian longline fisheries. Feather samples were collected from live birds monitored for breeding status and breeding success on Midway Atoll in the northwestern Hawaiian Islands, birds salvaged as fisheries-bycatch, and birds added to museum collections before 1924. During the chick-rearing season (sampled April-May), means and variances of stable isotope values of birds with the highest, most consistent reproductive success were distinct from less productive conspecifics and completely different from birds caught in Hawaiian or Alaskan longline fisheries, suggesting birds with higher multi-annual reproductive success were less likely to associate with these fisheries. Contemporary birds with the highest reproductive success had mean values most similar to historic birds. Values of colony-bound, courting prebreeders were similar to active breeders but distinct from prebreeders caught in Alaskan longline fisheries. During the breeding season, δ15N values were highly variable for both contemporary and historic birds. Although some historic birds exhibited extremely low δ15N values unmatched by contemporary birds (fisheries.

  12. Ethical implications of using the minipig in regulatory toxicology studies.

    Science.gov (United States)

    Webster, John; Bollen, Peter; Grimm, Herwig; Jennings, Maggy

    2010-01-01

    Two key questions are addressed in this article. What are the potential harms to minipigs relative to the harms for dogs and non-human primates and can these harms be reduced more easily in minipigs than in other species? Are there potential benefits resulting from the use of minipigs relative to dogs and non-human primates? In considering the answers to these questions, we present an ethical framework which was developed taking into account the viewpoint of all concerned parties. This ethical matrix provides a framework upon which to identify and explore issues raised by the moral imperative to seek a fair compromise between the differing needs of different interest groups, which includes both the moral agents and the moral patients. The moral agents are the different groups of human stakeholders including society at large, regulatory bodies, industrialists and animal care staff. The moral patients are the laboratory animals, both breeding stock held by the animal supplier, and experimental animals in laboratories. In considering these animals it cannot be assumed that dogs, monkeys and minipigs differ with regard to the pain and suffering that they may experience and undergo when treated in studies designed for safety assessment. On this basis we rejected the argument that minipigs are more acceptable experimental animals than dogs or monkeys despite the fact that their use may prove less offensive to some groups within society at large. Species selection must be made on a case-by-case basis where the benefits are assessed by weighing the scientific evidence relating to the predictivity of the animal model, against the harm that may accrue to the animals both from the test procedures and their lifetime experience within the laboratory environment.

  13. Taphonomy for taxonomists: Implications of predation in small mammal studies

    Science.gov (United States)

    Fernández-Jalvo, Yolanda; Andrews, Peter; Denys, Christiane; Sesé, Carmen; Stoetzel, Emmanuelle; Marin-Monfort, Dolores; Pesquero, Dolores

    2016-05-01

    Predation is one of the most recurrent sources of bone accumulations. The influence of predation is widely studied for large mammal sites where humans, acting as predators, produce bone accumulations similar to carnivore accumulations. Similarly, small mammal fossil sites are mainly occupation levels of predators (nests or dens). In both cases, investigations of past events can be compared with present day equivalents or proxies. Chewing marks are sometimes present on large mammal predator accumulations, but digestion traits are the most direct indication of predation, and evidence for this is always present in small mammal (prey) fossil assemblages. Digestion grades and frequency indicates predator type and this is well established since the publication of Andrews (1990). The identification of the predator provides invaluable information for accurate interpretation of the palaeoenvironment. Traditionally, palaeoenvironmental interpretations are obtained from the taxonomic species identified in the site, but rather than providing direct interpretations of the surrounding palaeoenvironment, this procedure actually describes the dietary preferences of the predators and the type of occupation (nests, marking territory, dens, etc). This paper reviews the identification of traits produced by predators on arvicolins, murins and soricids using a method that may be used equally by taxonomists and taphonomists. It aims to provide the "tools" for taxonomists to identify the predator based on their methodology, which is examining the occlusal surfaces of teeth rather than their lateral aspects. This will greatly benefit both the work of taphonomists and taxonomists to recognize signs of predation and the improvement of subsequent palaeoecological interpretations of past organisms and sites by identifying both the prey and the predator.

  14. REELIN-RELATED DISTURBANCES IN DEPRESSION: IMPLICATIONS FOR TRANSLATIONAL STUDIES

    Directory of Open Access Journals (Sweden)

    Hector J eCaruncho

    2016-02-01

    Full Text Available The finding that reelin expression is significantly decreased in mood and psychotic disorders, together with evidence that reelin can regulate key aspects of hippocampal plasticity in the adult brain, brought our research group and others to study the possible role of reelin in the pathogenesis of depression. This review describes recent progress on this topic using an animal model of depression that makes use of repeated corticosterone injections. This methodology produces depression-like symptoms in both rats and mice that are reversed by antidepressant treatment. We have reported that corticosterone causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone, where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated corticosterone treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase; that deficits in reelin might also create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype. We also observed alterations in the pattern of membrane protein clustering in peripheral lymphocytes in animals with low levels of reelin. Importantly, we found parallel changes in membrane protein clustering in depression patients, which differentiated two subpopulations of naïve depression patients that showed a different therapeutic response to antidepressant treatment. Here we review these findings and develop the hypothesis that restoring reelin-related function could represent a novel approach for antidepressant therapies.

  15. Optimal use of video for teaching the practical implications of studying business information systems

    DEFF Research Database (Denmark)

    Fog, Benedikte; Ulfkjær, Jacob Kanneworff Stigsen; Schlichter, Bjarne Rerup

    that video should be introduced early during a course to prevent students’ misconceptions of working with business information systems, as well as to increase motivation and comprehension within the academic area. It is also considered of importance to have a trustworthy person explaining the practical......The study of business information systems has become increasingly important in the Digital Economy. However, it has been found that students have difficulties understanding the practical implications thereof and this leads to a motivational decreases. This study aims to investigate how to optimize...... the use of video to increase comprehension of the practical implications of studying business information systems. This qualitative study is based on observations and focus group interviews with first semester business students. The findings suggest that the video examined in the case study did...

  16. CCNA Cisco Certified Network Associate Study Guide

    CERN Document Server

    Lammle, Todd

    2011-01-01

    Learn from the Best - Cisco Networking Authority Todd LammleWritten by Cisco networking authority Todd Lammle, this comprehensive guide has been completely updated to reflect the latest CCNA 640-802 exam. Todd's straightforward style provides lively examples, hands on and written labs, easy-to-understand analogies, and real-world scenarios that will not only help you prepare for the exam, but also give you a solid foundation as a Cisco networking professional.This Study Guide teaches you how toDescribe how a network worksConfigure, verify and troubleshoot a switch with VLANs and interswitch co

  17. The association of heavy and light chain variable domains in antibodies: implications for antigen specificity.

    KAUST Repository

    Chailyan, Anna

    2011-06-28

    The antigen-binding site of immunoglobulins is formed by six regions, three from the light and three from the heavy chain variable domains, which, on association of the two chains, form the conventional antigen-binding site of the antibody. The mode of interaction between the heavy and light chain variable domains affects the relative position of the antigen-binding loops and therefore has an effect on the overall conformation of the binding site. In this article, we analyze the structure of the interface between the heavy and light chain variable domains and show that there are essentially two different modes for their interaction that can be identified by the presence of key amino acids in specific positions of the antibody sequences. We also show that the different packing modes are related to the type of recognized antigen.

  18. Habitat fragmentation is associated to gut microbiota diversity of an endangered primate: implications for conservation.

    Science.gov (United States)

    Barelli, Claudia; Albanese, Davide; Donati, Claudio; Pindo, Massimo; Dallago, Chiara; Rovero, Francesco; Cavalieri, Duccio; Tuohy, Kieran Michael; Hauffe, Heidi Christine; De Filippo, Carlotta

    2015-10-07

    The expansion of agriculture is shrinking pristine forest areas worldwide, jeopardizing the persistence of their wild inhabitants. The Udzungwa red colobus monkey (Procolobus gordonorum) is among the most threatened primate species in Africa. Primarily arboreal and highly sensitive to hunting and habitat destruction, they provide a critical model to understanding whether anthropogenic disturbance impacts gut microbiota diversity. We sampled seven social groups inhabiting two forests (disturbed vs. undisturbed) in the Udzungwa Mountains of Tanzania. While Ruminococcaceae and Lachnospiraceae dominated in all individuals, reflecting their role in extracting energy from folivorous diets, analysis of genus composition showed a marked diversification across habitats, with gut microbiota α-diversity significantly higher in the undisturbed forest. Functional analysis suggests that such variation may be associated with food plant diversity in natural versus human-modified habitats, requiring metabolic pathways to digest xenobiotics. Thus, the effects of changes in gut microbiota should not be ignored to conserve endangered populations.

  19. Nitrogen compounds in the apoplastic sap of sugarcane stem: some implications in the association with endophytes.

    Science.gov (United States)

    Tejera, Noel; Ortega, Eduardo; Rodes, Rosa; Lluch, Carmen

    2006-01-01

    Several nitrogen compounds were identified and quantified in the apoplastic and symplastic sap of sugarcane stems. The sap of stems was composed mainly of soluble sugars, which constituted 95% of the total organic compounds detected. Sap also contained nitrogen compounds, with amino acids (50-70% of N) and proteins (20-30% of N), being the main nitrogenous substances, as well as inorganic forms as ammonium, nitrite and nitrate, in low concentrations (Gluconacetobacter diazotrophicus. The total amino acid content of apoplastic sap was six to nine times lower in non-nitrogen fertilized plants than in fertilized ones. The possible roles of these substances to regulate endophytic associations with sugarcane are also discussed.

  20. Association of Arsenic and Phosphorus with Iron Nanoparticles between Streams and Aquifers: Implications for Arsenic Mobility.

    Science.gov (United States)

    Hartland, Adam; Larsen, Joshua R; Andersen, Martin S; Baalousha, Mohammed; O'Carroll, Denis

    2015-12-15

    The microbial oxidation of organic matter coupled to reductive iron oxide dissolution is widely recognized as the dominant mechanism driving elevated arsenic (As) concentrations in aquifers. This paper considers the potential of nanoparticles to increase the mobility of As in aquifers, thereby accounting for discrepancies between predicted and observed As transport reported elsewhere. Arsenic, phosphorus, and iron size distributions and natural organic matter association were examined along a flow path from surface water via the hyporheic zone to shallow groundwater. Our analysis demonstrates that the colloidal Fe concentration (>1 kDa) correlates with both colloidal P and colloidal As concentrations. Importantly, increases in the concentration of colloidal P (>1 kDa) were positively correlated with increases in the concentration of nominally dissolved As (aquifer matrix. Dynamic redox fronts at the interface between streams and aquifers may therefore provide globally widespread conditions for the generation of Fe nanoparticles, a mobile phase for As adsorption currently not a part of reactive transport models.

  1. Soil metal concentrations and toxicity: Associations with distances to industrial facilities and implications for human health

    Energy Technology Data Exchange (ETDEWEB)

    Aelion, C. Marjorie [Department of Environmental Health Sciences, University of South Carolina, 921 Assembly Street, Columbia, SC 29208 (United States); Department of Public Health, University of Massachusetts, 715 North Pleasant Street, Amherst, MA 01003 (United States)], E-mail: maelion@schoolph.umass.edu; Davis, Harley T. [Department of Environmental Health Sciences, University of South Carolina, 921 Assembly Street, Columbia, SC 29208 (United States); McDermott, Suzanne [Department of Family and Preventive Medicine, University of South Carolina, 3209 Colonial Drive, Columbia, SC 29203 (United States); Lawson, Andrew B. [Department of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, 135 Cannon Street, Charleston, SC 29425 (United States)

    2009-03-15

    Urban and rural areas may have different levels of environmental contamination and different potential sources of exposure. Many metals, i.e., arsenic (As), lead (Pb), and mercury (Hg), have well-documented negative neurological effects, and the developing fetus and young children are particularly at risk. Using a database of mother and child pairs, three areas were identified: a rural area with no increased prevalence of mental retardation and developmental delay (MR/DD) (Area A), and a rural area (Area B) and an urban area (Area C) with significantly higher prevalence of MR/DD in children as compared to the state-wide average. Areas were mapped and surface soil samples were collected from nodes of a uniform grid. Samples were analyzed for As, barium (Ba), beryllium (Be), chromium (Cr), copper (Cu), Pb, manganese (Mn), nickel (Ni), and Hg concentrations and for soil toxicity, and correlated to identify potential common sources. ArcGIS was used to determine distances between sample locations and industrial facilities, which were correlated with both metal concentrations and soil toxicity. Results indicated that all metal concentrations (except Be and Hg) in Area C were significantly greater than those in Areas A and B (p {<=} 0.0001) and that Area C had fewer correlations between metals suggesting more varied sources of metals than in rural areas. Area C also had a large number of facilities whose distances were significantly correlated with metals, particularly Cr (maximum r = 0.33; p = 0.0002), and with soil toxicity (maximum r = 0.25; p = 0.007) over a large spatial scale. Arsenic was not associated with distance to any facility and may have a different anthropogenic, or natural source. In contrast to Area C, both rural areas had lower concentrations of metals, lower soil toxicity, and a small number of facilities with significant associations between distance and soil metals.

  2. The implication of frontostriatal circuits in young smokers: A resting-state study.

    Science.gov (United States)

    Yuan, Kai; Yu, Dahua; Bi, Yanzhi; Li, Yangding; Guan, Yanyan; Liu, Jixin; Zhang, Yi; Qin, Wei; Lu, Xiaoqi; Tian, Jie

    2016-06-01

    The critical roles of frontostriatal circuits had been revealed in addiction. With regard to young smokers, the implication of frontostriatal circuits resting-state functional connectivity (RSFC) in smoking behaviors and cognitive control deficits remains unclear. In this study, the volume of striatum subsets, i.e., caudate, putamen, and nucleus accumbens, and corresponding RSFC differences were investigated between young smokers (n1  = 60) and nonsmokers (n2  = 60), which were then correlated with cigarette smoking measures, such as pack_years-cumulative effect of smoking, Fagerström Test for Nicotine Dependence (FTND)-severity of nicotine addiction, Questionnaire on Smoking Urges (QSU)-craving state, and Stroop task performances. Additionally, mediation analysis was carried out to test whether the frontostriatal RSFC mediates the relationship between striatum morphometry and cognitive control behaviors in young smokers when applicable. We revealed increased volume of right caudate and reduced RSFC between caudate and dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex in young smokers. Significant positive correlation between right caudate volume and QSU as well as negative correlation between anterior cingulate cortex-right caudate RSFC and FTND were detected in young smokers. More importantly, DLPFC-caudate RSFC strength mediated the relationship between caudate volume and incongruent errors during Stroop task in young smokers. Our results demonstrated that young smokers showed abnormal interactions within frontostriatal circuits, which were associated with smoking behaviors and cognitive control impairments. It is hoped that our study focusing on frontostriatal circuits could provide new insights into the neural correlates and potential novel therapeutic targets for treatment of young smokers. Hum Brain Mapp 37:2013-2026, 2016. © 2016 Wiley Periodicals, Inc.

  3. Implications of private sector participation in power generation-a case study from India

    Energy Technology Data Exchange (ETDEWEB)

    Balachandra, P. [Department of Management Studies, Indian Institute of Science, Bangalore 560 012 (India)]. E-mail: patilb@mgmt.iisc.ernet.in

    2006-11-15

    India suffers from widespread shortages of electricity supply. These shortages, among others, are detrimental to the economic growth. The prospects for the next decade do not seem to be much brighter. Efforts in expanding generation capacity by the state-owned electric utilities are hampered by severe resource constraints. Against this backdrop, to mobilize additional resources to help bridge the gap in demand and supply, the Government of India formulated a policy in 1991 with the objective to encourage greater investment by private enterprises in the electricity sector. To study the implications of such an initiative on various stakeholders, viz., public utilities, consumers and private sector, the present paper tries to analyse issues like planned rationing, guarantees to private sector, backing down of existing capacity. Using the state of Karnataka (in Southern India) as a case study, the paper develops multiple scenarios using an integrated mixed integer-programming model. The results show the advantage of marginal non-supply (rationing) of electricity in terms of achieving overall effective supply demand matching as well as providing economic benefits to the state that could be generated through cost savings. The results also show the negative impacts of high guarantees offered to the private sector in terms of the opportunity costs of reduced utilization of both the existing and the new public capacity. The estimated generation losses and the associated economic impacts of backing down of existing and new public capacity on account of guarantees are found to be significantly high. For 2011-12, depending on the type of scenarios, the estimated generation and economic losses are likely to be in the range of 3200-10,000 GWh and Rs. 4200-13,600 million respectively. The impact of these losses on the consumers could be in terms of significant increase in energy bills (in the range of 19-40% for different scenarios) due to rise in tariffs.

  4. Implications of private sector participation in power generation - a case study from India

    Energy Technology Data Exchange (ETDEWEB)

    Balachandra, P. [Indian Institute of Science, Bangalore (India). Dept. of Management Studies

    2006-11-15

    India suffers from widespread shortages of electricity supply. These shortages, among others, are detrimental to the economic growth. The prospects for the next decade do not seem to be much brighter. Efforts in expanding generation capacity by the state-owned electric utilities are hampered by severe resource constraints. Against this backdrop, to mobilize additional resources to help bridge the gap in demand and supply, the Government of India formulated a policy in 1991 with the objective to encourage greater investment by private enterprises in the electricity sector. To study the implications of such an initiative on various stakeholders, viz., public utilities, consumers and private sector, the present paper tries to analyse issues like planned rationing, guarantees to private sector, backing down of existing capacity. Using the state of Karnataka (in Southern India) as a case study, the paper develops multiple scenarios using an integrated mixed integer-programming model. The results show the advantage of marginal non-supply (rationing) of electricity in terms of achieving overall effective supply demand matching as well as providing economic benefits to the state that could be generated through cost savings. The results also show the negative impacts of high guarantees offered to the private sector in terms of the opportunity costs of reduced utilization of both the existing and the new public capacity. The estimated generation losses and the associated economic impacts of backing down of existing and new public capacity on account of guarantees are found to be significantly high. For 2011-12, depending on the type of scenarios, the estimated generation and economic losses are likely to be in the range of 3200-10,000 GWh and Rs. 4200-13,600 million respectively. The impact of these losses on the consumers could be in terms of significant increase in energy bills (in the range of 19-40% for different scenarios) due to rise in tariffs. (author)

  5. Digital mammography in a screening programme and its implications for pathology: a comparative study.

    LENUS (Irish Health Repository)

    Feeley, Linda

    2011-03-01

    Most studies comparing full-field digital mammography (FFDM) with conventional screen-film mammography (SFM) have been radiology-based. The pathological implications of FFDM have received little attention in the literature, especially in the context of screening programmes. The primary objective of this retrospective study is to compare FFDM with SFM in a population-based screening programme with regard to a number of pathological parameters.

  6. Increased drinking following social isolation rearing: implications for polydipsia associated with schizophrenia.

    Directory of Open Access Journals (Sweden)

    Emily R Hawken

    Full Text Available Primary polydipsia, excessive drinking without known medical cause, is especially associated with a diagnosis of schizophrenia. We used animal models of schizophrenia-like symptoms to examine the effects on schedule-induced polydipsia: post-weaning social isolation rearing, subchronic MK-801 treatment (an NMDA-receptor antagonist or the two combined. Male, Sprague-Dawley rats reared in groups or in isolation beginning at postnatal day 21 were further divided to receive subchronic MK-801 (0.5 mg/kg twice daily or saline for 7 days beginning on postnatal day 62. Following a 4-day withdrawal period, all groups were trained on a schedule-induced polydipsia paradigm. Under food-restriction, animals reared in isolation and receiving food pellets at 1-min intervals developed significantly more drinking behavior than those reared with others. The addition of subchronic MK-801 treatment did not significantly augment the amount of water consumed. These findings suggest a predisposition to polydipsia is a schizophrenia-like behavioral effect of post-weaning social isolation.

  7. Implication of the association between GBM transient 150914 and LIGO Gravitational Wave event GW150914

    CERN Document Server

    Li, Xiang; Yuan, Qiang; Jin, Zhi-Ping; Fan, Yi-Zhong; Liu, Si-Ming; Wei, Da-Ming

    2016-01-01

    On September 14, 2015 the two detectors of LIGO simultaneously detected a transient gravitational-wave signal GW150914 and the Fermi GBM observations found a weak short gamma-ray burst (SGRB)-like transient (i.e., the GBM transient 150914). The time and location coincidences favor the association between GW150904 and GBM transient 150914. We compared GBM transient 150914 with other SGRBs and found that such an event is indeed a distinct outlier in the $E_{\\rm p,rest}-E_{\\rm iso}$ and $E_{\\rm p,rest}-L_{\\gamma}$ diagrams ($E_{\\rm iso}$ is the isotropic-equivalent energy, $L_\\gamma$ is the luminosity and $E_{\\rm p,rest}$ is the rest frame peak energy of the prompt emission), possibly due to its specific binary-black-hole merger origin. However, the presence of a "new" group of SGRBs with "low" $L_\\gamma$ and $E_{\\rm iso}$ but high $E_{\\rm p,rest}$ is also possible. If the outflow of GBM transient 150914 was launched by the accretion onto the nascent black hole, we estimate the accretion disk mass to be $\\sim 10...

  8. Cancer genetic association studies in the genome-wide age

    OpenAIRE

    Savage, Sharon A

    2008-01-01

    Genome-wide association studies of hundreds of thousands of SNPs have led to a deluge of studies of genetic variation in cancer and other common diseases. Large case–control and cohort studies have identified novel SNPs as markers of cancer risk. Genome-wide association study SNP data have also advanced understanding of population-specific genetic variation. While studies of risk profiles, combinations of SNPs that may increase cancer risk, are not yet clinically applicable, future, large-sca...

  9. Associations among Nonword Repetition and Phonemic and Vocabulary Awareness: Implications for Intervention

    Science.gov (United States)

    Tattersall, Patricia J.; Nelson, Nickola Wolf; Tyler, Ann A.

    2015-01-01

    Prior research has shown possible relations among nonword repetition (NWR), vocabulary, and phonological processing skills in children with and without language impairment. This study was designed to investigate whether relationships would differ for students with primary language impairment (PLI) and typical language (TL) and whether they would…

  10. An Empirical Bayes Mixture Model for Effect Size Distributions in Genome-Wide Association Studies

    DEFF Research Database (Denmark)

    Thompson, Wesley K.; Wang, Yunpeng; Schork, Andrew J.;

    2015-01-01

    for discovery, and polygenic risk prediction. To this end, previous work has used effect-size models based on various distributions, including the normal and normal mixture distributions, among others. In this paper we propose a scale mixture of two normals model for effect size distributions of genome......-wide association study (GWAS) test statistics. Test statistics corresponding to null associations are modeled as random draws from a normal distribution with zero mean; test statistics corresponding to non-null associations are also modeled as normal with zero mean, but with larger variance. The model is fit via...... minimizing discrepancies between the parametric mixture model and resampling-based nonparametric estimates of replication effect sizes and variances. We describe in detail the implications of this model for estimation of the non-null proportion, the probability of replication in de novo samples, the local...

  11. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    DEFF Research Database (Denmark)

    Børglum, A D; Demontis, D; Grove, J;

    2014-01-01

    in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10...... was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.......Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals...

  12. Endocrine disruptors and dental materials: health implications associated with their use in Brazil

    Directory of Open Access Journals (Sweden)

    Antonio Jorge Molinário Coelho

    2002-04-01

    Full Text Available This study analyzes international historical trends in the use of different types of materials in dental practice. The author describes the chemical properties of their ingredients and the potential and observed adverse effects in patients and dental technicians resulting from clinical or occupational exposure to various metals like beryllium, used to produce metal alloys. The growing use of various products (resin cements, ionomer cements, aesthetic restorative materials, resins, endodontal cements, and others based on the compound bisphenol-A, whose chemical structure is similar to that of estrogen. Considering the demographic and contemporary work force characteristics of those involved in dental practice in the Brazil, the study highlights the possible effect of the use of these materials in both male and female patients and all age strata, as well as in health professionals with occupational exposure to products containing bisphenol-A.

  13. Naturalising Ethics: The Implications of Darwinism for the Study of Moral Philosophy

    Science.gov (United States)

    Cartwright, John

    2010-05-01

    The nature of moral values has occupied philosophers and educationalists for centuries and a variety of claims have been made about their origin and status. One tradition suggests they may be thoughts in the mind of God; another that they are eternal truths to be reached by rational reflection (much like the truths of mathematics) or alternatively through intuition; another that they are social conventions; and another (from the logical positivists) that they are not verifiable facts but simply the expression of emotional likes and dislikes. Standard introductory texts (e.g., Bowie 2004; Vardy and Grosch 1999) on the subject of ethics rarely mention Darwin or Darwinism (Mepham 2005 is a useful exception) possibly mindful of the fact that the relationship of evolutionary biology to moral questions has had a troublesome history. The effect of this has been that whole generations of moral philosophers have given the biological sciences a wide berth and consequently often remain poorly informed about recent advances in evolutionary thought and the neurosciences. On the other hand, scientists have developed interesting models of the evolution of the moral sentiments and are using new imaging techniques to explore the centres of the brain associated with emotion and motivation, but many have been fearful of committing the naturalistic fallacy and so have steered clear of extrapolating their findings to ethical questions. No one after all wants to be seen to be committing an elementary logical blunder. But in the last 20 years, evolutionary biologists have regained the confidence to explore the implications of evolution for the study of ethics (de Waal 1996; Wilson 1998; Wright 1994; Greene 2003). This paper is designed to encourage those entrusted with the teaching of ethics to be open to the potential of Darwinism as a source of ideas on the origins and status of ethical thought and behaviour. It is also hoped that it will illustrate for science educators the enormous

  14. Identification of aerosol types over Indo-Gangetic Basin: implications to optical properties and associated radiative forcing.

    Science.gov (United States)

    Tiwari, S; Srivastava, A K; Singh, A K; Singh, Sachchidanand

    2015-08-01

    The aerosols in the Indo-Gangetic Basin (IGB) are a mixture of sulfate, dust, black carbon, and other soluble and insoluble components. It is a challenge not only to identify these various aerosol types, but also to assess the optical and radiative implications of these components. In the present study, appropriate thresholds for fine-mode fraction and single-scattering albedo have been used to first identify the aerosol types over IGB. Four major aerosol types may be identified as polluted dust (PD), polluted continental (PC), black carbon-enriched (BCE), and organic carbon-enriched (OCE). Further, the implications of these different types of aerosols on optical properties and radiative forcing have been studied. The aerosol products derived from CIMEL sun/sky radiometer measurements, deployed under Aerosol Robotic Network program of NASA, USA were used from four different sites Karachi, Lahore, Jaipur, and Kanpur, spread over Pakistan and Northern India. PD is the most dominant aerosol type at Karachi and Jaipur, contributing more than 50% of all the aerosol types. OCE, on the other hand, contributes only about 12-15% at all the stations except at Kanpur where its contribution is ∼38%. The spectral dependence of AOD was relatively low for PD aerosol type, with the lowest AE values (1.0). SSA was found to be the highest for OCE (>0.9) and the lowest for BCE (<0.9) type aerosols, with drastically different spectral variability. The direct aerosol radiative forcing at the surface and in the atmosphere was found to be the maximum at Lahore among all the four stations in the IGB.

  15. Binding Modes of Aromatic Ligands to Mammalian Heme Peroxidases with Associated Functional Implications

    Science.gov (United States)

    Singh, Amit K.; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Srinivasan, Alagiri; Sharma, Sujata; Singh, Tej P.

    2009-01-01

    The binding and structural studies of bovine lactoperoxidase with three aromatic ligands, acetylsalicylic acid (ASA), salicylhydoxamic acid (SHA), and benzylhydroxamic acid (BHA) show that all the three compounds bind to lactoperoxidase at the substrate binding site on the distal heme side. The binding of ASA occurs without perturbing the position of conserved heme water molecule W-1, whereas both SHA and BHA displace it by the hydroxyl group of their hydroxamic acid moieties. The acetyl group carbonyl oxygen atom of ASA forms a hydrogen bond with W-1, which in turn makes three other hydrogen-bonds, one each with heme iron, His-109 Nϵ2, and Gln-105 Nϵ2. In contrast, in the complexes of SHA and BHA, the OH group of hydroxamic acid moiety in both complexes interacts with heme iron directly with Fe-OH distances of 3.0 and 3.2Å respectively. The OH is also hydrogen bonded to His-109 Nϵ2 and Gln-105Nϵ2. The plane of benzene ring of ASA is inclined at 70.7° from the plane of heme moiety, whereas the aromatic planes of SHA and BHA are nearly parallel to the heme plane with inclinations of 15.7 and 6.2°, respectively. The mode of ASA binding provides the information about the mechanism of action of aromatic substrates, whereas the binding characteristics of SHA and BHA indicate the mode of inhibitor binding. PMID:19465478

  16. Pickup ion processes associated with spacecraft thrusters: Implications for solar probe plus

    Science.gov (United States)

    Clemens, Adam; Burgess, David

    2016-03-01

    Chemical thrusters are widely used in spacecraft for attitude control and orbital manoeuvres. They create an exhaust plume of neutral gas which produces ions via photoionization and charge exchange. Measurements of local plasma properties will be affected by perturbations caused by the coupling between the newborn ions and the plasma. A model of neutral expansion has been used in conjunction with a fully three-dimensional hybrid code to study the evolution and ionization over time of the neutral cloud produced by the firing of a mono-propellant hydrazine thruster as well as the interactions of the resulting ion cloud with the ambient solar wind. Results are presented which show that the plasma in the region near to the spacecraft will be perturbed for an extended period of time with the formation of an interaction region around the spacecraft, a moderate amplitude density bow wave bounding the interaction region and evidence of an instability at the forefront of the interaction region which causes clumps of ions to be ejected from the main ion cloud quasi-periodically.

