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1.  Investigating the impact of chronic atrazine exposure on sexual development in zebrafish 
Atrazine (ATZ) is a selective triazine herbicide used primarily for pre-emergent weed control in corn, sorghum and sugar cane production. It is one of the most widely used herbicides in North America. Some research published over the last decade suggests that chronic exposure to environmentally relevant ATZ concentrations can adversely impact gonadal development and/or sexual differentiation in amphibians and fish, while other studies report no effect, or moderate effects. As a result, contrasting conclusions have been published regarding the potential effects of the herbicide ATZ on aquatic species. Two near-identical four-month studies in 2009 (Study I) and 2010 (Study II), were performed investigating the potential for chronic ATZ exposure to affect zebrafish (Danio rerio) sexual development and differentiation. Zebrafish, were chronically exposed to 0, 0.1, 1, 10 µM ATZ or 1 nM 17α-estradiol (E2). Fish were histologically examined to assign gender and to evaluate potential impacts of E2 or ATZ on gonadal development. Exposure to E2 consistently resulted in a significantly higher proportion of female fish to normal male fish when compared to unexposed fish (both studies). In both studies, ATZ exposure did not significantly influence the percentage of female or male fish when compared to unexposed fish. A greater percentage of abnormally developed male fish and fish lacking differentiated gonadal tissue was observed in Study II E2 exposures but not in ATZ exposures. Together, these studies indicate that long-term exposure to ATZ at or above environmentally relevant concentrations does not significantly impact zebrafish gonadal development or sexual differentiation.
doi:10.1002/bdrb.21016
PMCID: PMC4030637  PMID: 22581590
atrazine; zebrafish; chronic exposure; sexual development; sex differentiation
2.  Updated Physician’s Guide to the Off-label Uses of Oral Isotretinoin 
While oral isotretinoin is renowned for its ability to treat acne vulgaris, many of its off-label uses continue to go underappreciated. Since the last review on the unapproved indications of isotretinoin, relevant publications have surfaced with new recommendations. This article attempts to provide physicians with the latest information regarding successful and unsuccessful use of isotretinoin as an effective treatment for dermatological conditions, such as rosacea, psoriasis, pityriasis rubra pilaris, condyloma acuminatum, granuloma annulare, Darier’s disease, systemic cutaneous lupus erythematosus, nonmelanoma skin cancer, and hidradenitis suppurativa. Variations in dosage regimens and isotretinoin viability as an alternative to other standard treatments are also discussed in relation to these conditions.
PMCID: PMC3990537  PMID: 24765227
3.  Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis 
Journal of clinical immunology  2012;33(1):162-171.
Purpose
Acute Hemorrhagic Leukoencephalitis (AHLE) is a rare demyelinating disorder of acute onset, rapid deterioration and significant morbidity and mortality. Most often described as a post-infectious complication of an upper respiratory illness, its precise pathophysiology remains unclear. We describe two pediatric patients with AHLE with partial complement factor I (FI) deficiency whose successful treatment included the interleukin-1 (IL-1) receptor antagonist, anakinra, implicating a role for FI and IL-1 in this disorder.
Methods
Extensive clinical workup of two patients presenting with AHLE revealed complement abnormalities, specifically related to the alternative pathway and its regulator, FI. Aggressive management with steroids, immunoglobulin, and anakinra ultimately led to improvement of clinical status and near return to neurologic baseline in both patients. Genetic sequencing of the FI coding regions of the patients and their families was performed. In vitro protein expression studies and immunohistochemistry of fixed brain tissue was used to investigate pathogenic mechanisms.
Results
Two novel mutations in FI were identified in our patients, which result in failure to secrete FI. Immunohistochemical evaluation of brain tissue demonstrated positive staining for C3, membrane attack complex (MAC) and IL-1.
Conclusions
We propose AHLE is an unreported, rare phenotype for partial FI deficiency. The upregulation of C3, MAC and IL-1 with subsequent demyelination support a pathologic role for complement activation in AHLE, and suggest anakinra as an important adjunctive therapy in this disease.
doi:10.1007/s10875-012-9767-z
PMCID: PMC3540165  PMID: 22926405
Acute Hemorrhagic Leukoencephalitis; Complement Factor I; IL-1; IL-1 receptor antagonist
4.  A Multi-Omic View of Host-Pathogen-Commensal Interplay in Salmonella-Mediated Intestinal Infection 
PLoS ONE  2013;8(6):e67155.
The potential for commensal microorganisms indigenous to a host (the ‘microbiome’ or ‘microbiota’) to alter infection outcome by influencing host-pathogen interplay is largely unknown. We used a multi-omics “systems” approach, incorporating proteomics, metabolomics, glycomics, and metagenomics, to explore the molecular interplay between the murine host, the pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium), and commensal gut microorganisms during intestinal infection with S. Typhimurium. We find proteomic evidence that S. Typhimurium thrives within the infected 129/SvJ mouse gut without antibiotic pre-treatment, inducing inflammation and disrupting the intestinal microbiome (e.g., suppressing Bacteroidetes and Firmicutes while promoting growth of Salmonella and Enterococcus). Alteration of the host microbiome population structure was highly correlated with gut environmental changes, including the accumulation of metabolites normally consumed by commensal microbiota. Finally, the less characterized phase of S. Typhimurium’s lifecycle was investigated, and both proteomic and glycomic evidence suggests S. Typhimurium may take advantage of increased fucose moieties to metabolize fucose while growing in the gut. The application of multiple omics measurements to Salmonella-induced intestinal inflammation provides insights into complex molecular strategies employed during pathogenesis between host, pathogen, and the microbiome.
doi:10.1371/journal.pone.0067155
PMCID: PMC3694140  PMID: 23840608
5.  Real-Time Pharmacy Surveillance and Clinical Decision Support to Reduce Adverse Drug Events in Acute Kidney Injury 
Applied Clinical Informatics  2012;3(2):221-238.
Objectives
Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions.
Methods
The authors conducted a randomized clinical trial among 396 patients admitted to an academic, tertiary care hospital between June 1, 2010 and August 31, 2010 with an acute 0.5 mg/dl change in serum creatinine over 48 hours and a nephrotoxic or renally cleared medication order. Patients randomly assigned to the intervention group received surveillance from a clinical pharmacist using a web-based surveillance tool to monitor drug prescribing and kidney function trends. CDS alerting and standard pharmacy services were active in both study arms. Outcome measures included blinded adjudication of potential adverse drug events (pADEs), adverse drug events (ADEs) and time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications.