  17. Recurrent Glioblastomas Reveal Molecular Subtypes Associated with Mechanistic Implications of Drug-Resistance.

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    So Mee Kwon

    Full Text Available Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6 in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.

  18. Exhalites Associated with Pb-Zn Mineralization in Devonian System and Their Prospecting Implications,Qinling,China

    Institute of Scientific and Technical Information of China (English)

    1991-01-01

    The exhalation origin of the ankerite-siliceous rocks associated with Pb-Zn mineralizations in the Devonian system of Qinling is discussed in the light of geologic setting,sedimentary-tectonic environment,lithological and chemical characteristics.On this basis,criteria for distinguishing them and their potential role as an indicator in prospecting are described.Ankerite-siliceous rocks are developed in the strata-bound Pb-Zn polymetallic belt in the Devonian system of Qinling.They are microcrystalline,dark grey and compact in appearance and are commonly carbonaceous,As a persistent ore-bearing horizon in the region,their genetic relation to the Pb-Zn deposits in generally accepted.However,a consensus has yet to be reached among geologists concerning their origein as a product of hydrothermal metasomtism at the late stage of sedimentation or as exhalite resulting from submarine exhalation.Accumulating evidence from direct observations on modern submarine hydrothermal systems strongly indicates that seafloor exhalation is a much more common geologic process than previously thought nd its metallogenic implications have long been overlooked.Characteristics of the ankerite-siliceous rocks as a product of exhalation and their significance as a guide in prospecting are described on the basis or geological setting,lithology,lithochemistry,REE,and isotopic and trace element features.

  19. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  20. Habitat association and conservation implications of endangered Francois' langur (Trachypithecus francoisi.

    Directory of Open Access Journals (Sweden)

    Yajie Zeng

    Full Text Available Francois' langur (Trachypithecus francoisi is an endangered primate and endemic to the limestone forests of the tropical and subtropical zone of northern Vietnam and South-west China with a population of about 2,000 individuals. Conservation efforts are hampered by limited knowledge of habitat preference in its main distribution area. We surveyed the distribution of Francois' langur and modeled the relationship between the probability of use and habitat features in Mayanghe National Nature Reserve, Guizhou, China. The main objectives of this study were to provide quantitative information on habitat preference, estimating the availability of suitable habitat, and providing management guidelines for the effective conservation of this species. By comparing 92 used locations with habitat available in the reserve, we found that Francois' langur was mainly distributed along valleys and proportionally, used bamboo forests and mixed conifer-broadleaf forests more than their availability, whereas they tended to avoid shrubby areas and coniferous forests. The langur tended to occur at sites with lower elevation, steeper slope, higher tree canopy density, and a close distance to roads and water. The habitat occupancy probability was best modeled by vegetation type, vegetation coverage, elevation, slope degree, distances to nearest water, paved road, and farmland edge. The suitable habitat in this reserve concentrated in valleys and accounted for about 25% of the total reserve area. Our results showed that Francois' langur was not only restricted at the landscapes level at the regions with karst topography, limestone cliffs, and caves, but it also showed habitat preference at the local scale. Therefore, the protection and restoration of the langur preferred habitats such as mixed conifer-broadleaf forests are important and urgent for the conservation of this declining species.

  1. Monsoonal influence on variation of hydrochemistry and isotopic signatures: Implications for associated arsenic release in groundwater

    Science.gov (United States)

    Majumder, Santanu; Datta, Saugata; Nath, Bibhash; Neidhardt, Harald; Sarkar, Simita; Roman-Ross, Gabriela; Berner, Zsolt; Hidalgo, Manuela; Chatterjee, Debankur; Chatterjee, Debashis

    2016-04-01

    The present study examines the groundwater and surface water geochemistry of two different geomorphic domains within the Chakdaha block, West Bengal, in an attempt to decipher potential influences of groundwater abstraction on the hydrochemical evolution of the aquifer, the effect of different water inputs (monsoon rain, irrigation and downward percolation from surface water impoundments) to the groundwater system and concomitant As release. A low-land flood plain and a natural levee have been selected for this purpose. Although the stable isotopic signatures of oxygen (δ18O) and hydrogen (δ2H) are largely controlled by local precipitation, the isotopic composition falls sub-parallel to the Global Meteoric Water Line (GMWL). The Cl/Br molar ratio indicates vertical recharge into the wells within the flood plain area, especially during the post-monsoon season, while influences of both evaporation and vertical mixing are visible within the natural levee wells. Increase in mean DOC concentrations (from 1.33 to 6.29 mg/L), from pre- to post-monsoon season, indicates possible inflow of organic carbon to the aquifer during the monsoonal recharge. Concomitant increase in AsT, Fe(II) and HCO3- highlights a possible initial episode of reductive dissolution of As-rich Fe-oxyhydroxides. The subsequent sharp increase in the mean As(III) proportions (by 223%), particularly in the flood plain samples during the post-monsoon season, which is accompanied by a slight increase in mean AsT (7%) may refer to anaerobic microbial degradation of DOC coupled with the reduction of As(V) to As(III) without triggering additional As release from the aquifer sediments.

  2. Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study

    Science.gov (United States)

    Gottlieb, Daniel J.; Hek, Karin; Chen, Ting-hsu; Watson, Nathaniel F.; Eiriksdottir, Gudny; Byrne, Enda M.; Cornelis, Marilyn; Warby, Simon C.; Bandinelli, Stefania; Cherkas, Lynn; Evans, Daniel S.; Grabe, Hans J.; Lahti, Jari; Li, Man; Lehtimäki, Terho; Lumley, Thomas; Marciante, Kristin D.; Pérusse, Louis; Psaty, Bruce M.; Robbins, John; Tranah, Gregory J.; Vink, Jacqueline M.; Wilk, Jemma B.; Stafford, Jeanette M.; Bellis, Claire; Biffar, Reiner; Bouchard, Claude; Cade, Brian; Curhan, Gary C.; Eriksson, Johan G.; Ewert, Ralf; Ferrucci, Luigi; Fülöp, Tibor; Gehrman, Philip R.; Goodloe, Robert; Harris, Tamara B.; Heath, Andrew C.; Hernandez, Dena; Hofman, Albert; Hottenga, Jouke-Jan; Hunter, David J.; Jensen, Majken K.; Johnson, Andrew D.; Kähönen, Mika; Kao, Linda; Kraft, Peter; Larkin, Emma K.; Lauderdale, Diane S.; Luik, Annemarie I.; Medici, Marco; Montgomery, Grant W.; Palotie, Aarno; Patel, Sanjay R.; Pistis, Giorgio; Porcu, Eleonora; Quaye, Lydia; Raitakari, Olli; Redline, Susan; Rimm, Eric B.; Rotter, Jerome I.; Smith, Albert V.; Spector, Tim D.; Teumer, Alexander; Uitterlinden, André G.; Vohl, Marie-Claude; Widen, Elisabeth; Willemsen, Gonneke; Young, Terry; Zhang, Xiaoling; Liu, Yongmei; Blangero, John; Boomsma, Dorret I.; Gudnason, Vilmundur; Hu, Frank; Mangino, Massimo; Martin, Nicholas G.; O’Connor, George T.; Stone, Katie L.; Tanaka, Toshiko; Viikari, Jorma; Gharib, Sina A.; Punjabi, Naresh M.; Räikkönen, Katri; Völzke, Henry; Mignot, Emmanuel; Tiemeier, Henning

    2015-01-01

    Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35–80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 ×10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease. PMID:25469926

  3. Genome-wide association study of autistic-like traits in a general population study of young adults.

    Science.gov (United States)

    Jones, Rachel Maree; Cadby, Gemma; Melton, Phillip E; Abraham, Lawrence J; Whitehouse, Andrew J; Moses, Eric K

    2013-01-01

    Lay abstract: It has been proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD), representing the extreme end of this distribution. The current study undertook a genome-wide association (GWA) scan of 965 young Western Australian adults to identify novel risk variants associated with autistic-like traits. No associations reached genome-wide significance; however, a review of nominally associated single nucleotide polymorphisms (SNPs) indicated two positional candidate loci that have been previously implicated in autistic-like trait etiology. Scientific abstract: Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A GWA study using 2,462,046 SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine) Study. No SNP associations reached genome-wide significance (p CBLN1. The rs198198 SNP (p = 9.587 × 10(-6)), is located within an intron of the protein kinase C, beta 1 (PRKCB1) gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 × 10(-6)) is located in a region flanking the Cerebellin 1 (CBLN1) gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.

  4. Molecular sequences derived from Paleocene Fort Union Formation coals vs. associated produced waters: Implications for CBM regeneration

    Science.gov (United States)

    Klein, Donald A.; Flores, Romeo M.; Venot, Christophe; Gabbert, Kendra; Schmidt, Raleigh; Stricker, Gary D.; Pruden, Amy; Mandernack, Kevin

    2008-01-01

    Coalbed methane regeneration is of increasing interest, and is gaining global attention with respect to enhancement of gas recovery. The objective of this study is to determine if there are differences in methanogen nucleic acid sequences associated with low rank coals from the Powder River Basin, Wyoming, in comparison with sequences that can be recovered from coal bed-associated produced waters. Based on results obtained to date, the sequences from the coals appear to be associated with putatively deep-rooted thermophilic autotrophic methanogens, whereas the sequences from the waters are associated with thermophilic autotrophic and heterotrophic methanogens. The recovered sequences associated with coal thus appear to be both phylogenetically and functionally distinct from those that are more closely associated with the produced water. To be able to relate such recovered sequences to organisms that might be present and possibly active in these environments, it is suggested that direct observation, followed by isolation and single cell-based physiological/molecular analyses, be used to characterize methanogenic consortia possibly associated with coals and/or produced waters. It is also important to characterize the microenvironment where these microbes might be found, in both ecological and geological contexts, to be able to develop effective, ecologically relevant coalbed methane regeneration processes.

  5. Proactive interference and concurrent inhibitory processes do not differentially affect item and associative recognition: Implication for the age-related associative memory deficit.

    Science.gov (United States)

    Guez, Jonathan; Naveh-Benjamin, Moshe

    2016-09-01

    Previous studies have suggested an associative deficit hypothesis [Naveh-Benjamin, M. ( 2000 ). Adult age differences in memory performance: Tests of an associative deficit hypothesis. Journal of Experimental Psychology: Learning, Memory, and Cognition, 26, 1170-1187] to explain age-related episodic memory declines. The hypothesis attributes part of the deficient episodic memory performance in older adults to a difficulty in creating and retrieving cohesive episodes. In this article, we further evaluate this hypothesis by testing two alternative processes that potentially mediate associative memory deficits in older adults. Four experiments are presented that assess whether failure of inhibitory processes (proactive interference in Experiments 1 and 2), and concurrent inhibition (in Experiments 3 and 4) are mediating factors in age-related associative deficits. The results suggest that creating conditions that require the operation of inhibitory processes, or that interfere with such processes, cannot simulate associative memory deficit in older adults. Instead, such results support the idea that associative memory deficits reflect a unique binding failure in older adults. This failure seems to be independent of other cognitive processes, including inhibitory and other resource-demanding processes.

  6. Longitudinal Prediction of the One-Year Course of Preschool ADHD Symptoms: Implications for Models of Temperament-ADHD Associations.

    Science.gov (United States)

    Martel, Michelle M; Gremillion, Monica L; Roberts, Bethan A; Zastrow, Brittany L; Tackett, Jennifer L

    2014-07-01

    Despite the fact that Attention-Deficit/Hyperactivity Disorder (ADHD) is often conceptualized as an extreme trait, there remains controversy about the best way to understand associations between temperament traits and ADHD. The current study examines longitudinal associations between temperament traits and ADHD during early childhood in order to critically examine vulnerability and spectrum models of trait-ADHD associations. Study participants were 109 children between the ages of 3 and 6 and their primary caregivers and teachers/daycare providers, community-recruited for ADHD-related problems. Primary caregivers completed the Kiddie Disruptive Behavior Disorders Schedule semi-structured diagnostic interview at the initial appointment and one year later. At the initial appointment, primary caregivers completed the Child Behavior Questionnaire as a measure of child temperament traits. Results from the initial time point indicated that high neuroticism and high surgency were associated with inattentive and hyperactive-impulsive ADHD symptoms, and low effortful control was associated with hyperactive-impulsive ADHD symptoms. However, none of these traits predicted the one-year course of ADHD symptoms. Results are more consistent with a spectrum (vs. vulnerability) model of trait-psychopathology associations, suggesting that traits, but may not influence longitudinal course during early childhood.

  7. Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment

    Directory of Open Access Journals (Sweden)

    Boscarino JA

    2012-03-01

    interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.Keywords: posttraumatic stress disorder, genetic association study, single nucleotide polymorphism, risk alleles, trauma exposure, neuroticism, childhood adversity

  8. Associations of postural knowledge and basic motor skill with dyspraxia in autism: implication for abnormalities in distributed connectivity and motor learning.

    Science.gov (United States)

    Dowell, Lauren R; Mahone, E Mark; Mostofsky, Stewart H

    2009-09-01

    Children with autism often have difficulty performing skilled movements. Praxis performance requires basic motor skill, knowledge of representations of the movement (mediated by parietal regions), and transcoding of these representations into movement plans (mediated by premotor circuits). The goals of this study were (a) to determine whether dyspraxia in autism is associated with impaired representational ("postural") knowledge and (b) to examine the contributions of postural knowledge and basic motor skill to dyspraxia in autism. Thirty-seven children with autism spectrum disorder (ASD) and 50 typically developing (TD) children, ages 8-13, completed (a) an examination of basic motor skills, (b) a postural knowledge test assessing praxis discrimination, and (c) a praxis examination. Children with ASD showed worse basic motor skill and postural knowledge than did controls. The ASD group continued to show significantly poorer praxis than did controls after accounting for age, IQ, basic motor skill, and postural knowledge. Dyspraxia in autism appears to be associated with impaired formation of spatial representations, as well as transcoding and execution. Distributed abnormality across parietal, premotor, and motor circuitry, as well as anomalous connectivity, may be implicated.

  9. Ambivalent implications of health care information systems: a study in the Brazilian public health care system

    Directory of Open Access Journals (Sweden)

    João Porto de Albuquerque

    2011-01-01

    Full Text Available This article evaluates social implications of the "SIGA" Health Care Information System (HIS in a public health care organization in the city of São Paulo. The evaluation was performed by means of an in-depth case study with patients and staff of a public health care organization, using qualitative and quantitative data. On the one hand, the system had consequences perceived as positive such as improved convenience and democratization of specialized treatment for patients and improvements in work organization. On the other hand, negative outcomes were reported, like difficulties faced by employees due to little familiarity with IT and an increase in the time needed to schedule appointments. Results show the ambiguity of the implications of HIS in developing countries, emphasizing the need for a more nuanced view of the evaluation of failures and successes and the importance of social contextual factors.

  10. Reference group theory with implications for information studies: a theoretical essay

    Directory of Open Access Journals (Sweden)

    E. Murell Dawson

    2001-01-01

    Full Text Available This article explores the role and implications of reference group theory in relation to the field of library and information science. Reference group theory is based upon the principle that people take the standards of significant others as a basis for making self-appraisals, comparisons, and choices regarding need and use of information. Research that applies concepts of reference group theory to various sectors of library and information studies can provide data useful in enhancing areas such as information-seeking research, special populations, and uses of information. Implications are promising that knowledge gained from like research can be beneficial in helping information professionals better understand the role theory plays in examining ways in which people manage their information and social worlds.

  11. A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness

    Science.gov (United States)

    Lynch, Shannon M.; Mitra, Nandita; Ross, Michelle; Newcomb, Craig; Dailey, Karl; Jackson, Tara; Zeigler-Johnson, Charnita M.; Riethman, Harold; Branas, Charles C.; Rebbeck, Timothy R.

    2017-01-01

    Purpose Cancer results from complex interactions of multiple variables at the biologic, individual, and social levels. Compared to other levels, social effects that occur geospatially in neighborhoods are not as well-studied, and empiric methods to assess these effects are limited. We propose a novel Neighborhood-Wide Association Study(NWAS), analogous to genome-wide association studies(GWAS), that utilizes high-dimensional computing approaches from biology to comprehensively and empirically identify neighborhood factors associated with disease. Methods Pennsylvania Cancer Registry data were linked to U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood (n = 14,663 census variables) and prostate cancer aggressiveness(PCA) with n = 6,416 aggressive (Stage≥3/Gleason grade≥7 cases) vs. n = 70,670 non-aggressive (Stagehousing, employment, immigration, access to care, and social support. The top hits or most significant variables related to transportation (OR = 1.05;CI = 1.001–1.09) and poverty (OR = 1.07;CI = 1.01–1.12). Conclusions This study introduces the application of high-dimensional, computational methods to large-scale, publically-available geospatial data. Although NWAS requires further testing, it is hypothesis-generating and addresses gaps in geospatial analysis related to empiric assessment. Further, NWAS could have broad implications for many diseases and future precision medicine studies focused on multilevel risk factors of disease. PMID:28346484

  12. Implications of Ocean Acidification for Marine Microorganisms from the Free-Living to the Host-Associated

    Directory of Open Access Journals (Sweden)

    Paul A O'Brien

    2016-04-01

    Full Text Available Anthropogenic CO2 emissions are causing oceans to become more acidic, with consequences for all marine life including microorganisms. Studies reveal that from the microbes that occupy the open ocean to those intimately associated with their invertebrate hosts, changing ocean chemistry will alter the critical functions of these important organisms. Our current understanding indicates that bacterial communities associated with their host will shift as pH drops by another 0.2-0.4 units over the next 100 years. It is unclear what impacts this will have for host health, however increased vulnerability to disease seems likely for those associated with reef corals. Natural CO2 seeps have provided a unique setting for the study of microbial communities under OA in situ, where shifts in the bacterial communities associated with corals at the seep are correlated with a decline in abundance of the associated coral species. Changes to global biogeochemical cycles also appear likely as photosynthesis and nitrogen fixation by pelagic microbes becomes enhanced under low pH conditions. However, recent long-term studies have shown that pelagic microbes are also capable of evolutionary adaptation, with some physiological responses to a decline in pH restored after hundreds of generations at high pCO2 levels. The impacts of ocean acidification (OA also will not work in isolation, thus synergistic interactions with other potential stressors, such as rising seawater temperatures, will likely exacerbate the microbial response to OA. This review discusses our existing understanding of the impacts of OA on both pelagic and host-associated marine microbial communities, whilst highlighting the importance of controlled laboratory studies and in situ experiments, to fill the current gaps in our knowledge.

  13. Contribution of phytoliths to total biogenic silica volumes in the tropical rivers of Malaysia and associated implications for the marine biogeochemical cycle

    Science.gov (United States)

    Zang, Jiaye; Liu, Sen; Liu, Yanguang; Ma, Yongxing; Ran, Xiangbin

    2016-09-01

    The contribution of phytoliths to total biogenic silica (BSi) volumes in rivers worldwide, and the associated implications for the biogeochemical cycle, require in-depth study. Based on samples from rivers in Peninsular Malaysia, this project investigated the source and characteristics of BSi found in Asian tropical rivers, as well as the process of reverse weathering taking place in these fluvial systems. Results indicated that BSi samples collected in sediments consisted of phytolith, diatom and sponge spicules. Phytoliths, predominantly of the elongate form, comprised 92.8%-98.3% of BSi in the Pahang River. Diatom BSi in this river consisted mainly of pennatae diatoms, but represented a relatively small proportion of the total BSi volume. However, diatom BSi (predominantly of the Centricae form) was more prevalent in the Pontian and Endau Rivers with shares of 68.8% and 79.3% of the total BSi volumes, respectively, than Pahang River. Carbon contents of the BSi particulates ranged from 1.85% to 10.8% with an average of 4.79%. These values are higher than those recorded in other studies to date, and indicate that BSi plays a major role in controlling permanent carbon burial. This study suggests that phytoliths from terrestrial plants are the primary constituents of BSi in the rivers of Peninsular Malaysia, and therefore represent a significant proportion of the coastal silica budget.

  14. Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis

    Science.gov (United States)

    Pasanen, Anu; Karjalainen, Minna K.; Bont, Louis; Piippo-Savolainen, Eija; Ruotsalainen, Marja; Goksör, Emma; Kumawat, Kuldeep; Hodemaekers, Hennie; Nuolivirta, Kirsi; Jartti, Tuomas; Wennergren, Göran; Hallman, Mikko; Rämet, Mika; Korppi, Matti

    2017-01-01

    Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genome-wide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish–Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p bronchiolitis. These preliminary findings require further validation in a larger sample size. PMID:28139761

  15. Genome-wide association study of clinical dimensions of schizophrenia

    DEFF Research Database (Denmark)

    Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H;

    2012-01-01

    Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia....

  16. Current approaches of genome-wide association studies

    Institute of Scientific and Technical Information of China (English)

    Jianfeng Xu

    2008-01-01

    @@ With rapid advances in high-throughput genotyping technology and the great increase in information available on SNPs throughout the genuine, genuine-wide association(GWA) studies have now become feasible.

  17. Association between erectile dysfunction and chronic periodontitis: A clinical study

    Directory of Open Access Journals (Sweden)

    Ranjit Singh Uppal

    2014-01-01

    Conclusion: It may be concluded that chronic periodontitis and ED are associated with each other. However, further large scale studies with confounder analysis and longitudinal follow-up are warranted to explore the link between these two diseases.

  18. Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging.

    Science.gov (United States)

    Wheeler, Heather E; Metter, E Jeffrey; Tanaka, Toshiko; Absher, Devin; Higgins, John; Zahn, Jacob M; Wilhelmy, Julie; Davis, Ronald W; Singleton, Andrew; Myers, Richard M; Ferrucci, Luigi; Kim, Stuart K

    2009-10-01

    Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6 x 10(-5), empirical p = 0.01) that explains 1%-2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.

  19. Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging.

    Directory of Open Access Journals (Sweden)

    Heather E Wheeler

    2009-10-01

    Full Text Available Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR using combined data from the Baltimore Longitudinal Study of Aging (BLSA and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20 with kidney aging (uncorrected p = 3.6 x 10(-5, empirical p = 0.01 that explains 1%-2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.

  20. Do Emotional Eating Urges Regulate Affect? Concurrent and Prospective Associations and Implications for Risk Models of Binge Eating

    Science.gov (United States)

    Haedt-Matt, Alissa A.; Keel, Pamela K.; Racine, Sarah E.; Burt, S. Alexandra; Hu, Jean Yueqin; Boker, Steven; Neale, Michael; Klump, Kelly L.

    2014-01-01

    Objective Emotional eating (EE) reflects an urge to eat in response to emotional rather than physical cues and is a risk factor for the development of binge eating. EE has been conceptualized as an attempt to regulate negative affect (NA), a posited maintenance factor for binge eating. However, no study has examined whether EE urges regulate affect. Further, no studies have examined longitudinal associations between EE urges and positive affect (PA). Method We examined within-subject longitudinal associations between affect and EE urges in a community-based sample of female twins (mean age=17.8 years). Participants (N=239) completed ratings of affect and EE urges for 45 consecutive days. Results Greater NA was concurrently associated with greater EE urges. Additionally, greater EE urges predicted worse NA for both concurrent and prospective (next-day) analyses. Finally, lower PA was associated with greater EE urges in concurrent analyses, but there were no prospective associations between changes in PA and EE urges. Discussion EE urges do not appear to effectively regulate affect. EE urges in a community-based sample appears to have the same functional relationship with affect as binge eating in clinical samples, further supporting EE as a useful dimensional construct for examining processes related to binge eating. PMID:24431328

  1. Genome-wide association studies and contribution to cardiovascular physiology.

    Science.gov (United States)

    Munroe, Patricia B; Tinker, Andrew

    2015-09-01

    The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology.

  2. Genome-wide association study of pancreatic cancer in Japanese population.

    Directory of Open Access Journals (Sweden)

    Siew-Kee Low

    Full Text Available Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7 with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7, 3.30x10(-7, and 4.41x10(-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.

  3. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

    Science.gov (United States)

    Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; M. Maloney, Cliona; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P.R.; Mehta, Amar; van Iperen, Erik P.A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M.A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; Boer, Anthonius de; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goel, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Qing; Kleber, Marcus E.; Klein, Barbara E.K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshall, Vanessa; Melander, Olle; Mentch, Frank D.; J. Meyer, Nuala; Monda, Keri L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondahl, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszweski, Maciej; Verschuren, W.M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I.W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; D. Christie, Jason; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; März, Winfried; O'Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Grant, Struan F.A.; Munroe, Patricia B.; North, Kari E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.

    2011-01-01

    Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. PMID:21194676

  4. A genome-wide association analysis implicates SOX6 as a candidate gene for wrist bone mass

    Institute of Scientific and Technical Information of China (English)

    Shawn; LEVY

    2010-01-01

    Osteoporosis is a highly heritable common bone disease leading to fractures that severely impair the life quality of patients.Wrist fractures caused by osteoporosis are largely due to the scarcity of wrist bone mass.Here we report the results of a genome-wide association study (GWAS) of wrist bone mineral density (BMD).We examined ~500000 SNP markers in 1000 unrelated homogeneous Caucasian subjects and found a novel allelic association with wrist BMD at rs11023787 in the SOX6 (SRY (sex determining region Y)-box 6) gene (P=9.00×10-5).Subjects carrying the C allele of rs11023787 in SOX6 had significantly higher mean wrist BMD values than those with the T allele (0.485:0.462 g cm-2 for C allele vs.T allele carriers).For validation,we performed SOX6 association for BMD in an independent Chinese sample and found that SNP rs11023787 was significantly associated with wrist BMD in the Chinese sample (P=6.41×10-3).Meta-analyses of the GWAS scan and the replication studies yielded P-values of 5.20×10-6 for rs11023787.Results of this study,together with the functional relevance of SOX6 in cartilage formation,support the SOX6 gene as an important gene for BMD variation.

  5. Genetic association studies in lumbar disc degeneration: a systematic review.

    Directory of Open Access Journals (Sweden)

    Pasi J Eskola

    Full Text Available OBJECTIVE: Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI in humans. METHODS: A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990-2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines. RESULTS: Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat, COL11A1 (rs1676486, GDF5 (rs143383, SKT (rs16924573, THBS2 (rs9406328 and MMP9 (rs17576. CONCLUSIONS: Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.

  6. Genome-wide association study of serum selenium concentrations

    DEFF Research Database (Denmark)

    Gong, Jian; Hsu, Li; Harrison, Tabitha

    2013-01-01

    Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated...... this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We...... tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p

  7. SNP CHARACTERISTICS PREDICT REPLICATION SUCCESS IN ASSOCIATION STUDIES

    Science.gov (United States)

    Gorlov, Ivan P.; Moore, Jason H.; Peng, Bo; Jin, Jennifer L.; Gorlova, Olga Y.; Amos, Christopher I.

    2014-01-01

    Successful independent replication is the most direct approach for distinguishing real genotype-disease associations from false discoveries in Genome Wide Association Studies (GWAS). Selecting SNPs for replication has been primarily based on p-values from the discovery stage, although additional characteristics of SNPs may be used to improve replication success. We used disease-associated SNPs from more than 2,000 published GWASs to identify predictors of SNP reproducibility. SNP reproducibility was defined as a proportion of successful replications among all replication attempts. The study reporting association for the first time was considered to be discovery and all consequent studies targeting the same phenotype replications. We found that −Log(P), where P is a p-value from the discovery study, is the strongest predictor of the SNP reproducibility. Other significant predictors include type of the SNP (e.g. missense vs intronic SNPs) and minor allele frequency. Features of the genes linked to the disease-associated SNP also predict SNP reproducibility. Based on empirically defined rules, we developed a reproducibility score (RS) to predict SNP reproducibility independently of −Log(P). We used data from two lung cancer GWAS studies as well as recently reported disease-associated SNPs to validate RS. Minus Log(P) outperforms RS when the very top SNPs are selected, while RS works better with relaxed selection criteria. In conclusion, we propose an empirical model to predict SNP reproducibility, which can be used to select SNPs for validation and prioritization. PMID:25273843

  8. Delayed gastric emptying is associated with pylorus-preserving but not classical Whipple pancreaticoduodenectomy: A review of the literature and critical reappraisal of the implicated pathomechanism

    Institute of Scientific and Technical Information of China (English)

    Kosmas I Paraskevas; Costas Avgerinos; Costas Manes; Dimitris Lytras; Christos Dervenis

    2006-01-01

    Pylorus-preserving pancreaticoduodenectomy (PPPD)is nowadays considered the treatment of choice for periampullary tumors, namely carcinoma of the head,neck, or uncinate process of the pancreas, the ampulla of Vater, distal common bile duct or carcinoma of the peri-Vaterian duodenum. Delayed gastric emptying (DGE)comprises one of the most troublesome complications of this procedure. A search of the literature using Pubmed/Medline was performed to identify clinical trials examining the incidence rate of DGE following standard Whipple pancreaticoduodenectomy (PD) vs PPPD. Additionally we performed a thorough in-depth analysis of the implicated pathomechanism underlying the occurrence of DGE after PPPD. In contrast to early studies, the majority of recently performed clinical trials demonstrated no significant association between the occurrence of DGE with either PD or PPPD. PD and PPPD procedures are equally effective operations regarding the postoperative occurrence of DGE. Further randomized trials are required to investigate the efficacy of a recently reported (but not yet tested in largescale studies) modification, that is, PPPD with antecolic duodenojejunostomy.(C) 2006 The WJG Press. All rights reserved.