Results
Potential ADEs or ADEs occurred for 104 (8.0%) of control and 99 (7.1%) of intervention patient-medication pairs (p=0.4). Additionally, the time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications did not differ between control and intervention patients (33.4 hrs vs. 30.3hrs, p=0.3).
Conclusions
Pharmacy surveillance had no incremental benefit over previously implemented CDS alerts
doi:10.4338/ACI-2012-03-RA-0009
PMCID: PMC3377180  PMID: 22719796
Clinical decision support systems; electronic health records; randomized controlled trial; medication errors; medication error prevention and control; adverse drug reaction reporting systems
6.  CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion 
Lee, J.-M. | Ramos, E.M. | Lee, J.-H. | Gillis, T. | Mysore, J.S. | Hayden, M.R. | Warby, S.C. | Morrison, P. | Nance, M. | Ross, C.A. | Margolis, R.L. | Squitieri, F. | Orobello, S. | Di Donato, S. | Gomez-Tortosa, E. | Ayuso, C. | Suchowersky, O. | Trent, R.J.A. | McCusker, E. | Novelletto, A. | Frontali, M. | Jones, R. | Ashizawa, T. | Frank, S. | Saint-Hilaire, M.H. | Hersch, S.M. | Rosas, H.D. | Lucente, D. | Harrison, M.B. | Zanko, A. | Abramson, R.K. | Marder, K. | Sequeiros, J. | Paulsen, J.S. | Landwehrmeyer, G.B. | Myers, R.H. | MacDonald, M.E. | Gusella, J.F. | Durr, Alexandra | Rosenblatt, Adam | Frati, Luigi | Perlman, Susan | Conneally, Patrick M. | Klimek, Mary Lou | Diggin, Melissa | Hadzi, Tiffany | Duckett, Ayana | Ahmed, Anwar | Allen, Paul | Ames, David | Anderson, Christine | Anderson, Karla | Anderson, Karen | Andrews, Thomasin | Ashburner, John | Axelson, Eric | Aylward, Elizabeth | Barker, Roger A. | Barth, Katrin | Barton, Stacey | Baynes, Kathleen | Bea, Alexandra | Beall, Erik | Beg, Mirza Faisal | Beglinger, Leigh J. | Biglan, Kevin | Bjork, Kristine | Blanchard, Steve | Bockholt, Jeremy | Bommu, Sudharshan Reddy | Brossman, Bradley | Burrows, Maggie | Calhoun, Vince | Carlozzi, Noelle | Chesire, Amy | Chiu, Edmond | Chua, Phyllis | Connell, R.J. | Connor, Carmela | Corey-Bloom, Jody | Craufurd, David | Cross, Stephen | Cysique, Lucette | Santos, Rachelle Dar | Davis, Jennifer | Decolongon, Joji | DiPietro, Anna | Doucette, Nicholas | Downing, Nancy | Dudler, Ann | Dunn, Steve | Ecker, Daniel | Epping, Eric A. | Erickson, Diane | Erwin, Cheryl | Evans, Ken | Factor, Stewart A. | Farias, Sarah | Fatas, Marta | Fiedorowicz, Jess | Fullam, Ruth | Furtado, Sarah | Garde, Monica Bascunana | Gehl, Carissa | Geschwind, Michael D. | Goh, Anita | Gooblar, Jon | Goodman, Anna | Griffith, Jane | Groves, Mark | Guttman, Mark | Hamilton, Joanne | Harrington, Deborah | Harris, Greg | Heaton, Robert K. | Helmer, Karl | Henneberry, Machelle | Hershey, Tamara | Herwig, Kelly | Howard, Elizabeth | Hunter, Christine | Jankovic, Joseph | Johnson, Hans | Johnson, Arik | Jones, Kathy | Juhl, Andrew | Kim, Eun Young | Kimble, Mycah | King, Pamela | Klimek, Mary Lou | Klöppel, Stefan | Koenig, Katherine | Komiti, Angela | Kumar, Rajeev | Langbehn, Douglas | Leavitt, Blair | Leserman, Anne | Lim, Kelvin | Lipe, Hillary | Lowe, Mark | Magnotta, Vincent A. | Mallonee, William M. | Mans, Nicole | Marietta, Jacquie | Marshall, Frederick | Martin, Wayne | Mason, Sarah | Matheson, Kirsty | Matson, Wayne | Mazzoni, Pietro | McDowell, William | Miedzybrodzka, Zosia | Miller, Michael | Mills, James | Miracle, Dawn | Montross, Kelsey | Moore, David | Mori, Sasumu | Moser, David J. | Moskowitz, Carol | Newman, Emily | Nopoulos, Peg | Novak, Marianne | O'Rourke, Justin | Oakes, David | Ondo, William | Orth, Michael | Panegyres, Peter | Pease, Karen | Perlman, Susan | Perlmutter, Joel | Peterson, Asa | Phillips, Michael | Pierson, Ron | Potkin, Steve | Preston, Joy | Quaid, Kimberly | Radtke, Dawn | Rae, Daniela | Rao, Stephen | Raymond, Lynn | Reading, Sarah | Ready, Rebecca | Reece, Christine | Reilmann, Ralf | Reynolds, Norm | Richardson, Kylie | Rickards, Hugh | Ro, Eunyoe | Robinson, Robert | Rodnitzky, Robert | Rogers, Ben | Rosenblatt, Adam | Rosser, Elisabeth | Rosser, Anne | Price, Kathy | Price, Kathy | Ryan, Pat | Salmon, David | Samii, Ali | Schumacher, Jamy | Schumacher, Jessica | Sendon, Jose Luis Lópenz | Shear, Paula | Sheinberg, Alanna | Shpritz, Barnett | Siedlecki, Karen | Simpson, Sheila A. | Singer, Adam | Smith, Jim | Smith, Megan | Smith, Glenn | Snyder, Pete | Song, Allen | Sran, Satwinder | Stephan, Klaas | Stober, Janice | Sü?muth, Sigurd | Suter, Greg | Tabrizi, Sarah | Tempkin, Terry | Testa, Claudia | Thompson, Sean | Thomsen, Teri | Thumma, Kelli | Toga, Arthur | Trautmann, Sonja | Tremont, Geoff | Turner, Jessica | Uc, Ergun | Vaccarino, Anthony | van Duijn, Eric | Van Walsem, Marleen | Vik, Stacie | Vonsattel, Jean Paul | Vuletich, Elizabeth | Warner, Tom | Wasserman, Paula | Wassink, Thomas | Waterman, Elijah | Weaver, Kurt | Weir, David | Welsh, Claire | Werling-Witkoske, Chris | Wesson, Melissa | Westervelt, Holly | Weydt, Patrick | Wheelock, Vicki | Williams, Kent | Williams, Janet | Wodarski, Mary | Wojcieszek, Joanne | Wood, Jessica | Wood-Siverio, Cathy | Wu, Shuhua | Yastrubetskaya, Olga | de Yebenes, Justo Garcia | Zhao, Yong Qiang | Zimbelman, Janice | Zschiegner, Roland | Aaserud, Olaf | Abbruzzese, Giovanni | Andrews, Thomasin | Andrich, Jurgin | Antczak, Jakub | Arran, Natalie | Artiga, Maria J. Saiz | Bachoud-Lévi, Anne-Catherine | Banaszkiewicz, Krysztof | di Poggio, Monica Bandettini | Bandmann, Oliver | Barbera, Miguel A. | Barker, Roger A. | Barrero, Francisco | Barth, Katrin | Bas, Jordi | Beister, Antoine | Bentivoglio, Anna Rita | Bertini, Elisabetta | Biunno, Ida | Bjørgo, Kathrine | Bjørnevoll, Inga | Bohlen, Stefan | Bonelli, Raphael M. | Bos, Reineke | Bourne, Colin | Bradbury, Alyson | Brockie, Peter | Brown, Felicity | Bruno, Stefania | Bryl, Anna | Buck, Andrea | Burg, Sabrina | Burgunder, Jean-Marc | Burns, Peter | Burrows, Liz | Busquets, Nuria | Busse, Monica | Calopa, Matilde | Carruesco, Gemma T. | Casado, Ana Gonzalez | Catena, Judit López | Chu, Carol | Ciesielska, Anna | Clapton, Jackie | Clayton, Carole | Clenaghan, Catherine | Coelho, Miguel | Connemann, Julia | Craufurd, David | Crooks, Jenny | Cubillo, Patricia Trigo | Cubo, Esther | Curtis, Adrienne | De Michele, Giuseppe | De Nicola, A. | de Souza, Jenny | de Weert, A. Marit | de Yébenes, Justo Garcia | Dekker, M. | Descals, A. Martínez | Di Maio, Luigi | Di Pietro, Anna | Dipple, Heather | Dose, Matthias | Dumas, Eve M. | Dunnett, Stephen | Ecker, Daniel | Elifani, F. | Ellison-Rose, Lynda | Elorza, Marina D. | Eschenbach, Carolin | Evans, Carole | Fairtlough, Helen | Fannemel, Madelein | Fasano, Alfonso | Fenollar, Maria | Ferrandes, Giovanna | Ferreira, Jaoquim J. | Fillingham, Kay | Finisterra, Ana Maria | Fisher, K. | Fletcher, Amy | Foster, Jillian | Foustanos, Isabella | Frech, Fernando A. | Fullam, Robert | Fullham, Ruth | Gago, Miguel | García, RocioGarcía-Ramos | García, Socorro S. | Garrett, Carolina | Gellera, Cinzia | Gill, Paul | Ginestroni, Andrea | Golding, Charlotte | Goodman, Anna | Gørvell, Per | Grant, Janet | Griguoli, A. | Gross, Diana | Guedes, Leonor | BascuñanaGuerra, Monica | Guerra, Maria Rosalia | Guerrero, Rosa | Guia, Dolores B. | Guidubaldi, Arianna | Hallam, Caroline | Hamer, Stephanie | Hammer, Kathrin | Handley, Olivia J. | Harding, Alison | Hasholt, Lis | Hedge, Reikha | Heiberg, Arvid | Heinicke, Walburgis | Held, Christine | Hernanz, Laura Casas | Herranhof, Briggitte | Herrera, Carmen Durán | Hidding, Ute | Hiivola, Heli | Hill, Susan | Hjermind, Lena. E. | Hobson, Emma | Hoffmann, Rainer | Holl, Anna Hödl | Howard, Liz | Hunt, Sarah | Huson, Susan | Ialongo, Tamara | Idiago, Jesus Miguel R. | Illmann, Torsten | Jachinska, Katarzyna | Jacopini, Gioia | Jakobsen, Oda | Jamieson, Stuart | Jamrozik, Zygmunt | Janik, Piotr | Johns, Nicola | Jones, Lesley | Jones, Una | Jurgens, Caroline K. | Kaelin, Alain | Kalbarczyk, Anna | Kershaw, Ann | Khalil, Hanan | Kieni, Janina | Klimberg, Aneta | Koivisto, Susana P. | Koppers, Kerstin | Kosinski, Christoph Michael | Krawczyk, Malgorzata | Kremer, Berry | Krysa, Wioletta | Kwiecinski, Hubert | Lahiri, Nayana | Lambeck, Johann | Lange, Herwig | Laver, Fiona | Leenders, K.L. | Levey, Jamie | Leythaeuser, Gabriele | Lezius, Franziska | Llesoy, Joan Roig | Löhle, Matthias | López, Cristobal Diez-Aja | Lorenza, Fortuna | Loria, Giovanna | Magnet, Markus | Mandich, Paola | Marchese, Roberta | Marcinkowski, Jerzy | Mariotti, Caterina | Mariscal, Natividad | Markova, Ivana | Marquard, Ralf | Martikainen, Kirsti | Martínez, Isabel Haro | Martínez-Descals, Asuncion | Martino, T. | Mason, Sarah | McKenzie, Sue | Mechi, Claudia | Mendes, Tiago | Mestre, Tiago | Middleton, Julia | Milkereit, Eva | Miller, Joanne | Miller, Julie | Minster, Sara | Möller, Jens Carsten | Monza, Daniela | Morales, Blas | Moreau, Laura V. | Moreno, Jose L. López-Sendón | Münchau, Alexander | Murch, Ann | Nielsen, Jørgen E. | Niess, Anke | Nørremølle, Anne | Novak, Marianne | O'Donovan, Kristy | Orth, Michael | Otti, Daniela | Owen, Michael | Padieu, Helene | Paganini, Marco | Painold, Annamaria | Päivärinta, Markku | Partington-Jones, Lucy | Paterski, Laurent | Paterson, Nicole | Patino, Dawn | Patton, Michael | Peinemann, Alexander | Peppa, Nadia | Perea, Maria Fuensanta Noguera | Peterson, Maria | Piacentini, Silvia | Piano, Carla | Càrdenas, Regina Pons i | Prehn, Christian | Price, Kathleen | Probst, Daniela | Quarrell, Oliver | Quiroga, Purificacion Pin | Raab, Tina | Rakowicz, Maryla | Raman, Ashok | Raymond, Lucy | Reilmann, Ralf | Reinante, Gema | Reisinger, Karin | Retterstol, Lars | Ribaï, Pascale | Riballo, Antonio V. | Ribas, Guillermo G. | Richter, Sven | Rickards, Hugh | Rinaldi, Carlo | Rissling, Ida | Ritchie, Stuart | Rivera, Susana Vázquez | Robert, Misericordia Floriach | Roca, Elvira | Romano, Silvia | Romoli, Anna Maria | Roos, Raymond A.C. | Røren, Niini | Rose, Sarah | Rosser, Elisabeth | Rosser, Anne | Rossi, Fabiana | Rothery, Jean | Rudzinska, Monika | Ruíz, Pedro J. García | Ruíz, Belan Garzon | Russo, Cinzia Valeria | Ryglewicz, Danuta | Saft, Carston | Salvatore, Elena | Sánchez, Vicenta | Sando, Sigrid Botne | Šašinková, Pavla | Sass, Christian | Scheibl, Monika | Schiefer, Johannes | Schlangen, Christiane | Schmidt, Simone | Schöggl, Helmut | Schrenk, Caroline | Schüpbach, Michael | Schuierer, Michele | Sebastián, Ana Rojo | Selimbegovic-Turkovic, Amina | Sempolowicz, Justyna | Silva, Mark | Sitek, Emilia | Slawek, Jaroslaw | Snowden, Julie | Soleti, Francesco | Soliveri, Paola | Sollom, Andrea | Soltan, Witold | Sorbi, Sandro | Sorensen, Sven Asger | Spadaro, Maria | Städtler, Michael | Stamm, Christiane | Steiner, Tanja | Stokholm, Jette | Stokke, Bodil | Stopford, Cheryl | Storch, Alexander | Straßburger, Katrin | Stubbe, Lars | Sulek, Anna | Szczudlik, Andrzej | Tabrizi, Sarah | Taylor, Rachel | Terol, Santiago Duran-Sindreu | Thomas, Gareth | Thompson, Jennifer | Thomson, Aileen | Tidswell, Katherine | Torres, Maria M. Antequera | Toscano, Jean | Townhill, Jenny | Trautmann, Sonja | Tucci, Tecla | Tuuha, Katri | Uhrova, Tereza | Valadas, Anabela | van Hout, Monique S.E. | van Oostrom, J.C.H. | van Vugt, Jeroen P.P. | vanm, Walsem Marleen R. | Vandenberghe, Wim | Verellen-Dumoulin, Christine | Vergara, Mar Ruiz | Verstappen, C.C.P. | Verstraelen, Nichola | Viladrich, Celia Mareca | Villanueva, Clara | Wahlström, Jan | Warner, Thomas | Wehus, Raghild | Weindl, Adolf | Werner, Cornelius J. | Westmoreland, Leann | Weydt, Patrick | Wiedemann, Alexandra | Wild, Edward | Wild, Sue | Witjes-Ané, Marie-Noelle | Witkowski, Grzegorz | Wójcik, Magdalena | Wolz, Martin | Wolz, Annett | Wright, Jan | Yardumian, Pam | Yates, Shona | Yudina, Elizaveta | Zaremba, Jacek | Zaugg, Sabine W. | Zdzienicka, Elzbieta | Zielonka, Daniel | Zielonka, Euginiusz | Zinzi, Paola | Zittel, Simone | Zucker, Birgrit | Adams, John | Agarwal, Pinky | Antonijevic, Irina | Beck, Christopher | Chiu, Edmond | Churchyard, Andrew | Colcher, Amy | Corey-Bloom, Jody | Dorsey, Ray | Drazinic, Carolyn | Dubinsky, Richard | Duff, Kevin | Factor, Stewart | Foroud, Tatiana | Furtado, Sarah | Giuliano, Joe | Greenamyre, Timothy | Higgins, Don | Jankovic, Joseph | Jennings, Dana | Kang, Un Jung | Kostyk, Sandra | Kumar, Rajeev | Leavitt, Blair | LeDoux, Mark | Mallonee, William | Marshall, Frederick | Mohlo, Eric | Morgan, John | Oakes, David | Panegyres, Peter | Panisset, Michel | Perlman, Susan | Perlmutter, Joel | Quaid, Kimberly | Raymond, Lynn | Revilla, Fredy | Robertson, Suzanne | Robottom, Bradley | Sanchez-Ramos, Juan | Scott, Burton | Shannon, Kathleen | Shoulson, Ira | Singer, Carlos | Tabbal, Samer | Testa, Claudia | van, Kammen Dan | Vetter, Louise | Walker, Francis | Warner, John | Weiner, illiam | Wheelock, Vicki | Yastrubetskaya, Olga | Barton, Stacey | Broyles, Janice | Clouse, Ronda | Coleman, Allison | Davis, Robert | Decolongon, Joji | DeLaRosa, Jeanene | Deuel, Lisa | Dietrich, Susan | Dubinsky, Hilary | Eaton, Ken | Erickson, Diane | Fitzpatrick, Mary Jane | Frucht, Steven | Gartner, Maureen | Goldstein, Jody | Griffith, Jane | Hickey, Charlyne | Hunt, Victoria | Jaglin, Jeana | Klimek, Mary Lou | Lindsay, Pat | Louis, Elan | Loy, Clemet | Lucarelli, Nancy | Malarick, Keith | Martin, Amanda | McInnis, Robert | Moskowitz, Carol | Muratori, Lisa | Nucifora, Frederick | O'Neill, Christine | Palao, Alicia | Peavy, Guerry | Quesada, Monica | Schmidt, Amy | Segro, Vicki | Sperin, Elaine | Suter, Greg | Tanev, Kalo | Tempkin, Teresa | Thiede, Curtis | Wasserman, Paula | Welsh, Claire | Wesson, Melissa | Zauber, Elizabeth
Neurology  2012;78(10):690-695.
Objective:
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
Methods:
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
Results:
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Conclusions:
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
doi:10.1212/WNL.0b013e318249f683
PMCID: PMC3306163  PMID: 22323755
7.  MEGA5: Molecular Evolutionary Genetics Analysis Using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods 
Molecular Biology and Evolution  2011;28(10):2731-2739.