  9. Associations between ectomycorrhizal fungi and bacterial needle endophytes in Pinus radiata: implications for biotic selection of microbial communities

    Directory of Open Access Journals (Sweden)

    Megan Arlene Rúa

    2016-03-01

    Full Text Available Studies of the ecological and evolutionary relationships between plants and their associated microbes have long been focused on single microbes, or single microbial guilds, but in reality, plants associate with a diverse array of microbes from a varied set of guilds. As such, multitrophic interactions among plant-associated microbes from multiple guilds represent an area of developing research, and can reveal how complex microbial communities are structured around plants. Interactions between coniferous plants and their associated microbes provide a good model system for such studies, as conifers host a suite of microorganisms including mutualistic ectomycorrhizal (ECM fungi and foliar bacterial endophytes. To investigate the potential role ECM fungi play in structuring foliar bacterial endophyte communities, we sampled three isolated, native populations of Monterey pine (Pinus radiata, and used constrained analysis of principal coordinates to relate the community matrices of the ECM fungi and bacterial endophytes. Our results suggest that ECM fungi may be important factors for explaining variation in bacterial endophyte communities but this effect is influenced by population and environmental characteristics, emphasizing the potential importance of other factors — biotic or abiotic — in determining the composition of bacterial communities. We also classified ECM fungi into categories based on known fungal traits associated with substrate exploration and nutrient mobilization strategies since variation in these traits allows the fungi to acquire nutrients across a wide range of abiotic conditions and may influence the outcome of multi-species interactions. Across populations and environmental factors, none of the traits associated with fungal foraging strategy types significantly structured bacterial assemblages, suggesting these ECM fungal traits are not important for understanding endophyte-ECM interactions. Overall, our results suggest

  10. Worrying affects associative fear learning: a startle fear conditioning study.

    Directory of Open Access Journals (Sweden)

    Femke J Gazendam

    Full Text Available A valuable experimental model for the pathogenesis of anxiety disorders is that they originate from a learned association between an intrinsically non-aversive event (Conditioned Stimulus, CS and an anticipated disaster (Unconditioned Stimulus, UCS. Most anxiety disorders, however, do not evolve from a traumatic experience. Insights from neuroscience show that memory can be modified post-learning, which may elucidate how pathological fear can develop after relatively mild aversive events. Worrying--a process frequently observed in anxiety disorders--is a potential candidate to strengthen the formation of fear memory after learning. Here we tested in a discriminative fear conditioning procedure whether worry strengthens associative fear memory. Participants were randomly assigned to either a Worry (n = 23 or Control condition (n = 25. After fear acquisition, the participants in the Worry condition processed six worrisome questions regarding the personal aversive consequences of an electric stimulus (UCS, whereas the Control condition received difficult but neutral questions. Subsequently, extinction, reinstatement and re-extinction of fear were tested. Conditioned responding was measured by fear-potentiated startle (FPS, skin conductance (SCR and UCS expectancy ratings. Our main results demonstrate that worrying resulted in increased fear responses (FPS to both the feared stimulus (CS(+ and the originally safe stimulus (CS(-, whereas FPS remained unchanged in the Control condition. In addition, worrying impaired both extinction and re-extinction learning of UCS expectancy. The implication of our findings is that they show how worry may contribute to the development of anxiety disorders by affecting associative fear learning.

  11. Free Associations Mirroring Self- and World-Related Concepts: Implications for Personal Construct Theory, Psycholinguistics and Philosophical Psychology.

    Science.gov (United States)

    Kuška, Martin; Trnka, Radek; Kuběna, Aleš A; Růžička, Jiří

    2016-01-01

    People construe reality by using words as basic units of meaningful categorization. The present theory-driven study applied the method of a free association task to explore how people express the concepts of the world and the self in words. The respondents were asked to recall any five words relating with the word world. Afterward they were asked to recall any five words relating with the word self. The method of free association provided the respondents with absolute freedom to choose any words they wanted. Such free recall task is suggested as being a relatively direct approach to the respondents' self- and world-related conceptual categories, without enormous rational processing. The results provide us, first, with associative ranges for constructs of the world and the self, where some associative dimensions are defined by semantic polarities in the meanings of peripheral categories (e.g., Nature vs. Culture). Second, our analysis showed that some groups of verbal categories that were associated with the words world and self are central, while others are peripheral with respect to the central position. Third, the analysis of category networks revealed that some categories play the role of a transmitter, mediating the pathway between other categories in the network.

  12. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

    Directory of Open Access Journals (Sweden)

    Hwang Shih-Jen

    2007-09-01

    recently reported genome-wide association studies. In linkage analyses, several regions of genome-wide linkage were noted, confirming previously reported linkage of internal carotid artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Conclusion The results from this GWAS generate hypotheses regarding several SNPs that may be associated with SCA phenotypes in multiple arterial beds. Given the number of tests conducted, subsequent independent replication in a staged approach is essential to identify genetic variants that may be implicated in atherosclerosis.

  13. Prediction of disease and phenotype associations from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Stephanie N Lewis

    Full Text Available BACKGROUND: Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. METHODOLOGY/PRINCIPAL FINDINGS: Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. CONCLUSIONS/SIGNIFICANCE: The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

  14. Association between cancer and contact allergy: a linkage study

    DEFF Research Database (Denmark)

    Engkilde, Kaare; Thyssen, Jacob P; Menné, Torkil;

    2011-01-01

    and cancer, few have looked into the association between cancer and contact allergy, a type IV allergy. By linking two clinical databases, the authors investigate the possible association between contact allergy and cancer. Methods Record linkage of two different registers was performed: (1) a tertiary...... by logistic regression analysis. Results An inverse association between contact allergy and non-melanoma skin- and breast cancer, respectively, was identified in both sexes, and an inverse trend for brain cancer was found in women with contact allergy. Additionally, a positive association between contact......Background Contact allergy is a prevalent disorder. It is estimated that about 20% of the general population are allergic to one or more of the chemicals that constitute the European baseline patch test panel. While many studies have investigated associations between type I allergic disorders...

  15. Allelic association studies of genome wide association data can reveal errors in marker position assignments

    Directory of Open Access Journals (Sweden)

    Curtis David

    2007-06-01

    Full Text Available Abstract Background Genome wide association (GWA studies provide the opportunity to develop new kinds of analysis. Analysing pairs of markers from separate regions might lead to the detection of allelic association which might indicate an interaction between nearby genes. Methods 396,591 markers typed in 541 subjects were studied. 7.8*1010 pairs of markers were screened and those showing initial evidence for allelic association were subjected to more thorough investigation along with 10 flanking markers on either side. Results No evidence was detected for interaction. However 6 markers appeared to have an incorrect map position according to NCBI Build 35. One of these was corrected in Build 36 and 2 were dropped. The remaining 3 were left with map positions inconsistent with their allelic association relationships. Discussion Although no interaction effects were detected the method was successful in identifying markers with probably incorrect map positions. Conclusion The study of allelic association can supplement other methods for assigning markers to particular map positions. Analyses of this type may usefully be applied to data from future GWA studies.

  16. Emotion regulatory function of parent attention to child pain and associated implications for parental pain control behaviour.

    Science.gov (United States)

    Vervoort, Tine; Trost, Zina; Sütterlin, Stefan; Caes, Line; Moors, Agnes

    2014-08-01

    We investigated the function of parental attention to child pain in regulating parental distress and pain control behaviour when observing their child performing a painful (cold pressor) task (CPT); we also studied the moderating role of parental state anxiety. Participants were 62 schoolchildren and one of their parents. Parental attention towards or away from child pain (ie, attend to pain vs avoid pain) was experimentally manipulated during a viewing task pairing unfamiliar children's neutral and pain faces. Before and after the viewing task, parental distress regulation was assessed by heart rate (HR) and heart rate variability (HRV). In a subsequent phase, parents observed their own child perform a CPT task, allowing assessment of parental pain control behaviour (indexed by latency to stop their child's CPT performance) and parental distress, which was assessed via self-report before and after observation of child CPT performance. Eye tracking during the viewing task and self-reported attention to own child's pain confirmed successful attention manipulation. Further, findings indicated that the effect of attentional strategy on parental emotion regulation (indexed by HR, self-report) and pain control behaviour depended on parents' state anxiety. Specifically, whereas low anxious parents reported more distress and demonstrated more pain control behaviour in the Attend to Pain condition, high anxious parents reported more distress and showed more pain control behaviour in the Avoid Pain condition. This inverse pattern was likewise apparent in physiological distress indices (HR) in response to the initial viewing task. Theoretical/clinical implications and further research directions are discussed.

  17. Generalization of Rare Variant Association Tests for Longitudinal Family Studies.

    Science.gov (United States)

    Chien, Li-Chu; Hsu, Fang-Chi; Bowden, Donald W; Chiu, Yen-Feng

    2016-02-01

    Given the functional relevance of many rare variants, their identification is frequently critical for dissecting disease etiology. Functional variants are likely to be aggregated in family studies enriched with affected members, and this aggregation increases the statistical power to detect rare variants associated with a trait of interest. Longitudinal family studies provide additional information for identifying genetic and environmental factors associated with disease over time. However, methods to analyze rare variants in longitudinal family data remain fairly limited. These methods should be capable of accounting for different sources of correlations and handling large amounts of sequencing data efficiently. To identify rare variants associated with a phenotype in longitudinal family studies, we extended pedigree-based burden (BT) and kernel (KS) association tests to genetic longitudinal studies. Generalized estimating equation (GEE) approaches were used to generalize the pedigree-based BT and KS to multiple correlated phenotypes under the generalized linear model framework, adjusting for fixed effects of confounding factors. These tests accounted for complex correlations between repeated measures of the same phenotype (serial correlations) and between individuals in the same family (familial correlations). We conducted comprehensive simulation studies to compare the proposed tests with mixed-effects models and marginal models, using GEEs under various configurations. When the proposed tests were applied to data from the Diabetes Heart Study, we found exome variants of POMGNT1 and JAK1 genes were associated with type 2 diabetes.

  18. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

    Directory of Open Access Journals (Sweden)

    Rico Rueedi

    2014-02-01

    Full Text Available Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8 and independent associations between single nucleotide polymorphisms (SNP and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44 and lysine (rs8101881, P = 1.2×10(-33, respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

  19. Statistical trends in the Journal of the American Medical Association and implications for training across the continuum of medical education.

    Directory of Open Access Journals (Sweden)

    Lauren D Arnold

    Full Text Available BACKGROUND: Statistical training across the continuum of medical education may not have advanced at the pace of statistical reporting in the medical literature, yet a comprehensive understanding of statistical concepts most commonly presented in current research is critical to the effective practice of Evidence Based Medicine. The objective of this content analysis was to describe statistical techniques used in a leading medical journal, JAMA, across a 20-year period, with a focus on implications for medical education. METHODS AND FINDINGS: Two issues of JAMA published each month in 1990, 2000, and 2010 were randomly selected; from these, 361 articles were reviewed. Primary focus, study design, and statistical components were abstracted and examined by year of publication. The number of published RCTs and cohort studies differed significantly across years of interest, with an increasing trend of publication. The most commonly reported statistics over the 20-year period of interest included measures of morbidity and mortality, descriptive statistics, and epidemiologic outcomes. However, between 1990 and 2010, there was an increase in reporting of more advanced methods, such as multivariable regression, multilevel modeling, survival analysis, and sensitivity analysis. While this study is limited by a focus on one specific journal, a strength is that the journal examined is widely read by a range of clinical specialties and is considered a leading journal in the medical field, setting standards for published research. CONCLUSIONS: The increases in frequency and complexity of statistical reporting in the literature over the past two decades may suggest that moving beyond basic statistical concepts to a more comprehensive understanding of statistical methods is an important component of clinicians' ability to effectively read and use the medical research. These findings provide information to consider as medical schools and graduate medical education

  20. The implications of sex role identity and psychological capital for organisations: A South African study

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    Colleen Bernstein

    2016-04-01

    Full Text Available Orientation: A large body of research evidence indicates that both sex role identity (SRI and psychological capital (PsyCap may have critical implications for individual and organisational well-being. As SRI is constituted of sex-based personality traits it is possible that SRI may have implications for individuals’ PsyCap.Research purpose: The purpose of this study was to investigate the relationship between SRI and the positive psychological construct of PsyCap.Motivation for the study: Research on SRI and PsyCap has been explored independently of one another with a lack of research exploring the relationship between these two constructs. In addition, much of the previous research on SRI and organisational outcomes has only examined positive sex role identities, focusing almost exclusively on ‘positive’ or ‘socially desirable’ sex role identities. More recently, researchers have noted that this approach is theoretically and methodologically flawed, as it fails to account for negative traits or socially undesirable traits that may be contained within individuals’ SRI and which may have a number of deleterious implications for organisational outcome variables. Furthermore, there is a paucity of research within the South African context, which explores the adoption of positive and negative sexbased behavioural traits and their implications for PsyCap.Research design, approach and method: A quantitative study was conducted using a crosssectional design and a convenience sampling method to explore the relationship between SRI and PsyCap. Four hundred and seventy-eight respondents, all currently working in South African organisations, participated in this research. The composite questionnaire utilised for this research included a demographic questionnaire, The Extended Personal Attribute Questionnaire-Revised (EPAQ-R, and the PCQ-24 which measures PsyCap in terms of self-efficacy, hope, resilience and optimism.Main findings

  1. Tissue-specific genetic control of splicing: implications for the study of complex traits.

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    Erin L Heinzen

    2008-12-01

    Full Text Available Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.

  2. Power analysis for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Klein Robert J

    2007-08-01

    Full Text Available Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.

  3. Potential association of hyperhomocysteinemia with the progression of IgA nephropathy: a retrospective study

    Institute of Scientific and Technical Information of China (English)

    Duan Shuwei; Liu Shuwen; Sun Xuefeng; Zheng Ying; Liu Linchang; Yao Feixiang; Wu Jie

    2014-01-01

    Background The high blood homocysteine (Hcy) levels found in patients with hyperhomocysteinemia (HHcy) have been implicated in an increased risk of cardiovascular disease morbidity and mortality in end-stage renal disease (ESRD).This study investigated the association of HHcy with progression of IgA nephropathy.Methods We analyzed 108 participants newly diagnosed with IgA nephropathy between August 2005 and August 2007 in the Department of Nephrology,Chinese People's Liberation Army General Hospital.The association between clinicopathological factors and the Hcy levels were analyzed by Logistic regression and those with ESRD risk were analyzed by Cox regression.Results Patients were aged (35.71±10.73) years and included 45.71% women and 12.04% patients with HHcy.In multivariate Logistic regression analysis,HHcy was associated with arterial lesions (OR 2.60; 95% CI 1.55-4.34; P<0.001) even when age,body mass index,estimated glomerular filtration rate,mean arterial pressure,and initial proteinuria were taken into account.Mean follow-up was (67.37±16.21) months.HHcy was also associated with worse ESRD-free survival (HR 4.71; 95% CI 1.45 to 15.31; P=0.010).Conclusion HHcy is associated with the risk of intrarenal arterial lesions and may be useful for estimating the prognosis of IgA nephropathy.

  4. A genome-wide association study of copy number variations with umbilical hernia in swine.

    Science.gov (United States)

    Long, Yi; Su, Ying; Ai, Huashui; Zhang, Zhiyan; Yang, Bin; Ruan, Guorong; Xiao, Shijun; Liao, Xinjun; Ren, Jun; Huang, Lusheng; Ding, Nengshui

    2016-06-01

    Umbilical hernia (UH) is one of the most common congenital defects in pigs, leading to considerable economic loss and serious animal welfare problems. To test whether copy number variations (CNVs) contribute to pig UH, we performed a case-control genome-wide CNV association study on 905 pigs from the Duroc, Landrace and Yorkshire breeds using the Porcine SNP60 BeadChip and penncnv algorithm. We first constructed a genomic map comprising 6193 CNVs that pertain to 737 CNV regions. Then, we identified eight CNVs significantly associated with the risk for UH in the three pig breeds. Six of seven significantly associated CNVs were validated using quantitative real-time PCR. Notably, a rare CNV (CNV14:13030843-13059455) encompassing the NUGGC gene was strongly associated with UH (permutation-corrected P = 0.0015) in Duroc pigs. This CNV occurred exclusively in seven Duroc UH-affected individuals. SNPs surrounding the CNV did not show association signals, indicating that rare CNVs may play an important role in complex pig diseases such as UH. The NUGGC gene has been implicated in human omphalocele and inguinal hernia. Our finding supports that CNVs, including the NUGGC CNV, contribute to the pathogenesis of pig UH.

  5. Genome-wide association implicates numerous genes and pleiotropy underlying ecological trait variation in natural populations of Populus trichocarpa

    Energy Technology Data Exchange (ETDEWEB)

    McKown, Athena [University of British Columbia, Vancouver; Klapste, Jaroslav [University of British Columbia, Vancouver; Guy, Robert [University of British Columbia, Vancouver; Geraldes, Armando [University of British Columbia, Vancouver; Porth, Ilga [University of British Columbia, Vancouver; Hannemann, Jan [University of Victoria, Canada; Friedmann, Michael [University of British Columbia, Vancouver; Muchero, Wellington [ORNL; Tuskan, Gerald A [ORNL; Ehlting, Juergen [University of Victoria, Canada; Cronk, Quentin [University of British Columbia, Vancouver; El-Kassaby, Yousry [University of British Columbia, Vancouver; Mansfield, Shawn [University of British Columbia, Vancouver; Douglas, Carl [University of British Columbia, Vancouver

    2014-01-01

    To uncover the genetic basis of phenotypic trait variation, we used 448 unrelated wild accessions of black cottonwood (Populus trichocarpa Torr. & Gray) from natural populations throughout western North America. Extensive information from large-scale trait phenotyping (with spatial and temporal replications within a common garden) and genotyping (with a 34K Populus SNP array) of all accessions were used for gene discovery in a genome-wide association study (GWAS).

  6. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: Implications for HIV-1-associated neuropathology

    OpenAIRE

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E; Nawal M. Boukli; Xiong, Huangui

    2013-01-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human mon...

  7. An Exploratory Case Study of a Sexual Assault Telephone Hotline: Training and Practice Implications.

    Science.gov (United States)

    Colvin, Marianna L; Pruett, Jana A; Young, Stephen M; Holosko, Michael J

    2016-06-29

    Using archival data, this case study systematically examines telephone calls received by a regional sexual assault hotline in the Southeastern United States over a 5-year period. A stratified random sample (n = 383) reveals that hotline staff require diversity and depth in knowledge and skills, demonstrated by the hotline's primary use as a crisis service, combined with notable use by long-term survivors. Findings include the utility of the hotline by survivors and community stakeholders, categories of assault, the time gap between incidents occurring and contacting the hotline, call severity and urgency, and services and referrals provided. Implications for training, practice, and future research are discussed.

  8. Characterization of the Deleted in Autism 1 Protein Family: Implications for Studying Cognitive Disorders

    OpenAIRE

    Azhari Aziz; Harrop, Sean P.; Bishop, Naomi E.

    2011-01-01

    Autism spectrum disorders (ASDs) are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1) and cXorf36 or Deleted in Autism-1 Related (DIA1R) are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study D...

  9. Associations of heart failure with sleep quality: The rotterdam study

    NARCIS (Netherlands)

    L.A. Zuurbier (Lisette); A.I. Luik (Annemarie); M.J.G. Leening (Maarten); A. Hofman (Albert); R. Freak-Poli (Rosanne); O.H. Franco (Oscar); B.H. Stricker; H.W. Tiemeier (Henning)

    2015-01-01

    textabstractStudy Objectives: The prevalence of sleep disturbances and heart failure increases with age. We aimed to evaluate the associations of incident heart failure and cardiac dysfunction with changes in sleep quality. Methods: This prospective population-based study was conducted in the Rotter

  10. A genome-wide association study of anorexia nervosa

    NARCIS (Netherlands)

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, Annemarie; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countri

  11. MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer.

    Science.gov (United States)

    Torruella-Loran, Ignasi; Laayouni, Hafid; Dobon, Begoña; Gallego, Alicia; Balcells, Ingrid; Garcia-Ramallo, Eva; Espinosa-Parrilla, Yolanda

    2016-10-01

    Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine.

  12. Genome-Wide Association Studies of the Human Gut Microbiota.

    Directory of Open Access Journals (Sweden)

    Emily R Davenport

    Full Text Available The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both. These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%. For example, we identified an association between a taxon known to affect obesity (genus Akkermansia and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7. Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut.

  13. A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.

    Science.gov (United States)

    Ikeda, M; Takahashi, A; Kamatani, Y; Okahisa, Y; Kunugi, H; Mori, N; Sasaki, T; Ohmori, T; Okamoto, Y; Kawasaki, H; Shimodera, S; Kato, T; Yoneda, H; Yoshimura, R; Iyo, M; Matsuda, K; Akiyama, M; Ashikawa, K; Kashiwase, K; Tokunaga, K; Kondo, K; Saito, T; Shimasaki, A; Kawase, K; Kitajima, T; Matsuo, K; Itokawa, M; Someya, T; Inada, T; Hashimoto, R; Inoue, T; Akiyama, K; Tanii, H; Arai, H; Kanba, S; Ozaki, N; Kusumi, I; Yoshikawa, T; Kubo, M; Iwata, N

    2017-01-24

    Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10(-9)), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10(-10)), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10(-9)), TRANK1 (Pbest=2.1 × 10(-9)) and ODZ4 (Pbest=3.3 × 10(-9)). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10(-29), R(2)~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10(-13), R(2)~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.Molecular Psychiatry advance online publication, 24 January 2017; doi:10.1038/mp.2016.259.

  14. From Mental Game to Cultural Praxis: A Cultural Studies Model's Implications for the Future of Sport Psychology

    Science.gov (United States)

    Ryba, Tatiana V.; Wright, Handel Kashope

    2005-01-01

    This paper explores the implications of a cultural studies as praxis heuristic "model: for transforming sport psychology". It provides a brief introduction to both cultural studies and sport psychology and discusses a cultural studies intersection with sport studies and sport psychology. Cultural studies, it asserts, provides one of several…

  15. Long-Term Association Between Developmental Assets and Health Behaviors: An Exploratory Study.

    Science.gov (United States)

    Bleck, Jennifer; DeBate, Rita

    2016-10-01

    Introduction Based on internal and external assets, the positive youth development approach aims to increase the capacity among adolescents to overcome challenges as they transition to adulthood. Developmental assets have been found to be positively associated with academic achievement, a variety of health promoting behaviors, and improved physical and mental health. The purpose of this exploratory study was to assess the long-term association between positive youth developmental assets with health risk and promoting behaviors. Method A continuous scale of developmental assets was created using 30 items from Wave I of the National Longitudinal Study of Adolescent to Adult Health, when participants were in 7th to 12th grades. Health behavior outcomes including cigarette use, substance use, fast food consumption, and physical activity were measured at both Wave III (age 18-26) and Wave IV (age 24-32). Path analysis was employed to assess the relationship between these observed measures. Results The well-fitted path model revealed associations between developmental assets with each health behavior at Wave III. Developmental assets indirectly influenced each health behavior and direct associations were observed between assets with substance use and physical activity at Wave IV. Conclusion Findings provide additional support for the developmental assets approach to adolescent health. Implications include Healthy People 2020 objectives related to tobacco and alcohol use and nutrition and physical activity.

  16. Genetics of Myasthenia Gravis: A Case-Control Association Study in the Hellenic Population

    Directory of Open Access Journals (Sweden)

    Zoi Zagoriti

    2012-01-01

    Full Text Available Myasthenia gravis (MG is an heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5, TNFα-induced protein 3 (TNFAIP3, also known as A20, and interleukin-10 (IL-10, key molecules in the regulation of immune function. A statistical trend of association (P=0.068 between IL-10 promoter single nucleotide polymorphisms (SNPs and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG.

  17. The evolution of the European Union’s conception in the foreign policy discourse of Armenia: implications for U-turn and the path beyond the Association Agreement

    Directory of Open Access Journals (Sweden)

    Aram TERZYAN

    2016-12-01

    Full Text Available The question of why Armenia abruptly shifted from the Association Agreement (AA with the European Union (EU to the Russian-led Eurasian Economic Union (EEA has produced perplexing conclusions. Drawing on discourse analysis and semi-structured interviews, this study seeks to explain the evolution of the EU’s conception in foreign policy discourse of Armenia, delving into its implications for U-turn and the prospects of EU-Armenia further partnership. Departing from mainstream explanations, it argues that Armenia’s U-turn was preceded by marked disillusionment with the ‘expectation – capability’ gaps attributed to the Eastern Partnership (EaP. This has significantly influenced the EU’s conception in Armenia’s official discourse, shifting it from the notions of ‘normative’, ‘liberal’ and ‘status quo challenging’ power to ‘pragmatic’ actor and ‘political dwarf’. The paper concludes that a major breakthrough in bilateral ‘edited’ partnership cannot be expected anytime soon due to Armenia’s large - scale Eurasian integration and lower security expectations from the EU.

  18. Short-term Exposure to Microgravity and the Associated Risk of Sudden Cardiac Arrest: Implications for Commercial Spaceflight

    Science.gov (United States)

    Laing, Kevin J. C.; Russamono, Thais

    2013-02-01

    The likelihood of trained astronauts developing a life threatening cardiac event during spaceflight is relatively rare, whilst the incidence in untrained individuals is unknown. Space tourists who live a sedentary lifestyle have reduced cardiovascular function, but the associated danger of sudden cardiac arrest (SCA) during a suborbital spaceflight (SOSF) is unclear. Risk during SOSF was examined by reviewing several microgravity studies and methods of determining poor cardiovascular condition. Accurately assessing cardiovascular function and improving baroreceptor sensitivity through exercise is suggested to reduce the incidence of SCA during future SOSFs. Future studies will benefit from past participants sharing medical history; allowing creation of risk profiles and suitable guidelines.

  19. Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

    Science.gov (United States)

    Huang, Minjun; Graham, Britney E; Zhang, Ge; Harder, Reed; Kodaman, Nuri; Moore, Jason H; Muglia, Louis; Williams, Scott M

    2016-01-01

    Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with

  20. Genome-wide association study of circulating retinol levels.

    Science.gov (United States)

    Mondul, Alison M; Yu, Kai; Wheeler, William; Zhang, Hong; Weinstein, Stephanie J; Major, Jacqueline M; Cornelis, Marilyn C; Männistö, Satu; Hazra, Aditi; Hsing, Ann W; Jacobs, Kevin B; Eliassen, Heather; Tanaka, Toshiko; Reding, Douglas J; Hendrickson, Sara; Ferrucci, Luigi; Virtamo, Jarmo; Hunter, David J; Chanock, Stephen J; Kraft, Peter; Albanes, Demetrius

    2011-12-01

    Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10(-17)) and rs10882272 (P =6.04× 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10(-5)), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

  1. Planning and executing a genome wide association study (GWAS).

    Science.gov (United States)

    Sale, Michèle M; Mychaleckyj, Josyf C; Chen, Wei-Min

    2009-01-01

    In recent years, genome-wide association approaches have proven a powerful and successful strategy to identify genetic contributors to complex traits, including a number of endocrine disorders. Their success has meant that genome wide association studies (GWAS) are fast becoming the default study design for discovery of new genetic variants that influence a clinical trait or phenotype. This chapter focuses on a number of key elements that require consideration for the successful conduct of a GWAS. Although many of the considerations are common to any genetic study, the greater cost, extreme multiple testing, and greater openness to data sharing require specific awareness and planning by investigators. In the section on designing a GWAS, we reflect on ethical considerations, study design, selection of phenotype/s, power considerations, sample tracking and storage issues, and genotyping product selection. During execution, important considerations include DNA quantity and preparation, genotyping methods, quality control checks of genotype data, in silico genotyping (imputation), tests of association, and replication of association signals. Although the field of human genetics is rapidly evolving, recent experiences can help guide an investigator in making practical and methodological choices that will eventually determine the overall quality of GWAS results. Given the investment to recruit patient populations or cohorts that are powered for a GWAS, and the still substantial costs associated with genotyping, it is helpful to be aware of these aspects to maximize the likelihood of success, especially where there is an opportunity for implementing them prospectively.

  2. Recommendations for using standardised phenotypes in genetic association studies

    Directory of Open Access Journals (Sweden)

    Naylor Melissa G

    2009-07-01

    Full Text Available Abstract Genetic association studies of complex traits often rely on standardised quantitative phenotypes, such as percentage of predicted forced expiratory volume and body mass index to measure an underlying trait of interest (eg lung function, obesity. These phenotypes are appealing because they provide an easy mechanism for comparing subjects, although such standardisations may not be the best way to control for confounders and other covariates. We recommend adjusting raw or standardised phenotypes within the study population via regression. We illustrate through simulation that optimal power in both population- and family-based association tests is attained by using the residuals from within-study adjustment as the complex trait phenotype. An application of family-based association analysis of forced expiratory volume in one second, and obesity in the Childhood Asthma Management Program data, illustrates that power is maintained or increased when adjusted phenotype residuals are used instead of typical standardised quantitative phenotypes.

  3. Genome-wide association analysis of tolerance to methylmercury toxicity in Drosophila implicates myogenic and neuromuscular developmental pathways.

    Directory of Open Access Journals (Sweden)

    Sara L Montgomery

    Full Text Available Methylmercury (MeHg is a persistent environmental toxin present in seafood that can compromise the developing nervous system in humans. The effects of MeHg toxicity varies among individuals, despite similar levels of exposure, indicating that genetic differences contribute to MeHg susceptibility. To examine how genetic variation impacts MeHg tolerance, we assessed developmental tolerance to MeHg using the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP. We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86. To investigate the influence of dietary factors, we measured MeHg toxicity with caffeine supplementation in the DGRP lines. We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80. We performed genome-wide association (GWA analysis for both traits, and identified candidate genes that fall into several gene ontology categories, with enrichment for genes involved in muscle and neuromuscular development. Overexpression of glutamate-cysteine ligase, a MeHg protective enzyme, in a muscle-specific manner leads to a robust rescue of eclosion of flies reared on MeHg food. Conversely, mutations in kirre, a pivotal myogenic gene identified in our GWA analyses, modulate tolerance to MeHg during development in accordance with kirre expression levels. Finally, we observe disruptions of indirect flight muscle morphogenesis in MeHg-exposed pupae. Since the pathways for muscle development are evolutionarily conserved, it is likely that the effects of MeHg observed in Drosophila can be generalized across phyla, implicating muscle as an additional hitherto unrecognized target for MeHg toxicity. Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show

  4. Novel loci associated with usual sleep duration: The CHARGE Consortium Genome-Wide Association Study

    NARCIS (Netherlands)

    Gottlieb, D.J.; Hek, K.; Chen, T.H.; Watson, N.F.; Eiriksdottir, G.; Byrne, E.M.; Cornelis, M.; Warby, S.C.; Bandinelli, S.; Cherkas, L.; Evans, D.S.; Grabe, H.J.; Lahti, J.; Li, M.; Lehtimaki, T.; Lumley, T.; Marciante, K.D.; Pérusse, L.; Psaty, B.M.; Robbins, J.; Tranah, G.J.; Vink, J.M.; Wilk, J.B.; Stafford, J.M.; Bellis, C.; Biffar, R.; Bouchard, C.; Cade, B.; Curhan, G.C.; Eriksson, J.G.; Ewert, R.; Ferrucci, L.; Fulop, T.; Gehrman, P.R.; Goodloe, R.; Harris, T.B.; Heath, A.C.; Hernandez, D.G.; Hofman, A.; Hottenga, J.J.; Hunter, D.J.; Jensen, M.K.; Johnson, A.D.; Kahonen, M.; Kao, L.; Kraft, P.; Larkin, E.K.; Lauderdale, D.S.; Luik, A.I.; Medici, M.; Montgomery, G.W.; Palotie, A.; Patel, S.R.; Pistis, G.; Porcu, E.; Quaye, L.; Raitakari, O.; Redline, S.; Rimm, E.B.; Rotter, J.I.; Smith, A.V.; Spector, T.D.; Teumer, A.; Uitterlinden, A.G.; Vohl, M.C.; Widen, E.; Willemsen, G.; Young, T.; Zhang, X.; Liu, Y.; Blangero, J.; Boomsma, D.I.; Gudnason, V.; Hu, F.; Mangino, M.; Martin, N.G.; O'Connor, G.T.; Stone, K.L.; Tanaka, T.; Viikari, J.; Gharib, S.A.; Punjabi, N.M.; Raikkonen, K.; Völzke, H.; Mignot, E.; Tiemeier, H.

    2015-01-01

    Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based c

  5. Novel loci associated with usual sleep duration: The CHARGE Consortium Genome-Wide Association Study

    NARCIS (Netherlands)

    D.J. Gottlieb (Daniel J); K. Hek (Karin); T.-H. Chen; N.F. Watson; G. Eiriksdottir (Gudny); E.M. Byrne; M. Cornelis (Marilyn); S.C. Warby; S. Bandinelli; L. Cherkas (Lynn); D.S. Evans (Daniel); H.J. Grabe (Hans Jörgen); J. Lahti (Jari); M. Li (Man); T. Lehtimäki (Terho); T. Lumley (Thomas); K. Marciante (Kristin); L. Perusse (Louis); B.M. Psaty (Bruce); J. Robbins; G.J. Tranah (Gregory); J.M. Vink; J.B. Wilk; J.M. Stafford; C. Bellis (Claire); R. Biffar; C. Bouchard (Claude); B. Cade; G.C. Curhan (Gary); J. Eriksson; R. Ewert; L. Ferrucci (Luigi); T. Fülöp; P.R. Gehrman (Philip); R. Goodloe (Robert); T.B. Harris (Tamara B.); A.C. Heath (Andrew C.); D.G. Hernandez (Dena); A. Hofman (Albert); J.J. Hottenga (Jouke Jan); D. Hunter (David); M.K. Jensen (Majken K.); A.D. Johnson (Andrew); M. Kähönen (Mika); W.H.L. Kao (Wen); P. Kraft (Peter); E.K. Larkin; D.S. Lauderdale; A.I. Luik (Annemarie I); M. Medici; G.W. Montgomery (Grant W.); A. Palotie; S.R. Patel (Sanjay); G. Pistis (Giorgio); E. Porcu; L. Quaye (Lydia); O. Raitakari (Olli); S. Redline (Susan); E.B. Rimm (Eric B.); J.I. Rotter; A.V. Smith; T.D. Spector (Timothy); A. Teumer (Alexander); A.G. Uitterlinden (André); M.-C. Vohl (Marie-Claude); E. Widen; G.A.H.M. Willemsen (Gonneke); T.L. Young (Terri L.); X. Zhang; Y. Liu; J. Blangero (John); D.I. Boomsma (Dorret); V. Gudnason (Vilmundur); F. Hu; M. Mangino; N.G. Martin (Nicholas); G.T. O'Connor (George); K.L. Stone (Katie L); T. Tanaka; J. Viikari (Jorma); S.A. Gharib (Sina); N.M. Punjabi (Naresh); K. Räikkönen (Katri); H. Völzke (Henry); E. Mignot; H.W. Tiemeier (Henning)

    2015-01-01

    textabstractUsual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 popula

  6. Association study in eating disorders : TPH2 associates with anorexia nervosa and self-induced vomiting

    NARCIS (Netherlands)

    't Landt, M. C. T. Slof-Op; Meulenbelt, I.; Bartels, M.; Suchiman, E.; Middeldorp, C. M.; Houwing-Duistermaat, J. J.; van Trier, J.; Onkenhout, E. J.; Vink, J. M.; van Beijsterveldt, C. E. M.; Brandys, M. K.; Sanders, N.; Zipfel, S.; Herpertz-Dahlmann, B.; Klampfl, K.; Fleischhaker, C.; Zeeck, A.; de Zwaan, M.; Herpertz, S.; Ehrlich, S.; van Elburg, A. A.; Adan, R. A. H.; Scherag, S.; Hinney, A.; Hebebrand, J.; Boomsma, D. I.; van Furth, E. F.; Slagboom, P. E.; Herzog, W.

    2011-01-01

    Twin studies suggest that genetic factors play a substantial role in anorexia nervosa (AN) and self-induced vomiting (SV), a key symptom that is shared among different types of eating disorders (EDs). We investigated the association of 25 single nucleotide polymorphisms (SNPs), capturing 71-91% of t

  7. Genome-wide association study identifies 74 loci associated with educational attainment

    NARCIS (Netherlands)

    Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark Alan; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Brge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bonnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldorsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kahonen, Mika; Kanoni, Stavroula; Keltigangas-Jarvinen, Liisa; Kiemeney, Lambertus A. L. M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Mael P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C. M.; Loukola, Anu; Madden, Pamela A.; Magi, Reedik; Maki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E. R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Raikkonen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J. A.; Venturini, Cristina; Vinkhuyzen, Anna A. E.; Volker, Uwe; Volzke, Henry; Vonk, Judith M.; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jorgen; Gratten, Jacob; Groenen, Patrick J. F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppnen, Elina; Iacono, William G.; Jacobsson, Bo; Jarvelin, Marjo-Riitta; Jockel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L. R.; Lehtimaki, Terho; Lehrer, Steven F.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W. J. H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sorensen, Thorkild I. A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, Andre G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tonu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

    2016-01-01

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends

  8. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

    NARCIS (Netherlands)

    D.B. Hancock (Dana); M. Eijgelsheim (Mark); J.B. Wilk (Jemma); S.A. Gharib (Sina); L.R. Loehr (Laura); K. Marciante (Kristin); N. Franceschini (Nora); Y.M.T.A. van Durme; T.H. Chen; R.G. Barr (Graham); M.B. Schabath (Matthew); D.J. Couper (David); G.G. Brusselle (Guy); B.M. Psaty (Bruce); P. Tikka-Kleemola (Päivi); J.I. Rotter (Jerome); A.G. Uitterlinden (André); A. Hofman (Albert); N.M. Punjabi (Naresh); F. Rivadeneira Ramirez (Fernando); A.C. Morrison (Alanna); P.L. Enright (Paul); K.E. North (Kari); S.R. Heckbert (Susan); T. Lumley (Thomas); B.H.Ch. Stricker (Bruno); G.T. O'Connor (George); S.J. London (Stephanie)

    2010-01-01

    textabstractSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and it

  9. Genome-wide association study reveals regions associated with gestation length in two pig populations

    NARCIS (Netherlands)

    Hidalgo, A.M.; Lopes, M.S.; Harlizius, B.; Bastiaansen, J.W.M.

    2016-01-01

    Reproduction traits, such as gestation length (GLE), play an important role in dam line breeding in pigs. The objective of our study was to identify single nucleotide polymorphisms (SNPs) that are associated with GLE in two pig populations. Genotypes and deregressed breeding values were available

  10. Genome-Wide Association Study of Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Naomi Ogawa

    2010-01-01

    Full Text Available Coronary artery disease (CAD is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.

  11. Genome-Wide Association Study of Meiotic Recombination Phenotypes

    Science.gov (United States)

    Begum, Ferdouse; Chowdhury, Reshmi; Cheung, Vivian G.; Sherman, Stephanie L.; Feingold, Eleanor

    2016-01-01

    Meiotic recombination is an essential step in gametogenesis, and is one that also generates genetic diversity. Genome-wide association studies (GWAS) and molecular studies have identified genes that influence of human meiotic recombination. RNF212 is associated with total or average number of recombination events, and PRDM9 is associated with the locations of hotspots, or sequences where crossing over appears to cluster. In addition, a common inversion on chromosome 17 is strongly associated with recombination. Other genes have been identified by GWAS, but those results have not been replicated. In this study, using new datasets, we characterized additional recombination phenotypes to uncover novel candidates and further dissect the role of already known loci. We used three datasets totaling 1562 two-generation families, including 3108 parents with 4304 children. We estimated five different recombination phenotypes including two novel phenotypes (average recombination counts within recombination hotspots and outside of hotspots) using dense SNP array genotype data. We then performed gender-specific and combined-sex genome-wide association studies (GWAS) meta-analyses. We replicated associations for several previously reported recombination genes, including RNF212 and PRDM9. By looking specifically at recombination events outside of hotspots, we showed for the first time that PRDM9 has different effects in males and females. We identified several new candidate loci, particularly for recombination events outside of hotspots. These include regions near the genes SPINK6, EVC2, ARHGAP25, and DLGAP2. This study expands our understanding of human meiotic recombination by characterizing additional features that vary across individuals, and identifying regulatory variants influencing the numbers and locations of recombination events. PMID:27733454

  12. Replication of genetic association studies in aortic stenosis in adults.

    Science.gov (United States)

    Gaudreault, Nathalie; Ducharme, Valérie; Lamontagne, Maxime; Guauque-Olarte, Sandra; Mathieu, Patrick; Pibarot, Philippe; Bossé, Yohan

    2011-11-01

    Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10⁻¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10⁻¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.

  13. The Association between Work-Related Rumination and Heart Rate Variability: A Field Study

    Science.gov (United States)

    Cropley, Mark; Plans, David; Morelli, Davide; Sütterlin, Stefan; Inceoglu, Ilke; Thomas, Geoff; Chu, Chris

    2017-01-01

    The objective of this study was to examine the association between perseverative cognition in the form of work-related rumination, and heart rate variability (HRV). We tested the hypothesis that high ruminators would show lower vagally mediated HRV relative to low ruminators during their leisure time. Individuals were classified as being low (n = 17) or high ruminators (n = 19), using the affective scale on the work-related rumination measure. HRV was assessed using a wrist sensor band (Microsoft Band 2). HRV was sampled between 8 pm and 10 pm over three workday evenings (Monday to Wednesday) while individuals carried out their normal evening routines. Compared to the low ruminators, high affective ruminators demonstrated lower HRV in the form of root mean square successive differences (RMSSDs), relative to the low ruminators, indicating lower parasympathetic activity. There was no significant difference in heart rate, or activity levels between the two groups during the recording periods. The current findings of this study may have implications for the design and delivery of interventions to help individuals unwind post work and to manage stress more effectively. Limitations and implications for future research are discussed. PMID:28197087

  14. Susceptibility to chronic mucus hypersecretion, a genome wide association study.

    Directory of Open Access Journals (Sweden)

    Akkelies E Dijkstra

    Full Text Available BACKGROUND: Chronic mucus hypersecretion (CMH is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA study of CMH in Caucasian populations. METHODS: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years. Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP. RESULTS: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6, OR = 1.17, located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1 on chromosome 3. The risk allele (G was associated with higher mRNA expression of SATB1 (4.3×10(-9 in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. CONCLUSIONS: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

  15. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

    Science.gov (United States)

    Dijkstra, Akkelies E.; Smolonska, Joanna; van den Berge, Maarten; Wijmenga, Ciska; Zanen, Pieter; Luinge, Marjan A.; Platteel, Mathieu; Lammers, Jan-Willem; Dahlback, Magnus; Tosh, Kerrie; Hiemstra, Pieter S.; Sterk, Peter J.; Spira, Avi; Vestbo, Jorgen; Nordestgaard, Borge G.; Benn, Marianne; Nielsen, Sune F.; Dahl, Morten; Verschuren, W. Monique; Picavet, H. Susan J.; Smit, Henriette A.; Owsijewitsch, Michael; Kauczor, Hans U.; de Koning, Harry J.; Nizankowska-Mogilnicka, Eva; Mejza, Filip; Nastalek, Pawel; van Diemen, Cleo C.; Cho, Michael H.; Silverman, Edwin K.; Crapo, James D.; Beaty, Terri H.; Lomas, David A.; Bakke, Per; Gulsvik, Amund; Bossé, Yohan; Obeidat, M. A.; Loth, Daan W.; Lahousse, Lies; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Andre; Stricker, Bruno H.; Brusselle, Guy G.; van Duijn, Cornelia M.; Brouwer, Uilke; Koppelman, Gerard H.; Vonk, Judith M.; Nawijn, Martijn C.; Groen, Harry J. M.; Timens, Wim; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Background Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH. PMID:24714607

  16. Genome-wide association study reveals regions associated with gestation length in two pig populations.

    Science.gov (United States)

    Hidalgo, A M; Lopes, M S; Harlizius, B; Bastiaansen, J W M

    2016-04-01

    Reproduction traits, such as gestation length (GLE), play an important role in dam line breeding in pigs. The objective of our study was to identify single nucleotide polymorphisms (SNPs) that are associated with GLE in two pig populations. Genotypes and deregressed breeding values were available for 2081 Dutch Landrace-based (DL) and 2301 Large White-based (LW) pigs. We identified two QTL regions for GLE, one in each population. For DL, three associated SNPs were detected in one QTL region spanning 0.52 Mbp on Sus scrofa chromosome (SSC) 2. For LW, four associated SNPs were detected in one region of 0.14 Mbp on SSC5. The region on SSC2 contains the heparin-binding EGF-like growth factor (HBEGF) gene, which promotes embryo implantation and has been described to be involved in embryo survival throughout gestation. The associated SNP can be used for marker-assisted selection in the studied populations, and further studies of the HBEGF gene are warranted to investigate its role in GLE.

  17. Association study of interleukin-4 polymorphisms with paranoid schizophrenia in the Polish population: a critical approach.

    Science.gov (United States)

    Fila-Danilow, Anna; Kucia, Krzysztof; Kowalczyk, Malgorzata; Owczarek, Aleksander; Paul-Samojedny, Monika; Borkowska, Paulina; Suchanek, Renata; Kowalski, Jan

    2012-08-01

    Changes in immunological system are one of dysfunctions reported in schizophrenia. Some changes based on an imbalance between Th1 and Th2 cytokines results from cytokine gene polymorphisms. Interleukin-4 gene (IL4) is considered as a potential candidate gene in schizophrenia association studies. The aim of the current case-control study was to examine whether the -590C/T (rs2243250) and -33C/T (rs2070874) IL4 gene polymorphisms are implicated in paranoid schizophrenia development in the Polish population. Genotyping of polymorphisms was performed by using PCR-RFLP technique. The genotypes and alleles distribution of both SNPs were analysed in patients (n = 182) and healthy individuals constituted the control group (n = 215). The connection between some clinical variables and studied polymorphisms has been examined as well. We did not revealed any association between the -590C/T and -33C/T polymorphisms and paranoid schizophrenia. In case of both SNPs the homozygous TT genotype was extremely rare. Both polymorphic sites of the IL4 gene were found to be in a very strong linkage disequilibrium. However we did not identify a haplotype predispose to paranoid schizophrenia. No associations were also observed between the clinical course and psychopathology of the disease and the genotypes of both analysed polymorphisms. Our results suggest that the polymorphisms -590C/T in IL4 gene promoter region and -33C/T in the 5'-UTR are not involved in the pathophysiology of paranoid schizophrenia in Polish residents.

  18. Genome-wide association studies and resting heart rate

    DEFF Research Database (Denmark)

    Oskari Kilpeläinen, Tuomas

    2016-01-01

    Genome-wide association studies (GWASs) have revolutionized the search for genetic variants regulating resting heart rate. In the last 10 years, GWASs have led to the identification of at least 21 novel heart rate loci. These discoveries have provided valuable insights into the mechanisms...... and pathways that regulate heart rate and link heart rate to cardiovascular morbidity and mortality. GWASs capture majority of genetic variation in a population sample by utilizing high-throughput genotyping chips measuring genotypes for up to several millions of SNPs across the genome in thousands...... of individuals. This allows the identification of the strongest heart rate associated signals at genome-wide level. While GWASs provide robust statistical evidence of the association of a given genetic locus with heart rate, they are only the starting point for detailed follow-up studies to locate the causal...

  19. Genome-wide association study of relative telomere length.

    Science.gov (United States)

    Prescott, Jennifer; Kraft, Peter; Chasman, Daniel I; Savage, Sharon A; Mirabello, Lisa; Berndt, Sonja I; Weissfeld, Joel L; Han, Jiali; Hayes, Richard B; Chanock, Stephen J; Hunter, David J; De Vivo, Immaculata

    2011-05-10

    Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  20. Genome-wide association study of relative telomere length.

    Directory of Open Access Journals (Sweden)

    Jennifer Prescott

    Full Text Available Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003 identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  1. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes.

    Science.gov (United States)

    Arendt, Maja; Fall, Tove; Lindblad-Toh, Kerstin; Axelsson, Erik

    2014-10-01

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  2. Genome-wide association studies in nephrology: using known associations for data checks.

    Science.gov (United States)

    Wuttke, Matthias; Schaefer, Franz; Wong, Craig S; Köttgen, Anna

    2015-02-01

    Prior to conducting genome-wide association studies (GWAS) of renal traits and diseases, systematic checks to ensure data integrity and analytical work flow should be conducted. Using positive controls (ie, known associations between a single-nucleotide polymorphism [SNP] and a corresponding trait) allows for identifying errors that are not apparent solely from global evaluation of summary statistics. Strong genetic control associations of chronic kidney disease (CKD), as derived from GWAS, are lacking in the non-African ancestry CKD population; thus, in this perspective, we provide examples of and considerations for using positive controls among patients with CKD. Using data from individuals with CKD who participated in the CRIC (Chronic Renal Insufficiency Cohort) Study or PediGFR (Pediatric Investigation for Genetic Factors Linked to Renal Progression) Consortium, we evaluated 2 kinds of positive control traits: traits unrelated to kidney function (bilirubin level and body height) and those related to kidney function (cystatin C and urate levels). For the former, the proportion of variance in the control trait that is explained by the control SNP is the main determinant of the strength of the observable association, irrespective of adjustment for kidney function. For the latter, adjustment for kidney function can be effective in uncovering known associations among patients with CKD. For instance, in 1,092 participants in the PediGFR Consortium, the P value for the association of cystatin C concentrations and rs911119 in the CST3 gene decreased from 2.7×10(-3) to 2.4×10(-8) upon adjustment for serum creatinine-based estimated glomerular filtration rate. In this perspective, we give recommendations for the appropriate selection of control traits and SNPs that can be used for data checks prior to conducting GWAS among patients with CKD.

  3. Clinical study on antibody-associated limbic encephalitis

    Directory of Open Access Journals (Sweden)

    WANG Jia-wei

    2013-01-01

    Full Text Available In recent years, the antibody-associated limbic encephalitis (LE has attracted attentions of more and more clinicians. The associated antibodies mainly act on neuronal cell surface antigens, including the N-methyl-D-aspartate (NMDA receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA receptor, the γ-aminobutyric acid B (GABAB receptor, leucine-rich glioma-inactivated 1 (LGI1 and contactin-associated protein-like 2 (Caspr2 and so on. The clinical manifestation is primarily defined by the subacute onset of short-term memory loss, seizures, confusion and psychiatric symptoms suggesting the involvement of the limbic system. These severe and protracted disorders can affect children and young adults, occurring with or without tumor association. Routine detection of serum and cerebrospinal fluid (CSF and imaging tests show no specificity, but associated antibodies can be detected in serum and (or CSF. The patients respond well to tumor resection and immunotherapies, including corticosteroids, intravenous immunoglobulin (IVIg, plasma exchange or combination of them, but may relapse. This article aims to study the clinical features and treatment of antibody-associated limbic encephalitis and to improve the diagnosis and prognosis of these diseases.

  4. Association between Carotid Artery Stenosis and Cognitive Impairment in Stroke Patients: A Cross-Sectional Study

    Science.gov (United States)

    Zhu, Runxiu; Yan, Zhongrui; Zheng, Shouhuan; Wang, Jingwei; Huo, Jia; Liu, Yunlin; Li, Xin; Ji, Yong

    2016-01-01

    To investigate potential associations between carotid artery stenosis and cognitive impairment among patients with acute ischemic stroke and to provide important clinical implications. We measured the degree of carotid artery stenosis and recorded the Mini-Mental State Examination score (MMSE) at admission in 3116 acute ischemic stroke patients. The association between carotid stenosis and cognitive impairment assessed by MMSE was tested using multivariate regression analysis. Other clinical variables of interest were also studied. After adjusting for age, gender, education level, marriage, alcohol use, tobacco use, physical activity, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, myocardial infarction and NIHSS (National Institutes of Health Stroke Scale) score, we found that participants with high-grade stenosis of the carotid artery had a higher likelihood of cognitive impairment compared to those without carotid artery stenosis (OR = 1.49, 95%CI: 1.05–2.11, p<0.001). Left common carotid artery stenosis was associated with cognitive impairment in the univariate analysis, although this effect did not persist after adjustment for the NIHSS score. Cognitive impairment was associated with high-grade stenosis of the right carotid artery. PMID:26751070

  5. Association between Carotid Artery Stenosis and Cognitive Impairment in Stroke Patients: A Cross-Sectional Study.

    Directory of Open Access Journals (Sweden)

    Wei Yue

    Full Text Available To investigate potential associations between carotid artery stenosis and cognitive impairment among patients with acute ischemic stroke and to provide important clinical implications. We measured the degree of carotid artery stenosis and recorded the Mini-Mental State Examination score (MMSE at admission in 3116 acute ischemic stroke patients. The association between carotid stenosis and cognitive impairment assessed by MMSE was tested using multivariate regression analysis. Other clinical variables of interest were also studied. After adjusting for age, gender, education level, marriage, alcohol use, tobacco use, physical activity, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, myocardial infarction and NIHSS (National Institutes of Health Stroke Scale score, we found that participants with high-grade stenosis of the carotid artery had a higher likelihood of cognitive impairment compared to those without carotid artery stenosis (OR = 1.49, 95%CI: 1.05-2.11, p<0.001. Left common carotid artery stenosis was associated with cognitive impairment in the univariate analysis, although this effect did not persist after adjustment for the NIHSS score. Cognitive impairment was associated with high-grade stenosis of the right carotid artery.

  6. Increased mortality associated with HTLV-II infection in blood donors: a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Smith James W

    2004-03-01

    Full Text Available Abstract Background HTLV-I is associated with adult T-cell leukemia, and both HTLV-I and -II are associated with HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP. Several published reports suggest that HTLV-I may lead to decreased survival, but HTLV-II has not previously been associated with mortality. Results We examined deaths among 138 HTLV-I, 358 HTLV-II, and 759 uninfected controls enrolled in a prospective cohort study of U.S. blood donors followed biannually since 1992. Proportional hazards models yielded hazard ratios (HRs for the association between mortality and HTLV infection, controlling for sex, race/ethnicity, age, income, educational level, blood center, smoking, injection drug use history, alcohol intake, hepatitis C status and autologous donation. After a median follow-up of 8.6 years, there were 45 confirmed subject deaths. HTLV-I infection did not convey a statistically significant excess risk of mortality (unadjusted HR 1.9, 95%CI 0.8–4.4; adjusted HR 1.9, 95%CI 0.8–4.6. HTLV-II was associated with death in both the unadjusted model (HR 2.8, 95%CI 1.5–5.5 and in the adjusted model (HR 2.3, 95%CI 1.1–4.9. No single cause of death appeared responsible for the HTLV-II effect. Conclusions After adjusting for known and potential confounders, HTLV-II infection is associated with increased mortality among healthy blood donors. If replicated in other cohorts, this finding has implications for both HTLV pathogenesis and counseling of infected persons.

  7. The emerging role of SMPD1 mutations in Parkinson's disease: Implications for future studies.

    Science.gov (United States)

    Gan-Or, Ziv; Orr-Urtreger, Avi; Alcalay, Roy N; Bressman, Susan; Giladi, Nir; Rouleau, Guy A

    2015-10-01

    Recently, an additional study confirmed the association between SMPD1 mutations and Parkinson's disease (PD). While the first study on SMPD1 and PD suggested that only one SMPD1 mutations is responsible for the association to PD, the recent study argued that all SMPD1 mutations may be associated with an increased risk for PD. Since SMPD1 mutations are being routinely screened in some populations with high carrier frequencies, and since it will be further screened in additional PD populations, it is important to better define the association between SMPD1 and PD. We reanalyzed the data from the recent and previous papers, and we show that the association between SMPD1 and PD is indeed not driven by only one mutation, but it is also not driven by all SMPD1 mutations. In the Ashkenazi-Jewish population, the p.fs330P (OR = 3.03, p = 0.0026) and p.L302P (OR = 9.62, p < 0.0001) are associated with PD, and the p.R496L mutation is not (OR = 0.84, p = 0.71), and similar observation was noted in the Chinese population. Thus, we conclude that similar to the GBA gene where different mutations have differential effects, SMPD1 mutations also have a differential effects on the risk for PD. Future studies should therefore examine the association by mutation and not by accumulative risk of all mutations.

  8. Genome-wide association study identifies five new schizophrenia loci

    DEFF Research Database (Denmark)

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S;

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yiel...