Comparative analysis of molecular sequence data is essential for reconstructing the evolutionary histories of species and inferring the nature and extent of selective forces shaping the evolution of genes and species. Here, we announce the release of Molecular Evolutionary Genetics Analysis version 5 (MEGA5), which is a user-friendly software for mining online databases, building sequence alignments and phylogenetic trees, and using methods of evolutionary bioinformatics in basic biology, biomedicine, and evolution. The newest addition in MEGA5 is a collection of maximum likelihood (ML) analyses for inferring evolutionary trees, selecting best-fit substitution models (nucleotide or amino acid), inferring ancestral states and sequences (along with probabilities), and estimating evolutionary rates site-by-site. In computer simulation analyses, ML tree inference algorithms in MEGA5 compared favorably with other software packages in terms of computational efficiency and the accuracy of the estimates of phylogenetic trees, substitution parameters, and rate variation among sites. The MEGA user interface has now been enhanced to be activity driven to make it easier for the use of both beginners and experienced scientists. This version of MEGA is intended for the Windows platform, and it has been configured for effective use on Mac OS X and Linux desktops. It is available free of charge from http://www.megasoftware.net.
doi:10.1093/molbev/msr121
PMCID: PMC3203626  PMID: 21546353
8.  A case series evaluating the accuracy of manual muscle testing for predicting fetal sex 
Objective
The purpose of this study was to evaluate if manual muscle testing (MMT) could identify fetal sex in women who did not know the sex of their babies. The null hypothesis was that MMT is no more accurate than chance.
Methods
A prospective case series of 27 sequential pregnant patients who did not know the sex of their fetus were included in this study. The examiner was also blind to the sex of the fetus. Manual muscle testing was evaluated after the mother stated “I am having a boy.” Likelihood ratios, specificity, sensitivity, positive predictive value, and negative predictive value were calculated.
Results
Fourteen girl babies and 13 boy babies were born. Manual muscle testing accurately predicted the sex 13 times. The positive likelihood ratio was 0.92 (95% confidence interval, 0.42-2.03), sensitivity was 0.40, specificity was 0.54, positive predictive value was 0.46, and negative predictive value was 0.44.
Conclusion
Manual muscle testing was no better than chance at predicting fetal sex in this case series.
doi:10.1016/j.jcm.2011.06.010
PMCID: PMC3315852  PMID: 22942835
Chiropractic; Muscles; Diagnosis; Neurology; Pregnancy
9.  Survival, Growth and Reproduction of Non-Native Nile Tilapia II: Fundamental Niche Projections and Invasion Potential in the Northern Gulf of Mexico 
PLoS ONE  2012;7(7):e41580.
Understanding the fundamental niche of invasive species facilitates our ability to predict both dispersal patterns and invasion success and therefore provides the basis for better-informed conservation and management policies. Here we focus on Nile tilapia (Oreochromis niloticus Linnaeus, 1758), one of the most widely cultured fish worldwide and a species that has escaped local aquaculture facilities to become established in a coastal-draining river in Mississippi (northern Gulf of Mexico). Using empirical physiological data, logistic regression models were developed to predict the probabilities of Nile tilapia survival, growth, and reproduction at different combinations of temperature (14 and 30°C) and salinity (0–60, by increments of 10). These predictive models were combined with kriged seasonal salinity data derived from multiple long-term data sets to project the species' fundamental niche in Mississippi coastal waters during normal salinity years (averaged across all years) and salinity patterns in extremely wet and dry years (which might emerge more frequently under scenarios of climate change). The derived fundamental niche projections showed that during the summer, Nile tilapia is capable of surviving throughout Mississippi's coastal waters but growth and reproduction were limited to river mouths (or upriver). Overwinter survival was also limited to river mouths. The areas where Nile tilapia could survive, grow, and reproduce increased during extremely wet years (2–368%) and decreased during extremely dry years (86–92%) in the summer with a similar pattern holding for overwinter survival. These results indicate that Nile tilapia is capable of 1) using saline waters to gain access to other watersheds throughout the region and 2) establishing populations in nearshore, low-salinity waters, particularly in the western portion of coastal Mississippi.
doi:10.1371/journal.pone.0041580
PMCID: PMC3407231  PMID: 22848533
10.  Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in West Africa 
BMC Pediatrics  2012;12:95.
Background
There is little data on responses to combination antiretroviral therapy (cART) among HIV-infected children in the West African region. We describe treatment outcomes among HIV-1 and HIV-2 infected children initiating cART in a research clinic in The Gambia, West Africa.
Methods
All treatment naive HIV-infected children who initiated cART according to the WHO ART guidelines for children between October 2004 and December 2009 were included in the analysis. Kaplan-Meir estimates and sign-rank test were used to investigate the responses to treatment.
Results
65 HIV-1 and five HIV-2 infected children aged < 15 years were initiated on cART over this time period. HIV-1 infected children were treated with a combination of Zidovudine or Stavudine + Lamivudine + Nevirapine or Efavirenz while children with HIV-2 were treated with Zidovudine + Lamivudine + ritonavir-boosted Lopinavir. HIV-1 infected children were followed-up for a median (IQR) duration of 20.1 months (6.9 – 34.3), with their median (IQR) age at treatment initiation, CD4% and plasma viral load at baseline found to be 4.9 years (2.1 – 9.1), 13.0% (7.0 – 16.0) and 5.4 log10 copies/ml (4.4 – 6.0) respectively. The median age at treatment initiation of the five HIV-2 infected children was 12 years (range: 4.6 – 14.0) while their median baseline CD4+ T cell count and HIV-2 viral load were 140 cells/mm3 (Range: 40 – 570 cells/mm3) and 4.5 log10copies/mL (Range: 3.1 - 4.9 log10copies/mL) respectively.
Among HIV-1 infected children <5 years of age at ART initiation, the median (IQR) increases in CD4% from baseline to 12, 24 and 36 months were 14% (8 – 19; P = 0.0004), 21% (15 – 22; P = 0.005) and 15% (15 – 25; P = 0.0422) respectively, while the median (IQR) increase in absolute CD4 T cell count from baseline to 12, 24 and 36 months for those ≥5 years at ART initiation were 470 cells/mm3 (270 – 650; P = 0.0005), 230 cells/mm3 (30 – 610; P = 0.0196) and 615 cells/mm3 (250 – 1060; P = 0.0180) respectively. The proportions of children achieving undetectable HIV-1 viral load at 6-, 12-, 24- and 36 months of treatment were 24/38 (63.2%), 20/36 (55.6%), 8/22 (36.4%) and 7/12 (58.3%) respectively. The probability of survival among HIV-1 infected children after 12 months on ART was 89.9% (95% CI 78.8 – 95.3). CD4 T cell recovery was sub-optimal in all the HIV-2 infected children and none achieved virologic suppression. Two of the HIV-2 infected children died within 6 months of starting treatment while the remaining three were lost to follow-up.