  9. Genome-Wide Association Study of Serum Selenium Concentrations

    Directory of Open Access Journals (Sweden)

    Ulrike Peters

    2013-05-01

    Full Text Available Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening and the Women’s Health Initiative (WHI. We tested association between 2,474,333 single nucleotide polymorphisms (SNPs and serum selenium concentrations using linear regression models. In the first stage (PLCO 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003 in the second stage (WHI. Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11 and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI. Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

  10. Genome-wide association study identifies five new schizophrenia loci

    NARCIS (Netherlands)

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A.; Scolnick, Edward; Cichon, Sven; Clair, David St.; Corvin, Aiden; Gurling, Hugh; Werge, Thomas; Rujescu, Dan; Blackwood, Douglas H. R.; Pato, Carlos N.; Malhotra, Anil K.; Purcell, Shaun; Dudbridge, Frank; Neale, Benjamin M.; Rossin, Lizzy; Visscher, Peter M.; Posthuma, Danielle; Ruderfer, Douglas M.; Fanous, Ayman; Stefansson, Hreinn; Steinberg, Stacy; Mowry, Bryan J.; Golimbet, Vera; De Hert, Marc; Jonsson, Erik G.; Bitter, Istvan; Pietilainen, Olli P. H.; Collier, David A.; Tosato, Sarah; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amdur, Richard L.; Amin, Farooq; Bass, Nicholas; Bergen, Sarah E.; Black, Donald W.; Borglum, Anders D.; Brown, Matthew A.; Bruggeman, Richard; Buccola, Nancy G.; Byerley, William F.; Cahn, Wiepke; Cantor, Rita M.; Carr, Vaughan J.; Catts, Stanley V.; Choudhury, Khalid; Cloninger, C. Robert; Cormican, Paul; Craddock, Nicholas; Danoy, Patrick A.; Datta, Susmita; De Haan, Lieuwe; Demontis, Ditte; Dikeos, Dimitris; Djurovic, Srdjan; Donnelly, Peter; Donohoe, Gary; Duong, Linh; Dwyer, Sarah; Fink-Jensen, Anders; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Georgieva, Lyudmila; Giegling, Ina; Gill, Michael; Glenthoj, Birte; Godard, Stephanie; Hamshere, Marian; Hansen, Mark; Hansen, Thomas; Hartmann, Annette M.; Henskens, Frans A.; Hougaard, David M.; Hultman, Christina M.; Ingason, Andres; Jablensky, Assen V.; Jakobsen, Klaus D.; Jay, Maurice; Juergens, Gesche; Kahn, Renes; Keller, Matthew C.; Kenis, Gunter; Kenny, Elaine; Kim, Yunjung; Kirov, George K.; Konnerth, Heike; Konte, Bettina; Krabbendam, Lydia; Krasucki, Robert; Lasseter, Virginia K.; Laurent, Claudine; Lawrence, Jacob; Lencz, Todd; Lerer, F. Bernard; Liang, Kung-Yee; Lichtenstein, Paul; Lieberman, Jeffrey A.; Linszen, Don H.; Lonnqvist, Jouko; Loughland, Carmel M.; Maclean, Alan W.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Malloy, Pat; Mattheisen, Manuel; Mattingsdal, Morten; McGhee, Kevin A.; McGrath, John J.; McIntosh, Andrew; McLean, Duncan E.; McQuillin, Andrew; Melle, Ingrid; Michie, Patricia T.; Milanova, Vihra; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Moskvina, Valentina; Muglia, Pierandrea; Myin-Germeys, Inez; Nertney, Deborah A.; Nestadt, Gerald; Nielsen, Jimmi; Nikolov, Ivan; Nordentoft, Merete; Norton, Nadine; Noethen, Markus M.; O'Dushlaine, Colm T.; Olincy, Ann; Olsen, Line; O'Neill, F. Anthony; Orntoft, Torben F.; Owen, Michael J.; Pantelis, Christos; Papadimitriou, George; Pato, Michele T.; Peltonen, Leena; Petursson, Hannes; Pickard, Ben; Pimm, Jonathan; Pulver, Ann E.; Puri, Vinay; Quested, Digby; Quinn, Emma M.; Rasmussen, Henrik B.; Rethelyi, Janos M.; Ribble, Robert; Rietschel, Marcella; Riley, Brien P.; Ruggeri, Mirella; Schall, Ulrich; Schulze, Thomas G.; Schwab, Sibylle G.; Scott, Rodney J.; Shi, Jianxin; Sigurdsson, Engilbert; Silverman, Jeremy M.; Spencer, Chris C. A.; Stefansson, Kari; Strange, Amy; Strengman, Eric; Stroup, T. Scott; Suvisaari, Jaana; Terenius, Lars; Thirumalai, Srinivasa; Thygesen, Johan H.; Timm, Sally; Toncheva, Draga; van den Oord, Edwin; van Os, Jim; van Winkel, Ruud; Veldink, Jan; Walsh, Dermot; Wang, August G.; Wiersma, Durk; Wildenauer, Dieter B.; Williams, Hywel J.; Williams, Nigel M.; Wormley, Brandon; Zammit, Stan; Sullivan, Patrick F.; O'Donovan, Michael C.; Daly, Mark J.; Gejman, Pablo V.

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded

  11. Dental trauma in association with maxillofacial fractures: an epidemiological study

    NARCIS (Netherlands)

    Ruslin, M.; Wolff, J.; Boffano, P.; Brand, H.S.; Forouzanfar, T.

    2015-01-01

    Aim The aim of this study was to retrospectively investigate the incidence and associated factors of dental trauma in patients with maxillofacial fractures at the VU Medical Center in Amsterdam. Material and methods Data from 707 patients who were treated surgically for maxillofacial fractures were

  12. A study of type-1 diabetes associated autoantibodies in schizophrenia.

    Science.gov (United States)

    Hallford, Philomena; Clair, David St; Halley, Lorna; Mustard, Colette; Wei, Jun

    2016-10-01

    Epidemiological studies revealed an association between type-1 diabetes (T1D) and schizophrenia but the findings reported to date have been controversial. To clarify the inconsistency across studies, T1D-associated autoantibodies were examined in plasma samples collected from 272 patients with schizophrenia and 276 control subjects. An in-house enzyme-linked immunosorbent assay (ELISA) was developed using three linear peptide antigens, one of which was derived from glutamic acid decarboxylase (GAD) and two were derived from insulinoma-associated antigen 2 (IA2). Mann-Whitney U test showed a significant decrease in the levels of plasma IgG against the IA2b antigen in schizophrenia patients as compared to control subjects (Z=-3.54, p=0.0007), while no significant difference was found between these two groups either in anti-IA2a IgG levels (Z=-1.62, p=0.105) or in anti-GAD IgG levels (Z=-1.63, p=0.104). Linear regression analysis indicated no association of antipsychotic medication with the levels of plasma IgG against IA2a, IA2b or GAD, while the levels of plasma IgG for these 3 peptide antigens were significantly correlated with each other. Binary logistic regression showed that neither the DQ2.5 variant nor the DQ8 variant was associated with circulating levels of 3 T1D-associated autoantibodies in both the patient group and the control group. The coefficient of variation was 10.7% for anti-IA2a IgG assay, 10.1% for anti-IA2b IgG assay and 10.7% for anti-GAD IgG assay. The present work suggests that T1D-associated antibodies are unlikely to confer risk of schizophrenia and that the in-house ELISA developed with linear peptide antigens is highly reproducible.

  13. On the analysis of genome-wide association studies in family-based designs: a universal, robust analysis approach and an application to four genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Sungho Won

    2009-11-01

    Full Text Available For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1 in 4 genome-wide association studies.

  14. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.

    Science.gov (United States)

    Ramachandran, Dhanya; Zeng, Zhen; Locke, Adam E; Mulle, Jennifer G; Bean, Lora J H; Rosser, Tracie C; Dooley, Kenneth J; Cua, Clifford L; Capone, George T; Reeves, Roger H; Maslen, Cheryl L; Cutler, David J; Feingold, Eleanor; Sherman, Stephanie L; Zwick, Michael E

    2015-07-20

    The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

  15. A genome-wide association study identifies protein quantitative trait loci (pQTLs.

    Directory of Open Access Journals (Sweden)

    David Melzer

    2008-05-01

    Full Text Available There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57, CCL4L1 (p = 3.9x10(-21, IL18 (p = 6.8x10(-13, LPA (p = 4.4x10(-10, GGT1 (p = 1.5x10(-7, SHBG (p = 3.1x10(-7, CRP (p = 6.4x10(-6 and IL1RN (p = 7.3x10(-6 genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R, altered secretion rates of different sized proteins (LPA, variation in gene copy number (CCL4L1 and altered transcription (GGT1. We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha levels (p = 6.8x10(-40, but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis

  16. Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention.

    Directory of Open Access Journals (Sweden)

    Cosmeri Rizzato

    Full Text Available Helicobacter pylori (HP is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes pathogenicity island (cagPAI, a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS. This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty-six SNPs (11 non-synonymous and 14 synonymous showed statistically significant differences (P<0.05, and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07×10⁻⁶, and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations.

  17. Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS.

    LENUS (Irish Health Repository)

    Wilcz-Villega, E

    2013-11-29

    Increased intestinal permeability and altered expression of tight junction (TJ) proteins may be implicated in the pathogenesis of irritable bowel syndrome (IBS). This study aimed to investigate the expression of adherens junction (AJ) protein E-cadherin and TJ proteins zonula occludens (ZO)-1 and claudin (CLD)-1 and associations with IBS symptoms.

  18. An Epigenome-Wide Association Study of Total Serum Immunoglobulin E Concentration

    Science.gov (United States)

    Liang, Liming; Wong, Kenny C.C.; Davies, Gwyneth A.; Hudson, Thomas J.; Binia, Aristea; Hopkin, Julian M.; Yang, Ivana V.; Grundberg, Elin; Busche, Stephan; Hudson, Marie; Rönnblom, Lars; Pastinen, Tomi M.; Schwartz, David A.; Lathrop, G. Mark; Moffatt, Miriam F.; Cookson, William O.C.M.

    2014-01-01

    Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE benefit hay fever1 and allergic asthma1,2. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation3-6. We therefore surveyed epigenetic association between serum IgE concentrations and methylation at loci concentrated in CpG islands (CGI) genome-wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes (PBL). We validated positive results in additional families and in subjects from the general population. We show here replicated associations with a meta-analysis false discovery rate <10−4 between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors, and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining 10 fold higher variance than that derived from large SNP GWAS3,4. The study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases. PMID:25707804

  19. Genome-wide association studies in pediatric chronic kidney disease.

    Science.gov (United States)

    Gupta, Jayanta; Kanetsky, Peter A; Wuttke, Matthias; Köttgen, Anna; Schaefer, Franz; Wong, Craig S

    2016-08-01

    The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.

  20. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

    Directory of Open Access Journals (Sweden)

    Qiong Yang

    2012-01-01

    Full Text Available Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical or different types of components (e.g., some are continuous and others are categorical. We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  1. Study on multimers and their structures in molecular association mixture

    Institute of Scientific and Technical Information of China (English)

    NI Yi; DOU XiaoMing; ZHAO HaiYing; YIN GuangZhong; YAMAGUCHI Yoshinori; OZAKI Yukihiro

    2007-01-01

    Self-association system of (R)-1,3-butanediol in dilute carbon tetrachloride (CCl4) solution is studied as a model of molecular association mixture. Analysis methods including FSMWEFA (fixed-size moving window evolving factor analysis) combined with PCA (principal component analysis), SIMPLISMA (simple-to-use interactive self-modeling mixture analysis), and ITTFA (iterative target transformation factor analysis) are adopted to resolve infrared spectra of (R)-1,3-butanediol solution. Association number and equilibrium constant are computed. (R)-1,3-butanediol in dilute inert solution is determined as a monomer-trimer equilibrium system. Theoretical investigation of trimer structures is carried out with DFT (density functional theory), and structural factors are analyzed.

  2. Study on multimers and their structures in molecular association mixture

    Institute of Scientific and Technical Information of China (English)

    YAMAGUCHI; Yoshinori; OZAKI; Yukihiro

    2007-01-01

    Self-association system of(R)-1,3-butanediol in dilute carbon tetrachloride(CCl4)solution is studied as a model of molecular association mixture.Analysis methods including FSMWEFA(fixed-size moving window evolving factor analysis)combined with PCA(principal component analysis),SIMPLISMA (simple-to-use interactive self-modeling mixture analysis),and ITTFA(iterative target transformation factor analysis)are adopted to resolve infrared spectra of(R)-1,3-butanediol solution.Association number and equilibrium constant are computed.(R)-1,3-butanediol in dilute inert solution is determined as a monomer-trimer equilibrium system.Theoretical investigation of trimer structures is carried out with DFT(density functional theory),and structural factors are analyzed.

  3. Disease-Concordant Twins Empower Genetic Association Studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs...... concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases...... and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient...

  4. Commonly prescribed drugs associate with cognitive function: a cross-sectional study in UK Biobank

    Science.gov (United States)

    Nevado-Holgado, Alejo J; Winchester, Laura; Gallacher, John; Lovestone, Simon

    2016-01-01

    0.09 (0.03 to 0.14), breaction time 5 (3 to 6)). Conclusions In this large volunteer study, some commonly prescribed medications were associated with poor cognitive performance. Some associations may reflect underlying diseases for which the medications were prescribed, although the analysis controlled for the possible effect of diagnosis. Other drugs, whose association cannot be linked to the effect of any disease, may need vigilance for their implications in clinical practice. PMID:27903560

  5. Liposomes- and ethosomes-associated distamycins: a comparative study.

    Science.gov (United States)

    Cortesi, Rita; Romagnoli, Romeo; Drechsler, Markus; Menegatti, Enea; Zaid, Abdel N; Ravani, Laura; Esposito, Elisabetta

    2010-12-01

    The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A (DA) and two of its derivatives. Liposomes and ethosomes were prepared by classical methods, extruded through polycarbonate filters, and characterized in terms of dimensions, morphology, and encapsulation efficiency. It was found that DA was associated with vesicles (either liposomes or ethosomes) by around 16.0%, while both derivatives of DA showed a percentage of association around 80% in the case of liposomes and around 50% in the case of ethosomes. In vitro antiproliferative activity experiments performed on cultured human and mouse leukemic cells demonstrated that vesicles were able to increase the activity of both derivatives of DA. In addition, it was demonstrated that the aging of both liposomes- and ethosomes-associated distamycin suspensions did not heavily influence the vesicle size, while all samples showed a relevant drug leakage with time. Moreover, according to the different physicochemical characteristics of DA and its derivatives (i.e., log P), vesicle-associated DA showed the highest loss of drug with respect to both its derivatives. In conclusion, the enhancement of drug activity expressed by these specialized delivery systems-associated DD could be interesting to obtain an efficient therapeutic effect aimed at reducing or minimizing toxic effects occurring with distamycins administration.

  6. Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

    Science.gov (United States)

    Sung, Yun Ju; Pérusse, Louis; Sarzynski, Mark A.; Fornage, Myriam; Sidney, Steve; Sternfeld, Barbara; Rice, Treva; Terry, Gregg; Jacobs, David R.; Katzmarzyk, Peter; Curran, Joanne E; Carr, John Jeffrey; Blangero, John; Ghosh, Sujoy; Després, Jean-Pierre; Rankinen, Tuomo; Rao, D.C.; Bouchard, Claude

    2015-01-01

    Background To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). Subjects and Methods Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for BMI, and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2,513 subjects of European descent were available for the discovery phase. For replication, 2,171 European Americans and 772 African Americans were available. Results A total of 52 SNPs encompassing 7 loci showed suggestive evidence of association (p < 1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; p= 1.10 × 10−7), an association that was replicated (p = 0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; p= 2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (p < 5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (p = 3.97 × 10−8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (p= 0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. Conclusions Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2

  7. Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans

    Science.gov (United States)

    Adeyemo, Adebowale A.; Tekola-Ayele, Fasil; Doumatey, Ayo P.; Bentley, Amy R.; Chen, Guanjie; Huang, Hanxia; Zhou, Jie; Shriner, Daniel; Fasanmade, Olufemi; Okafor, Godfrey; Eghan, Benjamin; Agyenim-Boateng, Kofi; Adeleye, Jokotade; Balogun, Williams; Elkahloun, Abdel; Chandrasekharappa, Settara; Owusu, Samuel; Amoah, Albert; Acheampong, Joseph; Johnson, Thomas; Oli, Johnnie; Adebamowo, Clement; Collins, Francis; Dunston, Georgia; Rotimi, Charles N.

    2015-01-01

    Genome wide association studies (GWAS) for type 2 diabetes (T2D) undertaken in European and Asian ancestry populations have yielded dozens of robustly associated loci. However, the genomics of T2D remains largely understudied in sub-Saharan Africa (SSA), where rates of T2D are increasing dramatically and where the environmental background is quite different than in these previous studies. Here, we evaluate 106 reported T2D GWAS loci in continental Africans. We tested each of these SNPs, and SNPs in linkage disequilibrium (LD) with these index SNPs, for an association with T2D in order to assess transferability and to fine map the loci leveraging the generally reduced LD of African genomes. The study included 1775 unrelated Africans (1035 T2D cases, 740 controls; mean age 54 years; 59% female) enrolled in Nigeria, Ghana, and Kenya as part of the Africa America Diabetes Mellitus (AADM) study. All samples were genotyped on the Affymetrix Axiom PanAFR SNP array. Forty-one of the tested loci showed transferability to this African sample (p < 0.05, same direction of effect), 11 at the exact reported SNP and 30 others at SNPs in LD with the reported SNP (after adjustment for the number of tested SNPs). TCF7L2 SNP rs7903146 was the most significant locus in this study (p = 1.61 × 10−8). Most of the loci that showed transferability were successfully fine-mapped, i.e., localized to smaller haplotypes than in the original reports. The findings indicate that the genetic architecture of T2D in SSA is characterized by several risk loci shared with non-African ancestral populations and that data from African populations may facilitate fine mapping of risk loci. The study provides an important resource for meta-analysis of African ancestry populations and transferability of novel loci. PMID:26635871

  8. Genome-wide association study identifies 74 loci associated with educational attainment

    Science.gov (United States)

    Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

    2016-01-01

    Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

  9. Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye.

    Science.gov (United States)

    Lin, Tony; Walker, Gregory Brett; Kurji, Khaliq; Fang, Edward; Law, Geoffrey; Prasad, Shiv S; Kojic, Luba; Cao, Sijia; White, Valerie; Cui, Jing Z; Matsubara, Joanne A

    2013-06-01

    Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD

  10. Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women.

    Science.gov (United States)

    Polimanti, Renato; Kranzler, Henry R; Gelernter, Joel

    2016-10-01

    To identify novel traits associated with alleles known to predispose to alcohol and nicotine use, we conducted a phenome-wide association study (PheWAS) in a large multi-population cohort. We investigated 7688 African-Americans, 1133 Asian-Americans, 14 081 European-Americans, and 3492 Hispanic-Americans from the Women's Health Initiative, analyzing alleles at the CHRNA3-CHRNA5 locus, ADH1B, and ALDH2 with respect to phenotypic traits related to anthropometric characteristics, dietary habits, social status, psychological traits, reproductive history, health conditions, and nicotine/alcohol use. In ADH1B trans-population meta-analysis and population-specific analysis, we replicated prior associations with drinking behaviors and identified multiple novel phenome-wide significant and suggestive findings related to psychological traits, socioeconomic status, vascular/metabolic conditions, and reproductive health. We then applied Bayesian network learning algorithms to provide insight into the causative relationships of the novel ADH1B associations: ADH1B appears to affect phenotypic traits via both alcohol-mediated and alcohol-independent effects. In an independent sample of 2379 subjects, we also replicated the novel ADH1B associations related to socioeconomic status (household gross income and highest grade finished in school). For CHRNA3-CHRNA5 risk alleles, we replicated association with smoking behaviors, lung cancer, and asthma. There were also novel suggestive CHRNA3-CHRNA5 findings with respect to high-cholesterol-medication use and distrustful attitude. In conclusion, the genetics of alcohol and tobacco use potentially has broader implications on physical and mental health than is currently recognized. In particular, ADH1B may be a gene relevant for the human phenome via both alcohol metabolism-related mechanisms and other alcohol metabolism-independent mechanisms.

  11. A whole-genome association study for pig reproductive traits.

    Science.gov (United States)

    Onteru, S K; Fan, B; Du, Z-Q; Garrick, D J; Stalder, K J; Rothschild, M F

    2012-02-01

    A whole-genome association study was performed for reproductive traits in commercial sows using the PorcineSNP60 BeadChip and Bayesian statistical methods. The traits included total number born (TNB), number born alive (NBA), number of stillborn (SB), number of mummified foetuses at birth (MUM) and gestation length (GL) in each of the first three parities. We report the associations of informative QTL and the genes within the QTL for each reproductive trait in different parities. These results provide evidence of gene effects having temporal impacts on reproductive traits in different parities. Many QTL identified in this study are new for pig reproductive traits. Around 48% of total genes located in the identified QTL regions were predicted to be involved in placental functions. The genomic regions containing genes important for foetal developmental (e.g. MEF2C) and uterine functions (e.g. PLSCR4) were associated with TNB and NBA in the first two parities. Similarly, QTL in other foetal developmental (e.g. HNRNPD and AHR) and placental (e.g. RELL1 and CD96) genes were associated with SB and MUM in different parities. The QTL with genes related to utero-placental blood flow (e.g. VEGFA) and hematopoiesis (e.g. MAFB) were associated with GL differences among sows in this population. Pathway analyses using genes within QTL identified some modest underlying biological pathways, which are interesting candidates (e.g. the nucleotide metabolism pathway for SB) for pig reproductive traits in different parities. Further validation studies on large populations are warranted to improve our understanding of the complex genetic architecture for pig reproductive traits.

  12. A study of associated congenital anomalies with biliary atresia

    Directory of Open Access Journals (Sweden)

    Lucky Gupta

    2016-01-01

    Full Text Available Background/Purpose: This study aims to analyze the incidence and type of various associated anomalies among infants with extrahepatic biliary atresia (EHBA, compare their frequency with those quoted in the existing literature and assess their role in the overall management. Materials and Methods: A retrospective study was performed on 137 infants who underwent the Kasai procedure for EHBA during the past 12 years. The medical records were reviewed for the incidence and type of associated anomalies in addition to the details of the management of the EHBA. Results: Of the137 infants, 40 (29.2% were diagnosed as having 58 anomalies. The majority of patients had presented in the 3 rd month of life; mean age was 81 ± 33 days (range = 20-150 days. There were 32 males and 8 females; boys with EHBA had a higher incidence of associated anomalies. Of these 40 patients, 22 (37.9% had vascular anomalies, 13 patients (22.4% had hernias (umbilical-10, inguinal-3, 7 patients (12.1% had intestinal malrotation, 4 patients (6.8% had choledochal cyst, 1 patient (1.7% had Meckel′s diverticulum, 3 patients (5% had undergone prior treatment for jejunoileal atresias (jejunal-2, ileal-1, 2 patients (3.4% had undergone prior treatment for esophageal atresia and tracheoesophageal fistula, 2 patients (3.4% had spleniculi, and 2 patients (3.4% were diagnosed as having situs inversus. Conclusions: The most common associated anomalies in our study were related to the vascular variation at the porta hepatis and the digestive system. The existence of anomalies in distantly developing anatomic regions in patients with EHBA supports the possibility of a "generalized" insult during embryogenesis rather than a "localized" defect. In addition, male infants were observed to have significantly more associated anomalies as compared with the female infants in contrast to earlier reports.

  13. Association studies in common endocrine diseases (review article

    Directory of Open Access Journals (Sweden)

    Akrami SM

    2007-05-01

    Full Text Available Our understanding of the pathogenesis of endocrine disorders increase rapidly by genetic studies at the molecular level. Common endocrine disorders such as diabetes mellitus, obesity, osteoporosis, dyslipidemia and cancer follow the multifactorial model in the genetic aspect. This review tries to clarify the approach in molecular studies of such diseases for clinicians in different specialties. How to evaluate a possible association between a single nucleotide polymorphism and an endocrinopathy or its complication is the main concern of this review. Two approaches for gene mapping will be discussed as well as main challenges regarding each approach. All such genetic studies ideally include some test of the association between genome sequence variation and the phenotype of interest such as the trait itself, the presence of a given complication, or measures of some endocrinopathy-related intermediate trait. Despite different advances in this analysis, there are major concerns regarding the overall performance and robustness of genetic association studies. By using powerful new high-throughput methods, further insights to molecular basis of such endocrine disorders can be expected. Close correlation between geneticists and clinicians can effectively bridge between basic sciences and clinical investigations.

  14. Case-control association study of TGOLN2 in attempted suicide.

    Science.gov (United States)

    Mahon, Pamela B; Stütz, Adrian M; Seifuddin, Fayaz; Huo, Yuqing; Goes, Fernando S; Jancic, Dubravka; Judy, Jennifer T; Depaulo, J Raymond; Gershon, Elliot S; McMahon, Francis J; Zandi, Peter P; Potash, James B; Willour, Virginia L

    2010-07-01

    Family, twin, and adoption studies provide convincing evidence for a genetic contribution to suicidal behavior. The heritability for suicidal behavior depends in part on the transmission of psychiatric disorders, such as mood disorders and substance use disorders, but is also partly independent of them. Three linkage studies using the attempted suicide phenotype in pedigrees with bipolar disorder, major depression, or alcoholism have provided consistent evidence that 2p11-12 harbors a susceptibility gene for attempted suicide. A microarray expression study using postmortem brain samples has implicated a gene from the 2p11-12 candidate region, the trans-Golgi network protein 2 (TGOLN2) gene, as being consistently up-regulated in suicide cases as compared to controls. Here, we present a TGOLN2 case-control association study using nine single nucleotide polymorphisms (SNPs). These nine SNPs, which include seven tag SNPs and two coding SNPs, have been genotyped in 517 mood disorder subjects with a history of attempted suicide and 515 normal controls. Allelic and genotypic analyses of the case-control sample did not provide evidence for association with the attempted suicide phenotype. Eight of the nine SNPs provided supportive evidence for association (P-values ranging from 0.008 to 0.03) when we compared the attempted suicide cases with a history of alcoholism to the attempted suicide cases without a history of alcoholism. However, this association finding was not replicated in an independent sample. Taken together, these analyses do not provide support for the hypothesis that common genetic variation in TGOLN2 contributes significantly to the risk for attempted suicide in subjects with major mood disorders.

  15. A neurocognitive model of the ethical decision-making process: implications for study and practice.

    Science.gov (United States)

    Reynolds, Scott J

    2006-07-01

    The field of business ethics is entrenched in a cognitive approach that portrays the ethical decision-making process as a completely deliberate and reasoned exercise. In light of growing concerns about the veracity of this approach, I build upon current knowledge of how the brain functions to present a neurocognitive model of ethical decision making. The model suggests that ethical decision making involves 2 interrelated yet functionally distinct cycles, a reflexive pattern matching cycle and a higher order conscious reasoning cycle, and thereby describes not only reasoned analysis, but also the intuitive and retrospective aspects of ethical decision making. The model sparks research in new areas, holds significant implications for the study of ethical decision making, and provides suggestions for improving ethical behavior in organizations.

  16. High-frequency sea level variations and implications for coastal flooding: A case study of the Solent, UK

    Science.gov (United States)

    Ozsoy, Ozgun; Haigh, Ivan D.; Wadey, Matthew P.; Nicholls, Robert J.; Wells, Neil C.

    2016-07-01

    This study examines the occurrence and characteristics of high-frequency (energy events have a mean amplitude of approximately 0.6 m and a dominant period of around 4 h. These events correspond with periods of enhanced meteorological activity, namely a marked reduction in air pressure and onset of strong southwesterly-southeasterly winds. Sea level observations from tide gauges around the Solent and the wider English Channel region (23 in total) were used to assess the spatial characteristics of these events. Analysis of time series and phase information indicates the occurrence of standing waves oscillating across the English Channel between southern England and northern France. This study provides a unique example of standing waves generated by extra-tropical cyclones over a large basin (the English Channel) with implications for flood inundation. The event of 28th October 2013 - the highest-amplitude (1.16 m) event in the record - was associated with minor coastal flooding at Yarmouth, Isle of Wight. This flood occurred during a neap tide, when such events are widely thought to be impossible. Hence, our findings emphasize the relevance of high-frequency sea level variability for regional sea level forecasting and flood risk management.

  17. Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Valenti, Luca; Dongiovanni, Paola; Fargion, Silvia

    2012-08-07

    Nonalcoholic fatty liver disease (NAFLD), defined by excessive liver fat deposition related to the metabolic syndrome, is a leading cause of progressive liver disease, for which accurate non-invasive staging systems and effective treatments are still lacking. Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes. Recently, Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients.

  18. Characterization of the deleted in autism 1 protein family: implications for studying cognitive disorders.

    Directory of Open Access Journals (Sweden)

    Azhari Aziz

    Full Text Available Autism spectrum disorders (ASDs are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1 and cXorf36 or Deleted in Autism-1 Related (DIA1R are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1-related gene we named DIA1-Like (DIA1L, lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1-family members will have implications for our understanding of autism and mental

  19. Lipid nanotechnologies for structural studies of membrane-associated proteins.

    Science.gov (United States)

    Stoilova-McPhie, Svetla; Grushin, Kirill; Dalm, Daniela; Miller, Jaimy

    2014-11-01

    We present a methodology of lipid nanotubes (LNT) and nanodisks technologies optimized in our laboratory for structural studies of membrane-associated proteins at close to physiological conditions. The application of these lipid nanotechnologies for structure determination by cryo-electron microscopy (cryo-EM) is fundamental for understanding and modulating their function. The LNTs in our studies are single bilayer galactosylceramide based nanotubes of ∼20 nm inner diameter and a few microns in length, that self-assemble in aqueous solutions. The lipid nanodisks (NDs) are self-assembled discoid lipid bilayers of ∼10 nm diameter, which are stabilized in aqueous solutions by a belt of amphipathic helical scaffold proteins. By combining LNT and ND technologies, we can examine structurally how the membrane curvature and lipid composition modulates the function of the membrane-associated proteins. As proof of principle, we have engineered these lipid nanotechnologies to mimic the activated platelet's phosphtaidylserine rich membrane and have successfully assembled functional membrane-bound coagulation factor VIII in vitro for structure determination by cryo-EM. The macromolecular organization of the proteins bound to ND and LNT are further defined by fitting the known atomic structures within the calculated three-dimensional maps. The combination of LNT and ND technologies offers a means to control the design and assembly of a wide range of functional membrane-associated proteins and complexes for structural studies by cryo-EM. The presented results confirm the suitability of the developed methodology for studying the functional structure of membrane-associated proteins, such as the coagulation factors, at a close to physiological environment.

  20. Facial dermatosis associated with Demodex: a case-control study*

    OpenAIRE

    Zhao, Ya-e; Peng, Yan; Wang, Xiang-lan; Wu, Li-ping; Wang, Mei; Yan, Hu-ling; Xiao, Sheng-xiang

    2011-01-01

    Demodex has been considered to be related with multiple skin disorders, but controversy persists. In this case-control study, a survey was conducted with 860 dermatosis patients aged 12 to 84 years in Xi’an, China to identify the association between facial dermatosis and Demodex. Amongst the patients, 539 suffered from facial dermatosis and 321 suffered from non-facial dermatosis. Demodex mites were sampled and examined using the skin pressurization method. Multivariate regression analysis wa...

  1. Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility

    Science.gov (United States)

    Cook, James P; Morris, Andrew P

    2016-01-01

    Genome-wide association studies (GWAS) have traditionally been undertaken in homogeneous populations from the same ancestry group. However, with the increasing availability of GWAS in large-scale multi-ethnic cohorts, we have evaluated a framework for detecting association of genetic variants with complex traits, allowing for population structure, and developed a powerful test of heterogeneity in allelic effects between ancestry groups. We have applied the methodology to identify and characterise loci associated with susceptibility to type 2 diabetes (T2D) using GWAS data from the Resource for Genetic Epidemiology on Adult Health and Aging, a large multi-ethnic population-based cohort, created for investigating the genetic and environmental basis of age-related diseases. We identified a novel locus for T2D susceptibility at genome-wide significance (P<5 × 10−8) that maps to TOMM40-APOE, a region previously implicated in lipid metabolism and Alzheimer's disease. We have also confirmed previous reports that single-nucleotide polymorphisms at the TCF7L2 locus demonstrate the greatest extent of heterogeneity in allelic effects between ethnic groups, with the lowest risk observed in populations of East Asian ancestry. PMID:27189021

  2. Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity.

    Science.gov (United States)

    van den Bergen, J C; Wokke, B H A; Hulsker, M A; Verschuuren, J J G M; Aartsma-Rus, A M

    2015-03-01

    Becker muscular dystrophy is characterized by a variable disease course. Many factors have been implicated to contribute to this diversity, among which the expression of several components of the dystrophin associated glycoprotein complex. Together with dystrophin, most of these proteins anchor the muscle fiber cytoskeleton to the extracellular matrix, thus protecting the muscle from contraction induced injury, while nNOS is primarily involved in inducing vasodilation during muscle contraction, enabling adequate muscle oxygenation. In the current study, we investigated the role of three components of the dystrophin associated glycoprotein complex (beta-dystroglycan, gamma-sarcoglycan and nNOS) and the dystrophin homologue utrophin on disease severity in Becker patients. Strength measurements, data about disease course and fresh muscle biopsies of the anterior tibial muscle were obtained from 24 Becker patients aged 19 to 66. The designation of Becker muscular dystrophy in this study was based on the mutation and not on the clinical severity. Contrary to previous studies, we were unable to find a relationship between expression of nNOS, beta-dystroglycan and gamma-sarcoglycan at the sarcolemma and disease severity, as measured by muscle strength in five muscle groups and age at reaching several disease milestones. Unexpectedly, we found an inverse correlation between utrophin expression at the sarcolemma and age at reaching disease milestones.

  3. Activation of the NF-kappaB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy.

    Science.gov (United States)

    Jayandharan, Giridhara R; Aslanidi, George; Martino, Ashley T; Jahn, Stephan C; Perrin, George Q; Herzog, Roland W; Srivastava, Arun

    2011-03-01

    Because our in silico analysis with a human transcription factor database demonstrated the presence of several binding sites for NF-κB, a central regulator of cellular immune and inflammatory responses, in the adeno-associated virus (AAV) genome, we investigated whether AAV uses NF-κB during its life cycle. We used small molecule modulators of NF-κB in HeLa cells transduced with recombinant AAV vectors. VP16, an NF-κB activator, augmented AAV vector-mediated transgene expression up to 25-fold. Of the two NF-κB inhibitors, Bay11, which blocks both the canonical and the alternative NF-κB pathways, totally ablated transgene expression, whereas pyrrolidone dithiocarbamate, which interferes with the classical NF-κB pathway, had no effect. Western blot analyses confirmed the abundance of the nuclear p52 protein component of the alternative NF-κB pathway in the presence of VP16, which was ablated by Bay11, suggesting that AAV transduction activates the alternative NF-κB pathway. In vivo, hepatic AAV gene transfer activated the canonical NF-κB pathway within 2 h, resulting in expression of proinflammatory cytokines and chemokines (likely reflecting the sensing of viral particles by antigen-presenting cells), whereas the alternative pathway was activated by 9 h. Bay11 effectively blocked activation of both pathways without interfering with long-term transgene expression while eliminating proinflammatory cytokine expression. These studies suggest that transient immunosuppression with NF-κB inhibitors before transduction with AAV vectors should lead to a dampened immune response, which has significant implications in the optimal use of AAV vectors in human gene therapy.

  4. Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance.

    Science.gov (United States)

    Cherlyn, Suat Ying Tan; Woon, Puay San; Liu, Jian Jun; Ong, Wei Yi; Tsai, Guo Chuan; Sim, Kang

    2010-05-01

    Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time.

  5. Black Families' Lay Views on Health and the Implications for Health Promotion: A Community-Based Study in the UK

    Science.gov (United States)

    Ochieng, Bertha

    2012-01-01

    Many studies focusing on beliefs about health and health promotion have paid little attention to the life experiences of Black and other visible minority ethnic families in western societies. This paper is a report of a study exploring Black families' beliefs about health and the implications of such beliefs for health promotion. Ten Black…

  6. Adult Learning Open University Determinants (ALOUD) study: Psychological factors associated with study success

    NARCIS (Netherlands)

    Neroni, Joyce; De Groot, Renate; Kirschner, Paul A.

    2013-01-01

    Neroni, J., De Groot, R. H. M., & Kirschner, P. A. (2012, 7 November). Adult Learning Open University Determinants (ALOUD) study: Psychological factors associated with study success. Poster presentation at the International ICO Fall School, Girona, Spain.

  7. Adult Learning Open University Determinants study (ALOUD): Biological lifestyle factors associated with study success

    NARCIS (Netherlands)

    Gijselaers, Jérôme; De Groot, Renate; Kirschner, Paul A.

    2012-01-01

    Gijselaers, H. J. M., De Groot, R. H. M., & Kirschner, P. A. (2012, 7 November). Adult Learning Open University Determinants study (ALOUD): Biological lifestyle factors associated with study success. Poster presentation at the International ICO Fall School, Girona, Spain.

  8. Multiethnic genetic association studies improve power for locus discovery.

    Directory of Open Access Journals (Sweden)

    Sara L Pulit

    Full Text Available To date, genome-wide association studies have focused almost exclusively on populations of European ancestry. These studies continue with the advent of next-generation sequencing, designed to systematically catalog and test low-frequency variation for a role in disease. A complementary approach would be to focus further efforts on cohorts of multiple ethnicities. This leverages the idea that population genetic drift may have elevated some variants to higher allele frequency in different populations, boosting statistical power to detect an association. Based on empirical allele frequency distributions from eleven populations represented in HapMap Phase 3 and the 1000 Genomes Project, we simulate a range of genetic models to quantify the power of association studies in multiple ethnicities relative to studies that exclusively focus on samples of European ancestry. In each of these simulations, a first phase of GWAS in exclusively European samples is followed by a second GWAS phase in any of the other populations (including a multiethnic design. We find that nontrivial power gains can be achieved by conducting future whole-genome studies in worldwide populations, where, in particular, African populations contribute the largest relative power gains for low-frequency alleles (<5% of moderate effect that suffer from low power in samples of European descent. Our results emphasize the importance of broadening genetic studies to worldwide populations to ensure efficient discovery of genetic loci contributing to phenotypic trait variability, especially for those traits for which large numbers of samples of European ancestry have already been collected and tested.

  9. A preliminary study on the association between ventilation rates in classrooms and student performance.

    Science.gov (United States)

    Shaughnessy, R J; Haverinen-Shaughnessy, U; Nevalainen, A; Moschandreas, D

    2006-12-01

    Poor conditions leading to substandard indoor air quality (IAQ) in classrooms have been frequently cited in the literature over the past two decades. However, there is limited data linking poor IAQ in the classrooms to student performance. Whereas, it is assumed that poor IAQ results in reduced attendance and learning potential, and subsequent poor student performance, validating this hypothesis presents a challenge in today's school environment. This study explores the association between student performance on standardized aptitude tests that are administered to students on a yearly basis, to classroom carbon dioxide (CO2) concentrations, which provide a surrogate of ventilation being provided to each room. Data on classroom CO2 concentrations (over a 4-5 h time span within a typical school day) were recorded in fifth grade classrooms in 54 elementary schools within a school district in the USA. Results from this preliminary study yield a significant (P classroom-level ventilation rate and test results in math. They also indicate that non-linear effects may need to be considered for better representation of the association. A larger sample size is required in order to draw more definitive conclusions. Practical Implications Future studies could focus on (1) gathering more evidence on the possible association between classroom ventilation rates and students' academic performance; (2) the linear/non-linear nature of the association; and (3) whether it is possible to detect 'no observed adverse effect level' for adequate ventilation with respect to academic performance in schools. All of this information could be used to improve guidance and take regulatory actions to ensure adequate ventilation in schools. The high prevalence of low ventilation rates, combined with the growing evidence of the positive impact that sufficient ventilation has on human performance, suggests an opportunity for improving design and management of school facilities.

  10. A statistical study of post-flare-associated CME events

    Science.gov (United States)

    Youssef, M.; Mawad, R.; shaltout, Mosalam

    2013-04-01

    We present a statistical study of post-flare-associated CMEs (PFA-CMEs) during the period from 1996 to 2010. By investigating all CMEs and X-ray flares, respectively, in the LASCO and GOES archives, we found 15875 CMEs of which masses are well measured and 25112 X-ray flares of which positions are determined from their optical counterparts. Under certain temporal and spatial criteria of these CMEs and solar flare events, 291PFA-CMEs events have been selected. Linking the flare fluxes with CME speeds of these paired events, we found that there is a reasonable positive linear relation between the CME linear speed and associated flare flux. The results show also the CME width increases as the flux of its associated solar flare increases. Besides we found that there is a fine positive linear relation between the CME mass and its width. Matching the flare fluxes with CME masses of these paired events, we find the CME mass increases as the flux of its associated solar flare increases. Finally we find the PFA-CME events are in regular more decelerated than the other CMEs.

  11. [Association study of telomere length with idiopathic male infertility].

    Science.gov (United States)

    Shuyuan, Liu; Changjun, Zhang; Haiying, Peng; Xiaoqin, Huang; Hao, Sun; Keqin, Lin; Kai, Huang; Jiayou, Chu; Zhaoqing, Yang

    2015-11-01

    Telomeres are evolutionary conserved, multifunctional DNA-protein complexes located at the ends of eukaryotic chromosomes. Telomeres maintain chromosome stability and genome integrity and also play an important role in meiosis which aid in synapsis, homologous recombination, and segregation. Sperm telomere has been reported to play an important role in fertilization and embryo development. Nowadays, the association between telomere and reproduction is one of the major areas of interest, however whether sperm telomere associated with male infertility is not clear. In this study, in order to find out the association between Chinese idiopathic infertility and sperm telomere length, we analyzed the difference of sperm telomere length between idiopathic infertile men and normal fertile men, as well as the correlations between sperm telomere length and human semen characteristics. We analyzed 126 Chinese idiopathic infertile men and 138 normal fertile men for sperm telomere length by using quantitative PCR. We found that the relative sperm mean telomere length of infertile men was significantly shorter than that of fertile men (2.894 ± 0.115 vs. 4.016 ± 0.603, P=5.097 x 10⁻⁵). Both sperm count and semen progressive motility are related with telomere length. Our results suggest that sperm telomere length is associated with idiopathic male infertility of China and we proposed the possibility that shorter telomeres in sperm chromosome will reduce spermatogenesis and sperm functions, which finally affected the fertility of male.

  12. A Photometric Study of Stars in the MBM 12 Association

    Science.gov (United States)

    Herbst, William; Williams, Eric C.; Hawley, Wendy P.

    2004-03-01

    We have monitored four fields containing nine previously identified members of the MBM 12 association to search for photometric variability and periodicity in these pre-main-sequence stars. Seven of the nine are found to be variable and definite periodicity (of 1.2, 2.6, and 6.2 days) is found for three of them, including the classical T Tauri star LkHα 264. Two other members are possibly periodic, but each requires confirmation. In addition, a ``field'' star that is associated with the X-ray source RX J0255.9+2005 was discovered to be a variable with a period of 4.2 days. Our results indicate that the photometric variability characteristics of the known MBM 12 association members are typical of what is found in roughly few-million-year-old stellar groups such as IC 348, supporting arguments for a similar age. In particular, there is a mix of periodic and nonperiodic variables with typical amplitudes (in Cousins I) of 0.1-0.5 mag, in addition to a small number of larger amplitude variables. The periods, as a group, are somewhat shorter than in IC 348, but when allowance is made for the known dependence of period on mass in pre-main-sequence stars the difference may not be significant. Our data confirm and illustrate the value of photometric monitoring as a tool for identifying likely association members and for studying rotation in extremely young stellar groups.

  13. Poor replication validity of biomedical association studies reported by newspapers

    Science.gov (United States)

    Smith, Andy; Boraud, Thomas; Gonon, François

    2017-01-01

    Objective To investigate the replication validity of biomedical association studies covered by newspapers. Methods We used a database of 4723 primary studies included in 306 meta-analysis articles. These studies associated a risk factor with a disease in three biomedical domains, psychiatry, neurology and four somatic diseases. They were classified into a lifestyle category (e.g. smoking) and a non-lifestyle category (e.g. genetic risk). Using the database Dow Jones Factiva, we investigated the newspaper coverage of each study. Their replication validity was assessed using a comparison with their corresponding meta-analyses. Results Among the 5029 articles of our database, 156 primary studies (of which 63 were lifestyle studies) and 5 meta-analysis articles were reported in 1561 newspaper articles. The percentage of covered studies and the number of newspaper articles per study strongly increased with the impact factor of the journal that published each scientific study. Newspapers almost equally covered initial (5/39 12.8%) and subsequent (58/600 9.7%) lifestyle studies. In contrast, initial non-lifestyle studies were covered more often (48/366 13.1%) than subsequent ones (45/3718 1.2%). Newspapers never covered initial studies reporting null findings and rarely reported subsequent null observations. Only 48.7% of the 156 studies reported by newspapers were confirmed by the corresponding meta-analyses. Initial non-lifestyle studies were less often confirmed (16/48) than subsequent ones (29/45) and than lifestyle studies (31/63). Psychiatric studies covered by newspapers were less often confirmed (10/38) than the neurological (26/41) or somatic (40/77) ones. This is correlated to an even larger coverage of initial studies in psychiatry. Whereas 234 newspaper articles covered the 35 initial studies that were later disconfirmed, only four press articles covered a subsequent null finding and mentioned the refutation of an initial claim. Conclusion Journalists

  14. [Genome-wide association study for adolescent idiopathic scoliosis].

    Science.gov (United States)

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS.

  15. Factors associated with incomplete small bowel capsule endoscopy studies

    Institute of Scientific and Technical Information of China (English)

    Mitchell; M; Lee; Andrew; Jacques; Eric; Lam; Ricky; Kwok; Pardis; Lakzadeh; Ajit; Sandhar; Brandon; Segal; Sigrid; Svarta; Joanna; Law; Robert; Enns

    2010-01-01

    AIM:To identify patient risk factors associated with incomplete small bowel capsule endoscopy(CE) studies.METHODS:Data from all CE procedures performed at St.Paul's Hospital in Vancouver,British Columbia,Canada,between December 2001 and June 2008 were collected and analyzed on a retrospective basis.Data collection for complete and incomplete CE study groups included patient demographics as well as a number of potential risk factors for incomplete CE including indication for the procedure,hospitalization,dia...

  16. Genome-wide association study of antisocial personality disorder

    Science.gov (United States)

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53–3.14), P=1.9 × 10-5). Two polymorphisms at 6p21.2 LINC00951–LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37–1.85), P=1.6 × 10−9) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  17. Universal design of workplaces through the use of Poka-Yokes: Case study and implications

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    Cristóbal Miralles

    2011-10-01

    Full Text Available Purpose: Employment plays an important part in many people’s lives beyond merely providing income, since continued participation in work can have many therapeutic benefits for workers defined as disabled. However, disabled workers face a range of barriers to employment, despite legislation intended to improve workplace accessibility emphasizing adaptations to the workplace, which many employers often find difficult and expensive. The Poka-Yoke approach was developed in the manufacturing industry as a way of improving productivity by reducing errors using often very simple adaptations. This paper argues that, as Poka-Yokes are designed to make life easier and improve the performance of workers without impairments, they are closer to the philosophy of Universal Design than to Accessible Design, and offer an easy and inclusive way of making work more accessible for all kind of workers. Design/methodology/approach: This paper provides a case study demonstrating the use of the Poka-Yoke approach in a sheltered work centre for disabled; highlighting how they served to improve accessibility to work by fulfilling Universal Design principles. Findings: Our research allows us to demonstrate the great potential of Poka-yokes for gaining accessibility to the workplace. The real application of this approach, both in sheltered work centres and ordinary companies, can contribute to improve the high unemployment rates of disabled people. Research limitations/implications: The proposal is innovative and was applied in one specific company. Thus, a range of customized Poka-yokes would be desirable for different industrial sectors. Practical implications: Managers of sheltered work centres, and also of ordinary companies, can realize about the great potential of Poka-Yokes as an easy means of gaining flexibility and accessibility. Originality/value: There are very few papers relating lean manufacturing tools and disability. Our approach analyzes the benefits of

  18. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

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    Giuseppe Matullo

    Full Text Available Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM, a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes, causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14. Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28. These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

  19. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    Science.gov (United States)

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W B; de Klerk, Nicholas H; Hui, Jennie; Beilby, John; James, Alan L; Creaney, Jenette; Robinson, Bruce W; Mukherjee, Sutapa; Palmer, Lyle J; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

  20. Genome-wide association study and premature ovarian failure.

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    Christin-Maitre, S; Tachdjian, G

    2010-05-01

    Premature ovarian failure (POF) is defined as an amenorrhea for more than 4months, associated with elevated gonadotropins, usually higher than 20mIU/ml, occurring in a woman before the age of 40. Some candidate genes have been identified in the past 15years, such as FOXL2, FSHR, BMP15, GDF9, Xfra premutation. However, POF etiology remains unknown in more than 90% of cases. The first strategy to identify candidate gene, apart from studying genes involved in ovarian failure in animal models, relies on the study of X chromosome deletions and X;autosome translocations in patients. The second strategy is based on linkage analysis, the third one on Comparative Genomic Hybridization (CGH) array. The latest strategy relies on Genome-Wide Association Studies (GWAS). This technique consists in screening single nucleotide polymorphisms (SNPs) in patients and controls. So far, three studies have been performed and have identified different loci potentially linked to POF, such as PTHB1 and ADAMTS19. However, replications in independent cohorts need to be performed. GWAS studies on large cohorts of women with POF should find new candidate genes in the near future.

  1. Phenome-wide association study (PheWAS in EMR-linked pediatric cohorts

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    Bahram eNamjou

    2014-11-01

    Full Text Available Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS using electronic medical records (EMRs. Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts.Method: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs of two large academic centers in five different genotyped cohorts. After standard quality controls, removing missing data and outliers based on principal components (PC analyses, 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach was implemented.Results: This PheWAS replicated a variety of common variants (MAF>10% with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JIA, Asthma, Autism and Pervasive Developmental Disorder (PDD and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings included a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p=4.33x10-7, OR=1.70, 95%CI=1.38-2.09, association at vicinity of (PLCL1, PRIP-1 gene for developmental delays and speech disorder (best SNP rs1595825, p=1.13x10-8, OR=0.65(0.57-0.76, a cluster of SNP associations in the IL5-IL13 region, previously implicated in Asthma, Allergy, and Eosinophilia, with Eosinophilic Esophagitis (EE (best SNP rs12653750, p=3.03x10-9, OR=1.73 95%CI=(1.44-2.07 and association of variants in GCKR and JAZF1, responsible for metabolic disease and diabetes in adults with allergic rhinitis in our pediatric cohorts (best SNP rs780093, p=2.18x10-5, OR=1.39, 95%CI=(1.19-1.61.Conclusion: By using the PheWAS approach and

  2. Genome-wide association study identifies multiple loci associated with bladder cancer risk

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    Figueroa, Jonine D.; Ye, Yuanqing; Siddiq, Afshan; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P.; Malats, Núria; Baris, Dalsu; Purdue, Mark; Jacobs, Eric J.; Albanes, Demetrius; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Tang, Wei; Bas Bueno-de-Mesquita, H.; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M.; Lerner, Seth P.; Barton Grossman, H.; Lin, Jie; Gu, Jian; Pu, Xia; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schwenn, Molly; Karagas, Margaret R.; Johnson, Alison; Schned, Alan; Armenti, Karla R.; Hosain, G.M.; Andriole, Gerald; Grubb, Robert; Black, Amanda; Ryan Diver, W.; Gapstur, Susan M.; Weinstein, Stephanie J.; Virtamo, Jarmo; Haiman, Chris A.; Landi, Maria T.; Caporaso, Neil; Fraumeni, Joseph F.; Vineis, Paolo; Wu, Xifeng; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel

    2014-01-01

    Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. PMID:24163127

  3. STUDY OF ASSOCIATION OF DIABETIC MACULOPATHY WITH HYPERLIPIDEMIA

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    Sivaramareddy

    2015-12-01

    Full Text Available BACKGROUND Diabetic maculopathy is the most common microvascular complication in diabetes, which can produce severe visual loss. Apart from diabetes, a number of systemic factor like hyperlipidemia has an important role in occurrence and progression of Diabetic Macular Edema. Thus control of these factors along with control of blood sugars can prevent or reverse the maculopathy and thereby restore the vision of diabetic patients. OBJECTIVES To study the association of diabetic maculopathy with Hyperlipidemia to highlight the effect of this factor on onset and/or progression of diabetic maculopathy. MATERIALS AND METHODS A cross-sectional comparative study was carried out in 100 diabetic patient with retinopathy more than 18 years attending Department of Ophthalmology. For all patients visual acuity, slit lamp examination, intraocular pressure, fundus examination was conducted. Patients were divided into 2 groups (Group1 - Retinopathy with maculopathy and Group 2 - Retinopathy without maculopathy. A detailed history of duration of diabetes, type of treatment, hyperlipidemia were taken from the patient. The significance of the hyperlipidemia was compared in both the groups involved in the study. RESULTS In the present study of 100 patients diagnosed with diabetic retinopathy, majority were males (54% in study group and 58% in control group by age 51-60 years. In the study group, majority (76% patients had duration of DM>10 years, whereas in control group majority of patients (70% had duration 5-10 years. The mean value of PPBS, HbA1C were significantly higher in study group than in control group. In this study among serum lipids, serum cholesterol, serum triglycerides, VLDL and LDL levels were significantly higher in study group compared to control group. CONCLUSION Diabetic maculopathy was significantly associated with hyperlipidemia. Thus early detection of this risk factor and their control prevent the development and progression of maculopathy

  4. Multiple Sclerosis Associated Risk Factors: A Case-Control Study

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    Jalal POOROLAJAL

    2015-11-01

    Full Text Available Background: Hamadan Province is one of the high-risk regions in Iran for Multiple sclerosis (MS. A majority of the epidemiological studies conducted in Iran addressing MS are descriptive. This study was conducted to assess MS and its associated risk factors in Hamadan Province, the west of Iran.Methods: This case-control study compared 100 patients with MS (case group and 100 patients with acute infectious diseases (control group from September 2013 to March 2014. A checklist was used to assess the demographic, medical, and family history of the patients. The Friedman-Rosenman questionnaire was also used to assess personality type. Statistical analysis was performed using logistic regression model with Stata 11 software program.Results: The adjusted odds ratio (OR estimate of MS was 4.37 (95% CI: 2.33, 8.20 for females compared to males; 0.15 (95% CI: 0.06, 0.43 for people aged above 50 years compared to aged 14 to 29 years; 0.44 (95% CI: 0.21, 0.91 for overweight or obese people compared to normal weights. Crude OR indicated a significant association between the occurrence of MS and exclusive breast feeding, season of birth, and smoking. However, the association was not statistically significant after adjustment for other covariates.Conclusion: The risk of MS is significantly lower in male gender, obese/overweight, and old people. Furthermore, non-smoking, non-exclusive breast-feeding, and born in autumn may increase the risk of MS but need further investigation. However, long-term large prospective cohort studies are needed to investigate the true effect of the potential risk factors on MS. Keywords: Multiple sclerosis, Risk factors, Case-control study, Iran

  5. Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma

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    Yucesoy, Berran; Kaufman, Kenneth M.; Lummus, Zana L.; Weirauch, Matthew T.; Zhang, Ge; Cartier, André; Boulet, Louis-Philippe; Sastre, Joaquin; Quirce, Santiago; Tarlo, Susan M.; Cruz, Maria-Jesus; Munoz, Xavier; Harley, John B.; Bernstein, David I.

    2015-01-01

    Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10−14). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10−9 and rs2514805, p = 1.22 × 10−8, respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10−6). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies. PMID:25918132

  6. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

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    Sandosh Padmanabhan

    2010-10-01

    Full Text Available Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹. The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91], reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027. In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003. In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

  7. A genome-wide association study in multiple system atrophy

    Science.gov (United States)

    Sailer, Anna; Nalls, Michael A.; Schulte, Claudia; Federoff, Monica; Price, T. Ryan; Lees, Andrew; Ross, Owen A.; Dickson, Dennis W.; Mok, Kin; Mencacci, Niccolo E.; Schottlaender, Lucia; Chelban, Viorica; Ling, Helen; O'Sullivan, Sean S.; Wood, Nicholas W.; Traynor, Bryan J.; Ferrucci, Luigi; Federoff, Howard J.; Mhyre, Timothy R.; Morris, Huw R.; Deuschl, Günther; Quinn, Niall; Widner, Hakan; Albanese, Alberto; Infante, Jon; Bhatia, Kailash P.; Poewe, Werner; Oertel, Wolfgang; Höglinger, Günter U.; Wüllner, Ullrich; Goldwurm, Stefano; Pellecchia, Maria Teresa; Ferreira, Joaquim; Tolosa, Eduardo; Bloem, Bastiaan R.; Rascol, Olivier; Meissner, Wassilios G.; Hardy, John A.; Revesz, Tamas; Holton, Janice L.; Gasser, Thomas; Wenning, Gregor K.; Singleton, Andrew B.

    2016-01-01

    Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10−6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps. PMID:27629089

  8. Sincipital Encephaloceles: A Study of Associated Brain Malformations

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    Shashidhar Vedavyas Achar

    2016-01-01

    Full Text Available Objective: The aim of this study was to evaluate the associated intracranial malformations in patients with sincipital encephaloceles. Materials and Methods: A hospital-based cross-sectional study was conducted over 8 years from June 2007 to May 2015 on 28 patients. The patients were evaluated by either computed tomography or magnetic resonance imaging whichever was feasible. Encephaloceles were described with respect to their types, contents, and extensions. A note was made on the associated malformations with sincipital encephaloceles. Results: Fifty percent of the patients presented before the age of 3 years and both the sexes were affected equally. Nasofrontal encephalocele was the most common type seen in 13 patients (46.4%, and corpus callosal agenesis (12 patients was the most common associated malformation. Other malformations noted were arachnoid cyst (10 patients, hydrocephalus (7 patients, and agyria-pachygyria complex (2 patients. Conclusion: Capital Brain malformations are frequently encountered in children with sincipital encephaloceles. Detail radiological evaluation is necessary to plan treatment and also to prognosticate such rare malformations.