Conclusions
The beneficial effects of cART among HIV-1 infected children in our setting are sustained in the first 24 months of treatment with a significant improvement in survival experience up to 36 months; however the outcome was poor in the few HIV-2 infected children initiated on cART.
doi:10.1186/1471-2431-12-95
PMCID: PMC3407729  PMID: 22770231
11.  Simulated Evolution of Protein-Protein Interaction Networks with Realistic Topology 
PLoS ONE  2012;7(6):e39052.
We model the evolution of eukaryotic protein-protein interaction (PPI) networks. In our model, PPI networks evolve by two known biological mechanisms: (1) Gene duplication, which is followed by rapid diversification of duplicate interactions. (2) Neofunctionalization, in which a mutation leads to a new interaction with some other protein. Since many interactions are due to simple surface compatibility, we hypothesize there is an increased likelihood of interacting with other proteins in the target protein’s neighborhood. We find good agreement of the model on 10 different network properties compared to high-confidence experimental PPI networks in yeast, fruit flies, and humans. Key findings are: (1) PPI networks evolve modular structures, with no need to invoke particular selection pressures. (2) Proteins in cells have on average about 6 degrees of separation, similar to some social networks, such as human-communication and actor networks. (3) Unlike social networks, which have a shrinking diameter (degree of maximum separation) over time, PPI networks are predicted to grow in diameter. (4) The model indicates that evolutionarily old proteins should have higher connectivities and be more centrally embedded in their networks. This suggests a way in which present-day proteomics data could provide insights into biological evolution.
doi:10.1371/journal.pone.0039052
PMCID: PMC3387198  PMID: 22768057
12.  Real-time pharmacy surveillance and clinical decision support to reduce adverse drug events in acute kidney injury: a randomized, controlled trial 
Applied clinical informatics  2012;3(2):221-238.
Objectives
Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions.
Methods
The authors conducted a randomized clinical trial among 396 patients admitted to an academic, tertiary care hospital between June 1, 2010 and August 31, 2010 with an acute 0.5 mg/dl change in serum creatinine over 48 hours and a nephrotoxic or renally cleared medication order. Patients randomly assigned to the intervention group received surveillance from a clinical pharmacist using a web-based surveillance tool to monitor drug prescribing and kidney function trends. CDS alerting and standard pharmacy services were active in both study arms. Outcome measures included blinded adjudication of potential adverse drug events (pADEs), adverse drug events (ADEs) and time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications.
Results
Potential ADEs or ADEs occurred for 104 (8.0%) of control and 99 (7.1%) of intervention patient-medication pairs (p=0.4). Additionally, the time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications did not differ between control and intervention patients (33.4 hrs vs. 30.3 hrs, p=0.3).
Conclusions
Pharmacy surveillance had no incremental benefit over previously implemented CDS alerts
doi:10.4338/ACI-2012-03-RA-0009
PMCID: PMC3377180  PMID: 22719796
Decision Support Systems; Clinical; Electronic Health Records; Randomized Controlled Trial; Medication Errors/prevention & control; Adverse Drug Reaction Reporting Systems
13.  Emergence of HBV resistance to lamivudine (3TC) in HIV/HBV co-infected patients in The Gambia, West Africa 
BMC Research Notes  2011;4:561.
Background
Lamivudine (3TC) is a potent inhibitor of both Hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) replication and is part of first-line highly active antiretroviral therapy (HAART) in the Gambia. Unfortunately, the effectiveness of 3TC against HBV is limited by the emergence of resistant strains.
Aim
The aim of this retrospective study was to characterise 3TC-resistant mutations in HBV from co-infected patients receiving HAART, by generating HBV polymerase sequence data and viral loads from HBV genotype E infected patients, both at initiation and during a course of 3TC therapy.
Method
Samples from 21 HBV chronic carriers co-infected with HIV-1 (n = 18), HIV-2 (n = 2) and HIV-dual (n = 1) receiving HAART for a period of 6-52 months were analysed for the emergence of 3TC-resistance mutations.
Findings
Sixteen out of 21 HBV/HIV co-infected patients responded well to HAART treatment maintaining suppression of HBV viraemia to low (≤ 104 copies/mL) (n = 5) or undetectable levels (< 260 copies/ml) (n = 11). Out of the 5 non-responders, 3 had developed 3TC-resistant HBV strains showing mutations in the YMDD motif at position 204 of the RT domain of the HBV polymerase. One patient showed the M204V+ L180M+ V173L+ triple mutation associated with a vaccine escape phenotype, which could be of public health concern in a country with a national HBV vaccination programme. All except one patient was infected with HBV genotype E.
Conclusions
Our findings confirm the risk of 3TC mutations in HAART patients following monotherapy. This is a novel study on 3TC resistance in HBV genotype E patients and encourage the use of tenofovir (in association with 3TC), which has not shown unequivocally documented HBV resistance to date, as part of first-line therapy in HIV/HBV co-infected patients in West Africa.
HBV- hepatitis B infection; HIV- human immunodeficiency virus; HAART- antiretroviral therapy.
doi:10.1186/1756-0500-4-561
PMCID: PMC3292846  PMID: 22195774
14.  Pre-treatment mortality and loss-to-follow-up in HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients eligible for antiretroviral therapy in The Gambia, West Africa 
Background
High early mortality rate among HIV infected patients following initiation of antiretroviral therapy (ART) in resource limited settings may indicate high pre-treatment mortality among ART-eligible patients. There is dearth of data on pre-treatment mortality in ART programmes in sub-Sahara Africa. This study aims to determine pre-treatment mortality rate and predictors of pre-treatment mortality among ART-eligible adult patients in a West Africa clinic-based cohort.
Methods
All HIV-infected patients aged 15 years or older eligible for ART between June 2004 and September 2009 were included in the analysis. Assessment for eligibility was based on the Gambia ART guideline. Survival following ART-eligibility was determined by Kaplan-Meier estimates and predictors of pre-treatment mortality determined by Cox proportional hazard models.