  9. A genome-wide association study of heat stress-associated SNPs in catfish.

    Science.gov (United States)

    Jin, Y; Zhou, T; Geng, X; Liu, S; Chen, A; Yao, J; Jiang, C; Tan, S; Su, B; Liu, Z

    2017-04-01

    Heat tolerance is a complex and economically important trait for catfish genetic breeding programs. With global climate change, it is becoming an increasingly important trait. To better understand the molecular basis of heat stress, a genome-wide association study (GWAS) was carried out using the 250 K catfish SNP array with interspecific backcross progenies, which derived from crossing female channel catfish with male F1 hybrid catfish (female channel catfish × male blue catfish). Three significant associated SNPs were detected by performing an EMMAX approach for GWAS. The SNP located on linkage group 14 explained 12.1% of phenotypical variation. The other two SNPs, located on linkage group 16, explained 11.3 and 11.5% of phenotypical variation respectively. A total of 14 genes with heat stress related functions were detected within the significant associated regions. Among them, five genes-TRAF2, FBXW5, ANAPC2, UBR1 and KLHL29- have known functions in the protein degradation process through the ubiquitination pathway. Other genes related to heat stress include genes involved in protein biosynthesis (PRPF4 and SYNCRIP), protein folding (DNAJC25), molecule and iron transport (SLC25A46 and CLIC5), cytoskeletal reorganization (COL12A1) and energy metabolism (COX7A2, PLCB1 and PLCB4) processes. The results provide fundamental information about genes and pathways that is useful for further investigation into the molecular mechanisms of heat stress. The associated SNPs could be promising candidates for selecting heat-tolerant catfish lines after validating their effects on larger and various catfish populations.

  10. Polycyclic aromatic hydrocarbons associated with road deposited solid and their ecological risk: Implications for road stormwater reuse.

    Science.gov (United States)

    Liu, Liang; Liu, An; Li, Yang; Zhang, Lixun; Zhang, Guijuan; Guan, Yuntao

    2016-09-01

    Reusing stormwater is becoming popular worldwide. However, urban road stormwater commonly contains toxic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), which could undermine reuse safety. This study investigated pollution level of PAHs and their composition build-up on urban roads in a typical megacity in South China. The potential ecological risk posed by PAHs associated with road deposited solid (RDS) was also assessed. Results showed that ecological risk levels varied based on different land use types, which could be significantly influenced by the composition of PAHs and characteristics of RDS. A higher percentage of high-ring PAHs, such as more than four rings, could pose higher ecological risk and are more likely to undermine stormwater reuse safety. Additionally, the degree of traffic congestion rather than traffic volume was found to exert a more significant influence on the generation of high-ring PAH generation. Therefore, stormwater from more congested roads might need proper treatment (particularly for removing high-ring PAHs) before reuse or could be suitable for purposes requiring low-water-quality. The findings of this study are expected to contribute to adequate stormwater reuse strategy development and to enhance the safety of urban road stormwater reuse.

  11. A genome-wide association study of optic disc parameters.

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    Wishal D Ramdas

    2010-06-01

    Full Text Available The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR. Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19 within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33 within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11 in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10 within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612, and the TwinsUK cohort (N = 843. Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant, and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.

  12. Feasibility study for banking loan using association rule mining classifier

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    Agus Sasmito Aribowo

    2015-03-01

    Full Text Available The problem of bad loans in the koperasi can be reduced if the koperasi can detect whether member can complete the mortgage debt or decline. The method used for identify characteristic patterns of prospective lenders in this study, called Association Rule Mining Classifier. Pattern of credit member will be converted into knowledge and used to classify other creditors. Classification process would separate creditors into two groups: good credit and bad credit groups. Research using prototyping for implementing the design into an application using programming language and development tool. The process of association rule mining using Weighted Itemset Tidset (WIT–tree methods. The results shown that the method can predict the prospective customer credit. Training data set using 120 customers who already know their credit history. Data test used 61 customers who apply for credit. The results concluded that 42 customers will be paying off their loans and 19 clients are decline

  13. Technological issues and experimental design of gene association studies.

    Science.gov (United States)

    Distefano, Johanna K; Taverna, Darin M

    2011-01-01

    Genome-wide association studies (GWAS), in which thousands of single-nucleotide polymorphisms (SNPs) spanning the genome are genotyped in individuals who are phenotypically well characterized, -currently represent the most popular strategy for identifying gene regions associated with common -diseases and related quantitative traits. Improvements in technology and throughput capability, development of powerful statistical tools, and more widespread acceptance of pooling-based genotyping approaches have led to greater utilization of GWAS in human genetics research. However, important considerations for optimal experimental design, including selection of the most appropriate genotyping platform, can enhance the utility of the approach even further. This chapter reviews experimental and technological issues that may affect the success of GWAS findings and proposes strategies for developing the most comprehensive, logical, and cost-effective approaches for genotyping given the population of interest.

  14. Study on acute burn injury survivors and the associated issues

    Institute of Scientific and Technical Information of China (English)

    Jonathan Bayuo; Pius Agbenorku; Richcane Amankwa

    2016-01-01

    Objective: To explore the phenomenon of surviving burn injury and its associated issues and concerns. Methods: A cross sectional survey approach was utilized to obtain data from one hundred burn survivors who were purposely selected. Descriptive statistics and content analysis were used to analyze data. Results: Findings from the study indicate that burns from flames stood out as a major cause of burns. Physical discomfort/pain, anxiety, needing assistance in meeting self-care needs, financial and social limitations were identified as the major impact of the injury. Furthermore, participants perceived the existence of societal stigma. In addition, hope in God or a spiritual being as well as family support were the two key resources participants relied on to cope effectively. Conclusions: Surviving burn injury is associated with varied physical, social and psy-chological factors and survivors may need professional assistance to fully adjust after discharge.

  15. Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies

    Science.gov (United States)

    Hedman, Åsa K.; Mendelson, Michael M.; Marioni, Riccardo E.; Gustafsson, Stefan; Joehanes, Roby; Irvin, Marguerite R.; Zhi, Degui; Sandling, Johanna K.; Yao, Chen; Liu, Chunyu; Liang, Liming; Huan, Tianxiao; McRae, Allan F.; Demissie, Serkalem; Shah, Sonia; Starr, John M.; Cupples, L. Adrienne; Deloukas, Panos; Spector, Timothy D.; Sundström, Johan; Krauss, Ronald M.; Arnett, Donna K.; Deary, Ian J.; Lind, Lars; Levy, Daniel

    2017-01-01

    Background— Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results— To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P<1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P=8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15–1.66; P=0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (PTC=0.004, PHDL-C=0.008 and Ptriglycerides=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus. Conclusions— We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol

  16. Facial dermatosis associated with Demodex: a case-control study.

    Science.gov (United States)

    Zhao, Ya-e; Peng, Yan; Wang, Xiang-lan; Wu, Li-ping; Wang, Mei; Yan, Hu-ling; Xiao, Sheng-xiang

    2011-12-01

    Demodex has been considered to be related with multiple skin disorders, but controversy persists. In this case-control study, a survey was conducted with 860 dermatosis patients aged 12 to 84 years in Xi'an, China to identify the association between facial dermatosis and Demodex. Amongst the patients, 539 suffered from facial dermatosis and 321 suffered from non-facial dermatosis. Demodex mites were sampled and examined using the skin pressurization method. Multivariate regression analysis was applied to analyze the association between facial dermatosis and Demodex infestation, and to identify the risk factors of Demodex infestation. The results showed that total detection rate of Demodex was 43.0%. Patients aged above 30 years had higher odds of Demodex infestation than those under 30 years. Compared to patients with neutral skin, patients with mixed, oily, or dry skin were more likely to be infested with Demodex (odds ratios (ORs) were 2.5, 2.4, and 1.6, respectively). Moreover, Demodex infestation was found to be statistically associated with rosacea (OR=8.1), steroid-induced dermatitis (OR=2.7), seborrheic dermatitis (OR=2.2), and primary irritation dermatitis (OR=2.1). In particular, ORs calculated from the severe infestation (≥5 mites/cm(2)) rate were significantly higher than those of the total rate. Therefore, we concluded that Demodex is associated with rosacea, steroid-induced dermatitis, seborrheic dermatitis, and primary irritation dermatitis. The rate of severe infestation is found to be more correlated with various dermatosis than the total infestation rate. The risk factors of Demodex infestation, age, and skin types were identified. Our study also suggested that good hygiene practice might reduce the chances of demodicosis and Demodex infestation.

  17. Facial dermatosis associated with Demodex: a case-control study

    Institute of Scientific and Technical Information of China (English)

    Ya-e ZHAO; Yah PENG; Xiang-lan WANG; Li-ping WU; Mei WANG; Hu-ling YAN; Sheng-xiang XIAO

    2011-01-01

    Demodex has been considered to be related with multiple skin disorders,but controversy persists.In this case-control study,a survey was conducted with 860 dermatosis patients aged 12 to 84 years in Xi'an,China to identify the association between facial dermatosis and Demodex.Amongst the patients,539 suffered from facial dermatosis and 321 suffered from non-facial dermatosis.Demodex mites were sampled and examined using the skin pressurization method.Multivariate regression analysis was applied to analyze the association between facial dermatosis and Demodex infestation,and to identify the risk factors of Demodex infestation.The results showed that total detection rate of Demodex was 43.0%.Patients aged above 30 years had higher odds of Demodex infestation than those under 30 years.Compared to patients with neutral skin,patients with mixed,oily,or dry skin were more likely to be infested with Demodex (odds ratios (ORs) were 2.5,2.4,and 1.6,respectively).Moreover,Demodex infestation was found to be statistically associated with rosacea (OR=8.1),steroid-induced dermatitis (OR=2.7),seborrheic dermatitis (OR=2.2),and primary irritation dermatitis (OR=2.1).In particular,ORs calculated from the severe infestation (≥5 mites/cm2) rate were significantly higher than those of the total rate.Therefore,we concluded that Demodex is associated with rosacea,steroid-induced dermatitis,seborrheic dermatitis,and primary irritation dermatitis.The rate of severe infestation is found to be more correlated with various dermatosis than the total infestation rate.The risk factors of Demodex infestation,age,and skin types were identified.Our study also suggested that good hygiene practice might reduce the chances of demodicosis and Demodex infestation.

  18. An ERP study of conflict monitoring in 4-8-year old children: associations with temperament.

    Science.gov (United States)

    Buss, Kristin A; Dennis, Tracy A; Brooker, Rebecca J; Sippel, Lauren M

    2011-04-01

    Although there is great interest in identifying the neural correlates of cognitive processes that create risk for psychopathology, there is a paucity of research in young children. One event-related potential (ERP), the N2, is thought to index conflict monitoring and has been linked cognitive and affective risk factors for anxiety. Most of this research, however, has been conducted with adults, adolescents, and older children, but not with younger children. To address this gap, the current study examined 26 4-8-year-olds, who completed a cued flanker task while EEG was continuously recorded. We assessed whether the N2 was detectable in this group of young children and examined associations between the N2 and factors reflecting affective risk (e.g., reduced executive attention, temperamental effortful control, and temperamental surgency). We documented an N2 effect (greater N2 amplitude to incongruent versus congruent flankers), but only in children older than 6 years of age. Increases in the N2 effect were associated with less efficient executive attention and lower temperamental effortful control. We discuss the implications of these findings and consider how they may inform future studies on biomarkers for cognitive and affective risk factors for anxiety.

  19. Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

    Science.gov (United States)

    Tin, Adrienne; Sorice, Rossella; Gorski, Mathias; Yeo, Nan Cher; Chu, Audrey Y.; Li, Man; Li, Yong; Mijatovic, Vladan; Ko, Yi-An; Taliun, Daniel; Luciani, Alessandro; Chen, Ming-Huei; Yang, Qiong; Foster, Meredith C.; Olden, Matthias; Hiraki, Linda T.; Tayo, Bamidele O.; Fuchsberger, Christian; Dieffenbach, Aida Karina; Shuldiner, Alan R.; Smith, Albert V.; Zappa, Allison M.; Lupo, Antonio; Kollerits, Barbara; Ponte, Belen; Stengel, Bénédicte; Krämer, Bernhard K.; Paulweber, Bernhard; Mitchell, Braxton D.; Hayward, Caroline; Helmer, Catherine; Meisinger, Christa; Gieger, Christian; Shaffer, Christian M.; Müller, Christian; Langenberg, Claudia; Ackermann, Daniel; Siscovick, David; Boerwinkle, Eric; Kronenberg, Florian; Ehret, Georg B.; Homuth, Georg; Waeber, Gerard; Navis, Gerjan; Gambaro, Giovanni; Malerba, Giovanni; Eiriksdottir, Gudny; Li, Guo; Wichmann, H. Erich; Grallert, Harald; Wallaschofski, Henri; Völzke, Henry; Brenner, Herrmann; Kramer, Holly; Leach, I. Mateo; Rudan, Igor; Hillege, Hans L.; Beckmann, Jacques S.; Lambert, Jean Charles; Luan, Jian'an; Zhao, Jing Hua; Chalmers, John; Coresh, Josef; Denny, Joshua C.; Butterbach, Katja; Launer, Lenore J.; Ferrucci, Luigi; Kedenko, Lyudmyla; Haun, Margot; Metzger, Marie; Woodward, Mark; Hoffman, Matthew J.; Nauck, Matthias; Waldenberger, Melanie; Pruijm, Menno; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Wareham, Nicholas J.; Endlich, Nicole; Soranzo, Nicole; Polasek, Ozren; van der Harst, Pim; Pramstaller, Peter Paul; Vollenweider, Peter; Wild, Philipp S.; Gansevoort, Ron T.; Rettig, Rainer; Biffar, Reiner; Carroll, Robert J.; Katz, Ronit; Loos, Ruth J.F.; Hwang, Shih-Jen; Coassin, Stefan; Bergmann, Sven; Rosas, Sylvia E.; Stracke, Sylvia; Harris, Tamara B.; Corre, Tanguy; Zeller, Tanja; Illig, Thomas; Aspelund, Thor; Tanaka, Toshiko; Lendeckel, Uwe; Völker, Uwe; Gudnason, Vilmundur; Chouraki, Vincent; Koenig, Wolfgang; Kutalik, Zoltan; O'Connell, Jeffrey R.; Parsa, Afshin; Heid, Iris M.; Paterson, Andrew D.; de Boer, Ian H.; Devuyst, Olivier; Lazar, Jozef; Endlich, Karlhans; Susztak, Katalin; Tremblay, Johanne; Hamet, Pavel; Jacob, Howard J.; Böger, Carsten A.

    2016-01-01

    Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria. PMID:26631737

  20. Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study.

    Directory of Open Access Journals (Sweden)

    Jingwei Yuan

    Full Text Available Egg number (EN, egg laying rate (LR and age at first egg (AFE are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens.

  1. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

    DEFF Research Database (Denmark)

    Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur

    2014-01-01

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.......Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects....

  2. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    Directory of Open Access Journals (Sweden)

    James D McKay

    2011-03-01

    Full Text Available Genome-wide association studies (GWAS have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷. Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸ located near DNA repair related genes HEL308 and FAM175A (or Abraxas and a 12q24 variant (rs4767364, p =2 × 10⁻⁸ located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2 gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸; rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02. These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  3. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    LENUS (Irish Health Repository)

    McKay, James D

    2011-03-01

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  4. A candidate gene association study on muscat flavor in grapevine (Vitis vinifera L.

    Directory of Open Access Journals (Sweden)

    Boursiquot Jean-Michel

    2010-11-01

    Full Text Available Abstract Background The sweet, floral flavor typical of Muscat varieties (Muscats, due to high levels of monoterpenoids (geraniol, linalool and nerol, is highly distinct and has been greatly appreciated both in table grapes and in wine since ancient times. Muscat flavor determination in grape (Vitis vinifera L. has up to now been studied by evaluating monoterpenoid levels through QTL analysis. These studies have revealed co-localization of 1-deoxy-D-xylulose 5-phosphate synthase (VvDXS with the major QTL positioned on chromosome 5. Results We resequenced VvDXS in an ad hoc association population of 148 grape varieties, which included muscat-flavored, aromatic and neutral accessions as well as muscat-like aromatic mutants and non-aromatic offsprings of Muscats. Gene nucleotide diversity and intragenic linkage disequilibrium (LD were evaluated. Structured association analysis revealed three SNPs in moderate LD to be significantly associated with muscat-flavored varieties. We identified a putative causal SNP responsible for a predicted non-neutral substitution and we discuss its possible implications for flavor metabolism. Network analysis revealed a major star-shaped cluster of reconstructed haplotypes unique to muscat-flavored varieties. Moreover, muscat-like aromatic mutants displayed unique non-synonymous mutations near the mutated site of Muscat genotypes. Conclusions This study is a crucial step forward in understanding the genetic regulation of muscat flavor in grapevine and it also sheds light on the domestication history of Muscats. VvDXS appears to be a possible human-selected locus in grapevine domestication and post-domestication. The putative causal SNP identified in Muscat varieties as well as the unique mutations identifying the muscat-like aromatic mutants under study may be immediately applied in marker-assisted breeding programs aimed at enhancing fragrance and aroma complexity respectively in table grape and wine cultivars.

  5. A synthesis of studies searching for school factors : implications for theory and research

    NARCIS (Netherlands)

    Kyriakides, Leonidas; Creemers, Bert; Antoniou, Panayiotis; Demetriou, Demetris

    2010-01-01

    This paper reports the results of a meta-analysis in which the dynamic model of educational effectiveness is used as a framework to search for school factors associated with student achievement. The methods and results of a synthesis of 67 studies are presented. Findings reveal that effective school

  6. Counseling a Student Presenting Borderline Personality Disorder in the Small College Context: Case Study and Implications

    Science.gov (United States)

    Draper, Matthew R.; Faulkner, Ginger E.

    2009-01-01

    This case study examines the dynamics and challenges associated with counseling a client experiencing borderline personality disorder in the small college institutional context. The work of counseling centers at small private institutions has been relatively unexplored in the extant college counseling literature. To help fill this gap, the current…

  7. Genome-wide association study identified a narrow chromosome 1 region associated with chicken growth traits.

    Directory of Open Access Journals (Sweden)

    Liang Xie

    Full Text Available Chicken growth traits are important economic traits in broilers. A large number of studies are available on finding genetic factors affecting chicken growth. However, most of these studies identified chromosome regions containing putative quantitative trait loci and finding causal mutations is still a challenge. In this genome-wide association study (GWAS, we identified a narrow 1.5 Mb region (173.5-175 Mb of chicken (Gallus gallus chromosome (GGA 1 to be strongly associated with chicken growth using 47,678 SNPs and 489 F2 chickens. The growth traits included aggregate body weight (BW at 0-90 d of age measured weekly, biweekly average daily gains (ADG derived from weekly body weight, and breast muscle weight (BMW, leg muscle weight (LMW and wing weight (WW at 90 d of age. Five SNPs in the 1.5 Mb KPNA3-FOXO1A region at GGA1 had the highest significant effects for all growth traits in this study, including a SNP at 8.9 Kb upstream of FOXO1A for BW at 22-48 d and 70 d, a SNP at 1.9 Kb downstream of FOXO1A for WW, a SNP at 20.9 Kb downstream of ENSGALG00000022732 for ADG at 29-42 d, a SNP in INTS6 for BW at 90 d, and a SNP in KPNA3 for BMW and LMW. The 1.5 Mb KPNA3-FOXO1A region contained two microRNA genes that could bind to messenger ribonucleic acid (mRNA of IGF1, FOXO1A and KPNA3. It was further indicated that the 1.5 Mb GGA1 region had the strongest effects on chicken growth during 22-42 d.

  8. A Case Study with an Identified Bully: Policy and Practice Implications

    Directory of Open Access Journals (Sweden)

    Huddleston, Lillie

    2011-07-01

    Full Text Available Objective: Bullying is a serious public health problem that may include verbal or physical injury as well as social isolation or exclusion. As a result, research is needed to establish a database for policies and interventions designed to prevent bullying and its negative effects. This paper presented a case study that contributed to the literature by describing an intervention for bullies that has implications for research, practice and related policies regarding bullying.Methods: An individualized intervention for an identified bully was implemented using the Participatory Culture-Specific Intervention Model (PCSIM; Nastasi, Moore, & Varjas, 2004 with a seventh-grade middle school student. Ecological and culture-specific perspectives were used to develop and implement the intervention that included psychoeducational sessions with the student and consultation with the parent and school personnel. A mixed methods intervention design was used with the following informants: the target student, the mother of the student, a teacher and the school counselor. Qualitative data included semi-structured interviews with the parent, teacher and student, narrative classroom observations and evaluation/feedback forms filled out by the student and interventionist. Quantitative data included the following quantitative surveys (i.e., Child Posttraumatic Stress Reaction Index [CPTS-RI] and the Behavior Assessment Scale for Children, 2nd Edition. Both qualitative and quantitative data were used to evaluate the acceptability, integrity and efficacy of this intervention.Results: The process of intervention design, implementation and evaluation are described through an illustrative case study. Qualitative and quantitative findings indicated a decrease in internalizing, externalizing and bullying behaviors as reported by the teacher and the mother, and a high degree of acceptability and treatment integrity as reported by multiple stakeholders.Conclusion: This case

  9. A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study.

    Directory of Open Access Journals (Sweden)

    Simon Baron-Cohen

    Full Text Available Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419 versus low (n = 183 mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10(-5, 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10(-6. In this analysis, one of the SNPs (rs789859 showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115 were nominally significant (lowest p-value 3.278 × 10(-4. Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64. The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.

  10. Functional implications of hippocampal degeneration in early Alzheimer's disease: a combined DTI and PET study

    Energy Technology Data Exchange (ETDEWEB)

    Yakushev, Igor; Mueller, Matthias J.; Schermuly, Ingrid; Fellgiebel, Andreas [University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz (Germany); Schreckenberger, Matthias [University Medical Center Mainz, Department of Nuclear Medicine, Mainz (Germany); Cumming, Paul [University of Munich, Department of Nuclear Medicine, Munich (Germany); Stoeter, Peter [University Medical Center Mainz, Institute of Neuroradiology, Mainz (Germany); Gerhard, Alex [University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz (Germany); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom)

    2011-12-15

    Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. Twenty patients with early AD (Mini-Mental State Examination 25.7 {+-} 1.7) were studied with [{sup 18}F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p< 0.005). The same correlation pattern was found for right hippocampal diffusivity (p< 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment. (orig.)

  11. Genome-wide association studies in pharmacogenomics of antidepressants.

    Science.gov (United States)

    Lin, Eugene; Lane, Hsien-Yuan

    2015-01-01

    Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD.

  12. Association between diabetes and tuberculosis: case-control study

    Science.gov (United States)

    Pereira, Susan Martins; de Araújo, Gleide Santos; Santos, Carlos Antônio de Souza Teles; de Oliveira, Maeli Gomes; Barreto, Maurício Lima

    2016-01-01

    ABSTRACT OBJECTIVE To test the association between diabetes and tuberculosis. METHODS It is a case-control study, matched by age and sex. We included 323 new cases of tuberculosis with positive results for bacilloscopy. The controls were 323 respiratory symptomatic patients with negative bacilloscopy, from the same health services, such as: ambulatory cases from three referral hospitals and six basic health units responsible for the notifications of new cases of tuberculosis in Salvador, Bahia. Data collection occurred between 2008 and 2010. The instruments used were structured interview, including clinical data, capillary blood glucose (during fasting or postprandial), and the CAGE questionnaire for screening of abusive consumption of alcohol. Descriptive, exploratory, and multivariate analysis was performed using conditional logistic regression. RESULTS The average age of the cases was 38.5 (SD = 14.2) years and of the controls, 38.5 (SD = 14.3) years. Among cases and controls, most subjects (61%) were male. In univariate analysis we found association between the occurrence of diabetes and tuberculosis (OR = 2.37; 95%CI 1.04–5.42), which remained statistically significant after adjustment for potential confounders (OR = 3.12; 95%CI 1.12–7.94). CONCLUSIONS The association between diabetes and tuberculosis can hinder the control of tuberculosis, contributing to the maintainance of the disease burden. The situation demands increasing early detection of diabetes among people with tuberculosis, in an attempt to improve disease control strategies. PMID:28099656

  13. Association between diabetes and tuberculosis: case-control study

    Directory of Open Access Journals (Sweden)

    Susan Martins Pereira

    Full Text Available ABSTRACT OBJECTIVE To test the association between diabetes and tuberculosis. METHODS It is a case-control study, matched by age and sex. We included 323 new cases of tuberculosis with positive results for bacilloscopy. The controls were 323 respiratory symptomatic patients with negative bacilloscopy, from the same health services, such as: ambulatory cases from three referral hospitals and six basic health units responsible for the notifications of new cases of tuberculosis in Salvador, Bahia. Data collection occurred between 2008 and 2010. The instruments used were structured interview, including clinical data, capillary blood glucose (during fasting or postprandial, and the CAGE questionnaire for screening of abusive consumption of alcohol. Descriptive, exploratory, and multivariate analysis was performed using conditional logistic regression. RESULTS The average age of the cases was 38.5 (SD = 14.2 years and of the controls, 38.5 (SD = 14.3 years. Among cases and controls, most subjects (61% were male. In univariate analysis we found association between the occurrence of diabetes and tuberculosis (OR = 2.37; 95%CI 1.04–5.42, which remained statistically significant after adjustment for potential confounders (OR = 3.12; 95%CI 1.12–7.94. CONCLUSIONS The association between diabetes and tuberculosis can hinder the control of tuberculosis, contributing to the maintainance of the disease burden. The situation demands increasing early detection of diabetes among people with tuberculosis, in an attempt to improve disease control strategies.

  14. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies.

    Science.gov (United States)

    Yang, Qiong; Wang, Yuanjia

    2012-05-01

    This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical) or different types of components (e.g., some are continuous and others are categorical). We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  15. Detecting rare variants in case-parents association studies.

    Directory of Open Access Journals (Sweden)

    Kuang-Fu Cheng

    Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

  16. QCD prediction of jet structure in 2D trigger-associated momentum correlations and implications for multiple parton interactions

    CERN Document Server

    Trainor, Thomas A

    2014-01-01

    The expression "multiple parton interactions" (MPI) denotes a conjectured QCD mechanism representing contributions from secondary (semi)hard parton scattering to the transverse azimuth region (TR) of jet-triggered p-p collisions. MPI is an object of underlying-event (UE) studies that consider variation of TR $n_{ch}$ or $p_t$ yields relative to a trigger condition (leading hadron or jet $p_t$). An alternative approach is 2D trigger-associated (TA) correlations on hadron transverse momentum $p_t$ or rapidity $y_t$ in which all hadrons from all p-p events are included. Based on a two-component (soft+hard) model (TCM) of TA correlations a jet-related TA hard component is isolated. Contributions to the hard component from the triggered dijet and from secondary dijets (MPI) can be distinguished, including their azimuth dependence relative to the trigger direction. Measured $e^+$-$e^-$ and p-\\=p fragmentation functions and a minimum-bias jet spectrum from 200 GeV p-\\=p collisions are convoluted to predict the 2D ha...

  17. Correlates of cortisol in human hair: implications for epidemiologic studies on health effects of chronic stress.

    Science.gov (United States)

    Wosu, Adaeze C; Valdimarsdóttir, Unnur; Shields, Alexandra E; Williams, David R; Williams, Michelle A

    2013-12-01

    Assessment of cortisol concentrations in hair is one of the latest innovations for measuring long-term cortisol exposure. We performed a systematic review of correlates of cortisol in human hair to inform the design, analysis, and interpretation of future epidemiologic studies. Relevant publications were identified through electronic searches on PubMed, WorldCat, and Web of Science using keywords, "cortisol," "hair," "confounders," "chronic," "stress," and "correlates." Thirty-nine studies were included in this review. Notwithstanding scarce data and some inconsistencies, investigators have found hair cortisol concentrations to be associated with stress-related psychiatric symptoms and disorders (e.g., post-traumatic stress disorder), medical conditions indicating chronic activation of the hypothalamic-pituitary-adrenal axis (e.g., Cushing's syndrome), and other life situations associated with elevated risk of chronic stress (e.g., shiftwork). Results from some studies suggest that physical activity, adiposity, and substance abuse may be correlates of hair cortisol concentrations. In contrast to measures of short-term cortisol release (saliva, blood, and urine), cigarette smoking and use of oral contraceptives appear not to be associated with hair cortisol concentrations. Studies of pregnant women indicate increased hair cortisol concentrations across successive trimesters. The study of hair cortisol presents a unique opportunity to assess chronic alterations in cortisol concentrations in epidemiologic studies.

  18. Factors associated with pharmacy student interest in international study.

    Science.gov (United States)

    Owen, Chelsea; Breheny, Patrick; Ingram, Richard; Pfeifle, William; Cain, Jeff; Ryan, Melody

    2013-04-12

    OBJECTIVES. To examine the interest of pharmacy students in international study, the demographic factors and involvement characteristics associated with that interest, and the perceived advantages and barriers of engaging in international opportunities during pharmacy school. METHODS. A self-administered electronic survey instrument was distributed to first-, second-, and third-year pharmacy students at the University of Kentucky College of Pharmacy. RESULTS. There were 192 total respondents, for a response rate of 50.9%. Seventy-two percent reported interest in international study. Previous international study experience (p=0.001), previous international travel experience (p=0.002), year in pharmacy school (p=0.03), level of academic involvement (pinternational study interest. Positive influences to international study included desire to travel and availability of scholarships. Perceived barriers included an inability to pay expenses and lack of foreign language knowledge. CONCLUSIONS. The needs and interests of pharmacy students should be considered in the development and expansion of internationalization programs in order to effectively optimize global partnerships and available international experiences. Colleges and schools of pharmacy should engage students early in the curriculum when interest in study-abroad opportunities is highest and seek to alleviate concerns about expenses as a primary influence on study-abroad decisions through provision of financial assistance.

  19. Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling.

    Science.gov (United States)

    Zheng, Y Z; Sakata, T; Matsusue, T; Umeyama, H; Kato, H; Miyata, T

    1994-10-01

    The molecular basis of protein C deficiency was studied in three type I and three type II heterozygotes. Three probands showed thrombotic complications. All the exons and intron/exon junctions of the protein C gene were studied using a strategy combining by the polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, and DNA sequencing of the PCR-amplified fragments. Six missense mutations were identified, including three novel ones. One was located in exon II, in which the initiating translation codon (ATG) encoding for Met at position -42 was replaced by ACG encoding for Thr. The other five were located in exon IX, and included TAC(Tyr399)-->CAC(His), CCG(Pro327)-->CTG(Leu), GAC(Asp359)-->AAC(Asn) in two cases, and GGG(Gly350)-->AGG(Arg). Four of the six missense mutations occurred in CG dinucleotide. Sequence analysis of the other exons excluded additional mutations. By restriction enzyme analysis, co-segregation of the mutation with protein C deficiency was observed in four families. The other two mutations at amino acid positions -42 and 350 were also considered to be associated with protein C deficiency due to the absence of these mutations in 50 normal individuals. A structural model of the protease domain of mutant activated protein C was constructed by the chimeric modelling method, and the resultant model suggested conformational changes due to each missense mutation identified in protein C deficiency. The present data also provide some evidence regarding the genetic heterogeneity of protein C deficiency.

  20. Polycyclic aromatic hydrocarbons associated with road deposited solid and their ecological risk: Implications for road stormwater reuse

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Liang [Graduate school at Shenzhen, Tsinghua University, Shenzhen 518055 (China); Liu, An [College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060 (China); Li, Yang; Zhang, Lixun; Zhang, Guijuan [Graduate school at Shenzhen, Tsinghua University, Shenzhen 518055 (China); State Environmental Protection Key Laboratory of Microorganism Application and Risk Control (MARC), Tsinghua University, Shenzhen 518055, Guangdong (China); Guan, Yuntao, E-mail: guanyt@tsinghua.edu.cn [Graduate school at Shenzhen, Tsinghua University, Shenzhen 518055 (China); State Environmental Protection Key Laboratory of Microorganism Application and Risk Control (MARC), Tsinghua University, Shenzhen 518055, Guangdong (China)

    2016-09-01

    Reusing stormwater is becoming popular worldwide. However, urban road stormwater commonly contains toxic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), which could undermine reuse safety. This study investigated pollution level of PAHs and their composition build-up on urban roads in a typical megacity in South China. The potential ecological risk posed by PAHs associated with road deposited solid (RDS) was also assessed. Results showed that ecological risk levels varied based on different land use types, which could be significantly influenced by the composition of PAHs and characteristics of RDS. A higher percentage of high-ring PAHs, such as more than four rings, could pose higher ecological risk and are more likely to undermine stormwater reuse safety. Additionally, the degree of traffic congestion rather than traffic volume was found to exert a more significant influence on the generation of high-ring PAH generation. Therefore, stormwater from more congested roads might need proper treatment (particularly for removing high-ring PAHs) before reuse or could be suitable for purposes requiring low-water-quality. The findings of this study are expected to contribute to adequate stormwater reuse strategy development and to enhance the safety of urban road stormwater reuse. - Highlights: • PAHs build-up on road surfaces varies with traffic and land use conditions. • RDS characteristics and PAH composition were considered in ecological risk assessment. • ΣPAH concentration attached to RDS cannot represent their overall ecological risk. • Higher percentage of 5–6 rings PAHs can pose higher ecological risk. • TC exerts more important influences on 5–6 rings PAHs build-up compared with TV.

  1. The implications of embodiment for behavior and cognition: animal and robotic case studies

    CERN Document Server

    Hoffmann, Matej

    2012-01-01

    In this paper, we will argue that if we want to understand the function of the brain (or the control in the case of robots), we must understand how the brain is embedded into the physical system, and how the organism interacts with the real world. While embodiment has often been used in its trivial meaning, i.e. 'intelligence requires a body', the concept has deeper and more important implications, concerned with the relation between physical and information (neural, control) processes. A number of case studies are presented to illustrate the concept. These involve animals and robots and are concentrated around locomotion, grasping, and visual perception. A theoretical scheme that can be used to embed the diverse case studies will be presented. Finally, we will establish a link between the low-level sensory-motor processes and cognition. We will present an embodied view on categorization, and propose the concepts of 'body schema' and 'forward models' as a natural extension of the embodied approach toward firs...

  2. Delaware Longitudinal Study of Fraction Learning: Implications for Helping Children With Mathematics Difficulties.

    Science.gov (United States)

    Jordan, Nancy C; Resnick, Ilyse; Rodrigues, Jessica; Hansen, Nicole; Dyson, Nancy

    2016-08-09

    The goal of the present article is to synthesize findings to date from the Delaware Longitudinal Study of Fraction Learning. The study followed a large cohort of children (N = 536) between Grades 3 and 6. The findings showed that many students, especially those with diagnosed learning disabilities, made minimal growth in fraction knowledge and that some showed only a basic grasp of the meaning of a fraction even after several years of instruction. Children with low growth in fraction knowledge during the intermediate grades were much more likely to fail to meet state standards on a broad mathematics measure at the end of Grade 6. Although a range of general and mathematics-specific competencies predicted fraction outcomes, the ability to estimate numerical magnitudes on a number line was a uniquely important marker of fraction success. Many children with mathematics difficulties have deep-seated problems related to whole number magnitude representations that are complicated by the introduction of fractions into the curriculum. Implications for helping students with mathematics difficulties are discussed.

  3. Reorganization of the injured brain: Implications for studies of the neural substrate of cognition

    Directory of Open Access Journals (Sweden)

    Jesper eMogensen

    2011-01-01

    Full Text Available In the search for a neural substrate of cognitive processes, a frequently utilized method is the scrutiny of posttraumatic symptoms exhibited by individuals suffering focal injury to the brain. For instance, the presence or absence of conscious awareness within a particular domain may, combined with knowledge of which regions of the brain have been injured, provide important data in the search for neural correlates of consciousness. Like all studies addressing the consequences of brain injury, however, such research has to face the fact that in most cases, posttraumatic impairments are accompanied by a functional recovery during which symptoms are reduced or eliminated. The apparent contradiction between localization and recovery, respectively, of functions constitutes a problem to almost all aspects of cognitive neuroscience. Several lines of investigation indicate that although the brain remains highly plastic throughout life, the posttraumatic plasticity does not recreate a copy of the neural mechanisms lost to injury. Instead, the uninjured parts of the brain are functionally reorganized in a manner which – in spite of not recreating the basic information processing lost to injury – is able to allow a more or less complete return of the surface phenomena (including manifestations of consciousness originally impaired by the trauma. A novel model (the REF-model of these processes is presented – and some of its implications discussed relative to studies of the neural substrates of cognition and consciousness.

  4. Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications.

    Science.gov (United States)

    Mo, Jiao; Guo, Yang; Yang, Yu-She; Shen, Jing-Shan; Jin, Guo-Zhang; Zhen, Xuechu

    2007-01-01

    Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.

  5. Genome Wide Association Study Identifies New Loci Associated with Undesired Coat Color Phenotypes in Saanen Goats.

    Directory of Open Access Journals (Sweden)

    Pauline Marie Martin

    Full Text Available This paper reports a quantitative genetics and genomic analysis of undesirable coat color patterns in goats. Two undesirable coat colors have routinely been recorded for the past 15 years in French Saanen goats. One fifth of Saanen females have been phenotyped "pink" (8.0% or "pink neck" (11.5% and consequently have not been included in the breeding program as elite animals. Heritability of the binary "pink" and "pink neck" phenotype, estimated from 103,443 females was 0.26 for "pink" and 0.21 for "pink neck". Genome wide association studies (using haplotypes or single SNPs were implemented using a daughter design of 810 Saanen goats sired by 9 Artificial Insemination bucks genotyped with the goatSNP50 chip. A highly significant signal (-log10pvalue = 10.2 was associated with the "pink neck" phenotype on chromosome 11, suggesting the presence of a major gene. Highly significant signals for the "pink" phenotype were found on chromosomes 5 and 13 (-log10p values of 7.2 and, 7.7 respectively. The most significant SNP on chromosome 13 was in the ASIP gene region, well known for its association with coat color phenotypes. Nine significant signals were also found for both traits. The highest signal for each trait was detected by both single SNP and haplotype approaches, whereas the smaller signals were not consistently detected by the two methods. Altogether these results demonstrated a strong genetic control of the "pink" and "pink neck" phenotypes in French Saanen goats suggesting that SNP information could be used to identify and remove undesired colored animals from the breeding program.

  6. A Pilot Study of the Association of Tumor Necrosis Factor Alpha Polymorphisms with Psoriatic Arthritis in the Romanian Population

    Directory of Open Access Journals (Sweden)

    Olivia M. Popa

    2011-08-01

    Full Text Available Tumor necrosis factor alpha (TNF-alpha is an important pro-inflammatory cytokine implicated in the pathogenesis of psoriatic arthritis. We have performed a case-control association study of three TNF-alpha gene polymorphisms in a group of Romanian psoriatic arthritis patients versus ethnically matched controls. A second group of patients with undifferentiated spondyloarthritis was used in order to look for similarities in the genetic background of the two rheumatic disorders. The −857C/T polymorphism was associated with susceptibility to psoriatic arthritis in our population at the individual level (p = 0.03, OR 1.65, 95% CI 1.05–2.57 and in combined haplotypes with the −238G/A and −308G/A SNPs. Regarding the investigated polymorphisms and derived haplotypes, no potential association was found with the susceptibility to undifferentiated spondyloarthritis in Romanian patients.

  7. A genome-wide association study identifies five loci influencing facial morphology in Europeans.

    Directory of Open Access Journals (Sweden)

    Fan Liu

    2012-09-01

    Full Text Available Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes--PRDM16, PAX3, TP63, C5orf50, and COL17A1--in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

  8. Implications of Reverse Innovation for Socio-Economic Sustainability: A Case Study of Philips China

    Directory of Open Access Journals (Sweden)

    Juan Shan

    2016-06-01

    Full Text Available The idea of reverse innovation, local innovation happening in emerging markets for the global market, has gained much academic and managerial attention in recent years. The purpose of this study is to understand how reverse innovation has successfully diffused into the product and market development strategies at Philips Inc., a prominent multinational company (MNC of the modern era. Furthermore, the study presents the success achieved by these innovations at both the domestic and global levels, along with their implications regarding socio-economic sustainability in emerging markets. In order to investigate the research questions, a case study of Philips China was conducted involving three product innovations that were found to be suitable examples of reverse innovation. After the study of extant literature on the topic, drawing from research databases, newspaper articles, and company press releases, five semi-structuredinterviews were conducted with key managers and a market practitioner to gain sufficient understanding for this exploratory study. Subsequent case analysis concludes that these innovations are examples of reverse innovation representing a new paradigm change in innovation flow. This flow of innovation from emerging markets to developed markets as confirmed by Corsi’s framework could potentially disrupt developed markets as well as contribute to ensure healthy living conditions for the population living in developing countries. If so, this represents a sustainable socio-economic change in-line with the United Nations' Sustainable Development Goal (SDG of “ensuring healthy lives and promoting well-being for all at all ages.” This is relevant as Philips aspires to be a prominent private sector player in achieving the above-stated goal by defeating non-communicable disease and strengthening local healthcare systems.

  9. Genome-wide association study of colorectal cancer in Hispanics

    Science.gov (United States)

    Schmit, Stephanie L.; Schumacher, Fredrick R.; Edlund, Christopher K.; Conti, David V.; Ihenacho, Ugonna; Wan, Peggy; Van Den Berg, David; Casey, Graham; Fortini, Barbara K.; Lenz, Heinz-Josef; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Moreno-Macías, Hortensia; Huerta-Chagoya, Alicia; Ordóñez-Sánchez, María Luisa; Rodríguez-Guillén, Rosario; Cruz-Bautista, Ivette; Rodríguez-Torres, Maribel; Muñóz-Hernández, Linda Liliana; Arellano-Campos, Olimpia; Gómez, Donají; Alvirde, Ulices; González-Villalpando, Clicerio; González-Villalpando, María Elena; Le Marchand, Loic; Haiman, Christopher A.; Figueiredo, Jane C.

    2016-01-01

    Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10−8. Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10−6) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47–2.36); P = 2.5×10−7], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21–1.55); P = 4.0×10−7), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36–2.01); P = 4.1×10−7) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37–2.08); P=7.8×10−7]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10–5) and 11q12.2 (P = 6.8×10−5), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations. PMID:27207650

  10. A genome-wide association study of anorexia nervosa.

    Science.gov (United States)

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-10-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

  11. A genome-wide association study of anorexia nervosa

    Science.gov (United States)

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Landt, Margarita CT Slof-Op t; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2015-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  12. Ethical implications of home telecare for older people: a framework derived from a multisited participative study

    NARCIS (Netherlands)

    Mort, M.; Roberts, C.; Pols, J.; Domenech, M.; Moser, I.

    2013-01-01

    Context Telecare and telehealth developments have recently attracted much attention in research and service development contexts, where their evaluation has predominantly concerned effectiveness and efficiency. Their social and ethical implications, in contrast, have received little scrutiny. Object

  13. Delta-associated molluscan life and death assemblages in the northern Adriatic Sea: Implications for paleoecology, regional diversity and conservation.

    Science.gov (United States)

    Weber, Kristina; Zuschin, Martin

    2013-01-15

    Life-death (LD) studies of shelly macrofauna are important to evaluate how well a fossil assemblage can reflect the original living community, but can also serve as a proxy for recent ecological shifts in marine habitats and in practice this has to be distinguished using taphonomic preservation pattern and estimates of time-averaging. It remains to be rigorously evaluated, however, how to distinguish between sources of LD disagreement. In addition, death assemblages (DAs) also preserve important information on regional diversity which is not available from single censuses of the life assemblages (LAs). The northern Adriatic Sea is an ecosystem under anthropogenic pressure, and we studied the distribution and abundance of living and dead bivalve and gastropod species in the physically stressful environments (tidal flat and shallow sublittoral soft bottoms) associated with the delta of the Isonzo River (Gulf of Trieste). Specifically we evaluated the fidelity of richness, evenness, abundance, habitat discrimination and beta diversity. A total of 10,740 molluscs from fifteen tidal flat and fourteen sublittoral sites were analyzed for species composition and distribution of living and dead molluscs. Of 78 recorded species, only eleven were numerically abundant. There were many more dead than living individuals and rarefied species richness in the DA was higher at all spatial scales, but the differences are lower in habitats and in the region than at individual stations. Evenness was always higher in death assemblages, and probably due to temporally more variable LAs the differences are stronger in the sublittoral habitats. Distinct assemblages characterized intertidal and sublittoral habitats, and the distribution and abundance of empty shells generally corresponded to that of the living species. Death assemblages have lower beta diversity than life assemblages, but empty shells capture compositional differences between habitats to a higher degree than living shells

  14. An evolutionary framework for association testing in resequencing studies.

    Directory of Open Access Journals (Sweden)

    C Ryan King

    2010-11-01

    Full Text Available Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing, generates a single test per gene (substantially reducing multiple testing concerns, facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4.

  15. Bipolar disorder and the pseudoautosomal region: An association study

    Energy Technology Data Exchange (ETDEWEB)

    Parsian, A.; Todd, R.D. [Washington Univ. School of Medicine, St. Louis, MO (United States)

    1994-03-15

    From family, adoption, and twin studies it is clear that genetic factors play an important role in the etiology of bipolar disorder (McGuffin and Katz: The Biology of Depression, Gaskell, London, 1986). Recently Yoneda et al. reported an association between an allele (A4) of a VNTR marker (DXYS20) for the pseudoautosomal region and bipolar disorder in a Japanese population. In order to test for this association in a Caucasian population, we have typed a sample of 52 subjects with bipolar disorder and 61 normal controls. The bipolar subjects are probands of multiple incidence families. The normal controls are an epidemiologically ascertained sample of middle-aged, unrelated individuals. The two groups were matched for sex and ethnic background. There were no significant differences in the allele or genotype frequencies of DXYS20 between the two groups. In particular, there was no significant difference in the frequency of the A4 allele in normal controls and bipolar patients (0.377 vs. 0.317, respectively). The prevalence of the A4 allele in bipolar patients and normal controls was 0.567 and 0.622, respectively. We were not able to replicate the results of the 1992 Yoneda et al. study. 15 refs., 2 tabs.

  16. A genome-wide association study of aging.

    Science.gov (United States)

    Walter, Stefan; Atzmon, Gil; Demerath, Ellen W; Garcia, Melissa E; Kaplan, Robert C; Kumari, Meena; Lunetta, Kathryn L; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J; Völker, Uwe; Yu, Lei; Arnold, Alice; Benjamin, Emelia J; Biffar, Reiner; Buchman, Aron S; Boerwinkle, Eric; Couper, David; De Jager, Philip L; Evans, Denis A; Harris, Tamara B; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J; Lohman, Kurt K; Lutsey, Pamela L; Mackenbach, Johan; Marciante, Kristin; Psaty, Bruce M; Reiman, Eric M; Rotter, Jerome I; Seshadri, Sudha; Shardell, Michelle D; Smith, Albert V; van Duijn, Cornelia; Walston, Jeremy; Zillikens, M Carola; Bandinelli, Stefania; Baumeister, Sebastian E; Bennett, David A; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimaki, Mika; Liu, Yongmei; Murabito, Joanne M; Newman, Anne B; Tiemeier, Henning; Franceschini, Nora

    2011-11-01

    Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

  17. GPFrontend and GPGraphics: graphical analysis tools for genetic association studies

    Directory of Open Access Journals (Sweden)

    Schanze Denny

    2010-09-01

    Full Text Available Abstract Background Most software packages for whole genome association studies are non-graphical, purely text based programs originally designed to run with UNIX-like operating systems. Graphical output is often not intended or supposed to be performed with other command line tools, e.g. gnuplot. Results Using the Microsoft .NET 2.0 platform and Visual Studio 2005, we have created a graphical software package to analyze data from microarray whole genome association studies, both for a DNA-pooling based approach as well as regular single sample data. Part of this package was made to integrate with GenePool 0.8.2, a previously existing software suite for GNU/Linux systems, which we have modified to run in a Microsoft Windows environment. Further modifications cause it to generate some additional data. This enables GenePool to interact with the .NET parts created by us. The programs we developed are GPFrontend, a graphical user interface and frontend to use GenePool and create metadata files for it, and GPGraphics, a program to further analyze and graphically evaluate output of different WGA analysis programs, among them also GenePool. Conclusions Our programs enable regular MS Windows users without much experience in bioinformatics to easily visualize whole genome data from a variety of sources.

  18. GDNF Gene Is Associated With Tourette Syndrome in a Family Study

    Science.gov (United States)

    Huertas-Fernández, Ismael; Gómez-Garre, Pilar; Madruga-Garrido, Marcos; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Martín-Rodríguez, Juan Francisco; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Carrillo, Fátima; Pascual, Alberto; Tischfield, Jay A.; King, Robert A.; Heiman, Gary A.; Mir, Pablo

    2016-01-01

    Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. PMID:26096985

  19. Family Stigma Associated With Epilepsy: A Qualitative Study

    Science.gov (United States)

    Nabi Amjad, Reza; Nikbakht Nasrabadi, Alireza; Navab, Elham

    2017-01-01

    Introduction: Harmful nature of epilepsy can affect the patient and their parent. Stigma, arising from it, affects the patient and their family. To relieve it understanding the experiences of the parent are useful. This study was aimed at understanding the experiences of parent of child with epilepsy in Iran. Methods: In this interpretative phenomenological study, 10 parents who took care of their child with epilepsy were participated. Data were collected through in-depth semi-structured interviews. After transcription, data were analyzed using Van Manen’s method. Results: Family stigma emerged as a main theme in data analysis with three subthemes including becoming verbally abusive, a dull and heavy shadowed look, and associates interference. Conclusion: Family stigma is a major challenge for parents of child with epilepsy need to special attention by health system. Nurses, as a big part of the system, can play an important role to manage this problem. PMID:28299298

  20. An association study between hypoxia inducible factor-1alpha (HIF-1α polymorphisms and osteonecrosis.

    Directory of Open Access Journals (Sweden)

    Georgia Chachami

    Full Text Available Bone hypoxia resulting from impaired blood flow is the final pathway for the development of osteonecrosis (ON. The aim of this study was to evaluate if HIF-1α, the major transcription factor triggered by hypoxia, is genetically implicated in susceptibility to ON. For this we analyzed frequencies of three known HIF-1α polymorphisms: one in exon 2 (C111A and two in exon 12 (C1772T and G1790A and their association with ON in a Greek population. Genotype analysis was performed using PCR-RFLP and rare alleles were further confirmed with sequencing. We found that genotype and allele frequency of C1772T and G1790A SNP of HIF-1α (SNPs found in our cohort were not significantly different in ON patients compared to control patients. Furthermore these SNPs could not be associated with the different subgroups of ON. At the protein level we observed that the corresponding mutations (P582S and A588T, respectively are not significant for protein function since the activity, expression and localization of the mutant proteins is practically indistinguishable from wt in HEK293 and Saos-2 cells. These results suggest that these missense mutations in the HIF-1α gene are not important for the risk of developing ON.

  1. Factors associated with medical student test anxiety in objective structured clinical examinations: a preliminary study

    Science.gov (United States)

    2016-01-01

    Objectives To investigate attributes of medical students associated with their test anxiety on Objective Structured Clinical Examinations (OSCEs). Methods A cross-sectional study using a self-administered questionnaire was conducted of all Year 3 and 4 students at a private medical school in South Korea in 2014. This 53-item questionnaire consisted of factors pertaining to test anxiety on the OSCE identified from a review of relevant literature, which included students’ motivational beliefs and achievement emotions, perceived values of the OSCE, and attitude and orientation towards patients. Participants’ test anxiety levels were measured using the Korean Achievement Emotions Questionnaire. Participants rated their responses using a five-point Likert-type scale. Univariate analysis was performed to examine relationships between the variables. Results A total of 94 students completed the questionnaire (a 93% response rate). No differences in the participants’ test anxiety scores were observed across genders, entry-levels, or years in medical school. Participants’ test anxiety on the OSCE showed moderate association with their class-related achievement emotions (i.e., anxiety and boredom), where r = 0.46 and 0.32, p OSCE (r = -0.21, p OSCE. These findings have implications for developing effective educational interventions for helping students cope with such a stress by enhancing our understanding of the various factors that influence their test anxiety in OSCEs. PMID:28035056

  2. A musculoskeletal model of low grade connective tissue inflammation in patients with thyroid associated ophthalmopathy (TAO: the WOMED concept of lateral tension and its general implications in disease

    Directory of Open Access Journals (Sweden)

    Moncayo Helga

    2007-02-01

    Full Text Available Abstract Background Low level connective tissue inflammation has been proposed to play a role in thyroid associated ophthalmopathy (TAO. The aim of this study was to investigate this postulate by a musculoskeletal approach together with biochemical parameters. Methods 13 patients with TAO and 16 controls were examined. Erythrocyte levels of Zn, Cu, Ca2+, Mg, and Fe were determined. The musculoskeletal evaluation included observational data on body posture with emphasis on the orbit-head region. The angular foot position in the frontal plane was quantified following gait observation. The axial orientation of the legs and feet was evaluated in an unloaded supine position. Functional propioceptive tests based on stretch stimuli were done by using foot inversion and foot rotation. Results Alterations in the control group included neck tilt in 3 cases, asymmetrical foot angle during gait in 2, and a reaction to foot inversion in 5 cases. TAO patients presented facial asymmetry with displaced eye fissure inclination (mean 9.1° as well as tilted head-on-neck position (mean 5.7°. A further asymmetry feature was external rotation of the legs and feet (mean 27°. Both foot inversion as well as foot rotation induced a condition of neuromuscular deficit. This condition could be regulated by gentle acupressure either on the lateral abdomen or the lateral ankle at the acupuncture points gall bladder 26 or bladder 62, respectively. In 5 patients, foot rotation produced a phenomenon of moving toes in the contra lateral foot. In addition foot rotation was accompanied by an audible tendon snapping. Lower erythrocyte Zn levels and altered correlations between Ca2+, Mg, and Fe were found in TAO. Conclusion This whole body observational study has revealed axial deviations and body asymmetry as well as the phenomenon of moving toes in TAO. The most common finding was an arch-like displacement of the body, i.e. eccentric position, with foot inversion and head tilt

  3. An advanced modeling study on the impacts and atmospheric implications of multiphase dimethyl sulfide chemistry.

    Science.gov (United States)

    Hoffmann, Erik Hans; Tilgner, Andreas; Schrödner, Roland; Bräuer, Peter; Wolke, Ralf; Herrmann, Hartmut

    2016-10-18

    Oceans dominate emissions of dimethyl sulfide (DMS), the major natural sulfur source. DMS is important for the formation of non-sea salt sulfate (nss-SO4(2-)) aerosols and secondary particulate matter over oceans and thus, significantly influence global climate. The mechanism of DMS oxidation has accordingly been investigated in several different model studies in the past. However, these studies had restricted oxidation mechanisms that mostly underrepresented important aqueous-phase chemical processes. These neglected but highly effective processes strongly impact direct product yields of DMS oxidation, thereby affecting the climatic influence of aerosols. To address these shortfalls, an extensive multiphase DMS chemistry mechanism, the Chemical Aqueous Phase Radical Mechanism DMS Module 1.0, was developed and used in detailed model investigations of multiphase DMS chemistry in the marine boundary layer. The performed model studies confirmed the importance of aqueous-phase chemistry for the fate of DMS and its oxidation products. Aqueous-phase processes significantly reduce the yield of sulfur dioxide and increase that of methyl sulfonic acid (MSA), which is needed to close the gap between modeled and measured MSA concentrations. Finally, the simulations imply that multiphase DMS oxidation produces equal amounts of MSA and sulfate, a result that has significant implications for nss-SO4(2-) aerosol formation, cloud condensation nuclei concentration, and cloud albedo over oceans. Our findings show the deficiencies of parameterizations currently used in higher-scale models, which only treat gas-phase chemistry. Overall, this study shows that treatment of DMS chemistry in both gas and aqueous phases is essential to improve the accuracy of model predictions.

  4. Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders.

    Directory of Open Access Journals (Sweden)

    Donna C Davidson

    Full Text Available Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND, indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1 positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.

  5. Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders.

    Science.gov (United States)

    Davidson, Donna C; Hirschman, Michael P; Sun, Anita; Singh, Meera V; Kasischke, Karl; Maggirwar, Sanjay B

    2012-01-01

    Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L) are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB) permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat) can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1) positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.

  6. The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia.

    Directory of Open Access Journals (Sweden)

    Pilar eSánchez-Blázquez

    2014-01-01

    Full Text Available The endocannabinoid system is widespread throughout the central nervous system and its type 1 receptor (CB1 plays a crucial role in preventing the neurotoxicity caused by activation of glutamate N-methyl-D-aspartate receptors (NMDARs. Indeed, it is the activity of NMDARs themselves that provides the demands on the endogenous cannabinoids in order to control their calcium currents. Therefore, a physiological role of this system is to maintain NMDAR activity within safe limits, thereby protecting neural cells from excitotoxicity. Thus, cannabinoids may be able to control NMDAR overactivation-related neural dysfunctions; however the major obstacles to the therapeutic utilization of these compounds are their psychotropic effects and negative influence on cognitive performance. Studies in humans have indicated that abuse of smoked cannabis can promote psychosis and even circumstantially precipitate symptoms of schizophrenia, although the latter appears to require a prior vulnerability in the individual. It is possible that cannabinoids provoke psychosis/schizophrenia reflecting a mechanism common to neuroprotection the reduction of NMDAR activity. Cannabinoids are proposed to produce such effect by reducing the pre-synaptic release of glutamate or interfering with postsynaptic NMDAR-regulated signaling pathways. The efficacy of such control requires the endocannabinoid system to apply its negative influence in a manner that is proportional to the strength of NMDAR signaling. Thus, cannabinoids acting at the wrong time or exerting an inappropriate influence on their receptors may cause NMDAR hypofunction. The purpose of the present review is to draw the attention of the reader to the newly described functional and physical CB1-NMDAR association, which may elucidate the scenario required for the rapid and efficacious control of NMDAR activity. Whether alterations in these mechanisms may increase NMDAR hypofunction leading to vulnerability to

  7. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.

    Science.gov (United States)

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E; Boukli, Nawal M; Xiong, Huangui

    2013-09-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.

  8. Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

    Science.gov (United States)

    Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

    1999-01-01

    Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated ne