Result
Overall, 790 patients were assessed as eligible for ART based on their clinical and/or immunological status among whom 510 (64.6%) started treatment, 26 (3.3%) requested transfer to another health facility, 136 (17.2%) and 118 (14.9%) were lost to follow-up and died respectively without starting ART. ART-eligible patients who died or were lost to follow-up were more likely to be male or to have a CD4 T-cell count < 100 cells/μL, while patients in WHO clinical stage 3 or 4 were more likely to die without starting treatment. The overall pre-treatment mortality rate was 21.9 deaths per 100 person-years (95% CI 18.3 - 26.2) and the rate for the composite end point of death or loss to follow-up was 47.1 per 100 person-years (95% CI 41.6 - 53.2). Independent predictors of pre-treatment mortality were CD4 T-cell count <100 cells/μL (adjusted Hazard ratio [AHR] 3.71; 95%CI 2.54 - 5.41) and WHO stage 3 or 4 disease (AHR 1.91; 95% CI 1.12 - 3.23). Forty percent of ART-eligible patients lost to follow-up seen alive at field visit cited difficulty with the requirement of disclosing their HIV status as reason for not starting ART.
Conclusion
Approximately one third of ART-eligible patients did not start ART and pre-treatment mortality rate was found high among HIV infected patients in our cohort. CD4 T-cell count <100 cells/μL is the strongest independent predictor of pre-treatment mortality. The requirement to disclose HIV status as part of ART preparation counselling constitutes a huge barrier for eligible patients to access treatment.
doi:10.1186/1742-6405-8-24
PMCID: PMC3152879  PMID: 21774813
15.  Extracting timing and status descriptors for colonoscopy testing from electronic medical records 
Colorectal cancer (CRC) screening rates are low despite confirmed benefits. The authors investigated the use of natural language processing (NLP) to identify previous colonoscopy screening in electronic records from a random sample of 200 patients at least 50 years old. The authors developed algorithms to recognize temporal expressions and ‘status indicators’, such as ‘patient refused’, or ‘test scheduled’. The new methods were added to the existing KnowledgeMap concept identifier system, and the resulting system was used to parse electronic medical records (EMR) to detect completed colonoscopies. Using as the ‘gold standard’ expert physicians' manual review of EMR notes, the system identified timing references with a recall of 0.91 and precision of 0.95, colonoscopy status indicators with a recall of 0.82 and precision of 0.95, and references to actually completed colonoscopies with recall of 0.93 and precision of 0.95. The system was superior to using colonoscopy billing codes alone. Health services researchers and clinicians may find NLP a useful adjunct to traditional methods to detect CRC screening status. Further investigations must validate extension of NLP approaches for other types of CRC screening applications.
doi:10.1136/jamia.2010.004804
PMCID: PMC2995656  PMID: 20595304
16.  Genome-wide promoter analysis of histone modifications in human monocyte-derived antigen presenting cells 
BMC Genomics  2010;11:642.
Background
Monocyte-derived macrophages and dendritic cells (DCs) are important in inflammatory processes and are often used for immunotherapeutic approaches. Blood monocytes can be differentiated into macrophages and DCs, which is accompanied with transcriptional changes in many genes, including chemokines and cell surface markers.
Results
To study the chromatin modifications associated with this differentiation, we performed a genome wide analysis of histone H3 trimethylation on lysine 4 (H3K4me3) and 27 (H3K27me3) as well as acetylation of H3 lysines (AcH3) in promoter regions. We report that both H3K4me3 and AcH3 marks significantly correlate with transcriptionally active genes whereas H3K27me3 mark is associated with inactive gene promoters. During differentiation, the H3K4me3 levels decreased on monocyte-specific CD14, CCR2 and CX3CR1 but increased on DC-specific TM7SF4/DC-STAMP, TREM2 and CD209/DC-SIGN genes. Genes associated with phagocytosis and antigen presentation were marked by H3K4me3 modifications. We also report that H3K4me3 levels on clustered chemokine and surface marker genes often correlate with transcriptional activity.
Conclusion
Our results provide a basis for further functional correlations between gene expression and histone modifications in monocyte-derived macrophages and DCs.
doi:10.1186/1471-2164-11-642
PMCID: PMC3091769  PMID: 21087476
17.  Evaluation of a Method to Identify and Categorize Section Headers in Clinical Documents 
Objective
Clinical notes, typically written in natural language, often contain substructure that divides them into sections, such as “History of Present Illness” or “Family Medical History.” The authors designed and evaluated an algorithm (“SecTag”) to identify both labeled and unlabeled (implied) note section headers in “history and physical examination” documents (“H&P notes”).
Design
The SecTag algorithm uses a combination of natural language processing techniques, word variant recognition with spelling correction, terminology-based rules, and naive Bayesian scoring methods to identify note section headers. Eleven physicians evaluated SecTag's performance on 319 randomly chosen H&P notes.
Measurements
The primary outcomes were the algorithm's recall and precision in identifying all document sections and a predefined list of twenty-nine major sections. A secondary outcome was to evaluate the algorithm's ability to recognize the correct start and end boundaries of identified sections.
Results
The SecTag algorithm identified 16,036 total sections and 7,858 major sections. Physician evaluators classified 15,329 as true positives and identified 160 sections omitted by SecTag. The recall and precision of the SecTag algorithm were 99.0 and 95.6% for all sections, 98.6 and 96.2% for major sections, and 96.6 and 86.8% for unlabeled sections. The algorithm determined the correct starting and ending text boundaries for 94.8% of labeled sections and 85.9% of unlabeled sections.
Conclusions
The SecTag algorithm accurately identified both labeled and unlabeled sections in history and physical documents. This type of algorithm may assist in natural language processing applications, such as clinical decision support systems or competency assessment for medical trainees.
doi:10.1197/jamia.M3037
PMCID: PMC3002123  PMID: 19717800
18.  Seroprevalence of hepatitis B and C virus in HIV-1 and HIV-2 infected Gambians 
Virology Journal  2010;7:230.
Background
The prevalence of HIV/hepatitis co-infection in sub-Saharan Africa is not well documented, while both HIV and HBV are endemic in this area.
Objective
The aim of this study is to determine the seroprevalence of HBV and HCV virus in HIV-infected subjects in the Gambia.
Methods
Plasma samples from HIV infected patients (190 individuals with clinically defined AIDS and 382 individuals without AIDS) were tested retrospectively for the presence of HBV sero-markers and for serum HBV DNA, screened for HCV infection by testing for anti-HCV antibody and HCV RNA.
Results
HBsAg prevalence in HIV-positive individuals is 12.2%. HIV/HBV co-infected individuals with CD4 count of <200 cells uL-1 have a higher HBV DNA viral load than patients with higher CD4 count (log 4.0 vs. log 2.0 DNA copies/ml, p < 0.05). Males (OR = 1.8, 95% CI: 1.0, 3.2) were more likely to be HBsAg positive than female. HCV seroprevalence was 0.9% in HIV-positive individuals.
Conclusion
The prevalence of HBsAg carriage in HIV- infected Gambians is similar to that obtained in the general population. However co-infected individuals with reduced CD4 levels, indicative of AIDS had higher prevalence of HBeAg retention and elevated HBV DNA levels compared to non-AIDS patients with higher CD4 count.
doi:10.1186/1743-422X-7-230
PMCID: PMC2949835  PMID: 20843322
19.  Tetra­quabis(5-fluoro­saccharinato)nickel(II) 
In the centrosymmetric title complex, [Ni(C7H3FNO3S)2(H2O)4], the NiII atom exhibits a slightly distorted trans-NiN2O4 octa­hedral coordination. The nitro­gen donors are provided by two 5-fluoro­saccharinate ligands and the oxygen donors are provided by four water mol­ecules. The crystal structure features O—H⋯O and bifurcated O—H⋯(F,O) hydrogen bonds, the latter involving the F atom of the 5-fluoro­saccharinate ligand.
doi:10.1107/S1600536809007053
PMCID: PMC2968838  PMID: 21582321
20.  Development of a Natural Language Processing System to Identify Timing and Status of Colonoscopy Testing in Electronic Medical Records 
Colorectal cancer (CRC) screening rates are low despite proven benefits. We developed natural language processing (NLP) algorithms to identify temporal expressions and status indicators, such as “patient refused” or “test scheduled.” The authors incorporated the algorithms into the KnowledgeMap Concept Identifier system in order to detect references to completed colonoscopies within electronic text. The modified NLP system was evaluated using 200 randomly selected electronic medical records (EMRs) from a primary care population aged ≥50 years. The system detected completed colonoscopies with recall and precision of 0.93 and 0.92. The system was superior to a query of colonoscopy billing codes to determine screening status.
PMCID: PMC2815478  PMID: 20351837
21.  Identification of a Novel Retinoid by Small Molecule Screening with Zebrafish Embryos 
PLoS ONE  2008;3(4):e1947.
Small molecules have played an important role in delineating molecular pathways involved in embryonic development and disease pathology. The need for novel small molecule modulators of biological processes has driven a number of targeted screens on large diverse libraries. However, due to the specific focus of such screens, the majority of the bioactive potential of these libraries remains unharnessed. In order to identify a higher proportion of compounds with interesting biological activities, we screened a diverse synthetic library for compounds that perturb the development of any of the multiple organs in zebrafish embryos. We identified small molecules that affect the development of a variety of structures such as heart, vasculature, brain, and body-axis. We utilized the previously known role of retinoic acid in anterior-posterior (A–P) patterning to identify the target of DTAB, a compound that caused A–P axis shortening in the zebrafish embryo. We show that DTAB is a retinoid with selective activity towards retinoic acid receptors γ and β. Thus, conducting zebrafish developmental screens using small molecules will not only enable the identification of compounds with diverse biological activities in a large chemical library but may also facilitate the identification of the target pathways of these biologically active molecules.
doi:10.1371/journal.pone.0001947
PMCID: PMC2275795  PMID: 18398471
22.  Artery/Vein Specification Is Governed by Opposing Phosphatidylinositol-3 Kinase and MAP Kinase/ERK Signaling 
Current biology : CB  2006;16(13):1366-1372.
Summary
Angioblasts are multipotent progenitor cells that give rise to arteries or veins [1]. Genetic disruption of the gridlock gene perturbs the artery/vein balance, resulting in generation of insufficient numbers of arterial cells [2]. However, within angioblasts the precise biochemical signals that determine the artery/vein cell-fate decision are poorly understood. We have identified by chemical screening two classes of compounds that compensate for a mutation in the gridlock gene [3]. Both target the VEGF signaling pathway and reveal two downstream branches emanating from the VEGF receptor with opposing effects on arterial specification. We show that activation of ERK (p42/44 MAP kinase) is a specific marker of early arterial progenitors and is among the earliest known determinants of arterial specification. In embryos, cells fated to contribute to arteries express high levels of activated ERK, whereas cells fated to contribute to veins do not. Inhibiting the phosphatidylinositol-3 kinase (PI3K) branch with GS4898 or known PI3K inhibitors, or by expression of a dominant-negative form of AKT promotes arterial specification. Conversely, inhibition of the ERK branch blocks arterial specification, and expression of constitutively active AKT promotes venous specification. In summary, chemical genetic analysis has uncovered unanticipated opposing roles of PI3K and ERK in artery/vein specification.
doi:10.1016/j.cub.2006.05.046
PMCID: PMC1930149  PMID: 16824925
23.  Antimicrobial activities of dialysate-elicited and resident human peritoneal macrophages. 
Infection and Immunity  1985;49(1):212-218.
Recent studies of the antimicrobial capacity of peritoneal macrophages (PM phi) isolated from patients undergoing chronic peritoneal dialysis have raised the question of whether these cells might be analogous to stimulated or activated murine PM phi. To explore this possibility, we compared PM phi from these patients (dialysate-elicited PM phi) with PM phi obtained from women undergoing laparoscopy (resident PM phi) in several in vitro assays of phagocyte function. Although bacterial phagocytosis by cells from both groups of donors was similar, significant differences were found in their chemiluminescence responses to opsonized zymosan. Although the mean peak luminol-enhanced chemiluminescence response of dialysate-elicited PM phi was 4.7 X 10(5) cpm, that of resident PM phi was only 1.3 X 10(5) cpm (P less than 0.05). In a lucigenin-enhanced chemiluminescence assay, dialysate-elicited PM phi again generated significantly greater chemiluminescence than did resident PM phi, suggesting that dialysate-elicited PM phi have a relatively increased capacity for O2- production. Using a fluorochrome microassay to assess the intracellular candidicidal activities of these cells, we found that dialysate-elicited PM phi killed 17% of cell-associated blastospores compared with only 1.5% killing by resident PM phi (P less than 0.05). These investigations led us to conclude that results of studies of the functional activity of dialysate-elicited PM phi cannot necessarily be extrapolated to resident PM phi and that dialysate-elicited PM phi do in some respects behave as stimulated or activated cells.
Images
PMCID: PMC262081  PMID: 3159679

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