PMCC PMCC

Search tips
Search criteria

Advanced

Important Notice

PubMed Central Canada to be taken offline in February 2018

On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

Read more

Results 1-25 (2268)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Innate and Adaptive Cellular Immune Responses to Mycobacterium tuberculosis Infection 
Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the coordinated efforts of innate and adaptive immune cells. Diverse pulmonary myeloid cell populations respond to Mtb with unique contributions to both host-protective and potentially detrimental inflammation. Although multiple cell types of the adaptive immune system respond to Mtb infection, CD4 T cells are the principal antigen-specific cells responsible for containment of Mtb infection, but they can also be major contributors to disease during Mtb infection in several different settings. Here, we will discuss the role of different myeloid populations as well as the dual nature of CD4 T cells in Mtb infection with a primary focus on data generated using in vivo cellular immunological studies in experimental animal models and in humans when available.
Diverse myeloid cell populations respond to tuberculosis infection. CD4 T cells are the main antigen-specific cells responsible for infection containment, but they can also play a role in driving tissue damage.
doi:10.1101/cshperspect.a018424
PMCID: PMC4665043  PMID: 26187873
2.  Abstracts from the Food Allergy and Anaphylaxis Meeting 2016 
Pouessel, Guillaume | Claverie, Claire | Labreuche, Julien | Renaudin, Jean-Marie | Dorkenoo, Aimée | Eb, Mireille | Moneret-Vautrin, Anne | Deschildre, Antoine | Leteurtre, Stephane | Grabenhenrich, Linus | Worm, Margitta | Dölle, Sabine | Scherer, Kathrin | Hutteger, Isidor | Christensen, Morten | Bindslev-Jensen, Carsten | Mortz, Charlotte | Eller, Esben | Kjaer, Henrik Fomsgaard | Carneiro-Leão, Leonor | Badas, Jenny | Coimbra, Alice | Levy, Dikla Pivko | Ben-Shoshan, Moshe | Rimon, Ayelet | Benor, Shira | Arends, Nicolette J. T. | Edelbroek, Nikki | de Groot, Hans | Emons, Joyce A. M. | Brand, H. Kim A. | Verhoeven, Dirk | van Veen, Leonieke N. | de Jong, Nicolette W. | Noh, Geunwoong | Jang, Eun Ha | Pascal, Mariona | Dominguez, Olga | Piquer, Mònica | Alvaro, Montserrat | Jimenez-Feijoo, Rosa | Lozano, Jaime | Machinena, Adriana | del Mar Folqué, Maria | Giner, Maria Teresa | Plaza, Ana María | Turner, Paul | Patel, Nandinee | Vazquez-Ortiz, Marta | Lindsley, Sarah | Walker, Lucy | Rosenberg, Simon | Mari, Adriano | Alessandri, Claudia | Giangrieco, Ivana | Tuppo, Lisa | Rafaiani, Chiara | Mitterer, Georg | Ciancamerla, Michela | Ferrara, Rosetta | Bernardi, Maria Livia | Zennaro, Danila | Tamburrini, Maurizio | Ciardiello, Maria Antonetta | Harwanegg, Christian | Fernandez, Antonio | Selb, Regina | Egenmann, Philippe | Epstein, Michelle | Hoffmann-Sommergruber, Karin | Koning, Frits | Lovik, Martinus | Clare Mills, E. N. | Moreno, Javier | van Loveren, Henk | Wal, Jean-Michel | Diesner, Susanne | Bergmayr, Cornelia | Pfitzner, Barbara | Assmann, Vera Elisabeth | Starkl, Philipp | Endesfelder, David | Eiwegger, Thomas | Szepfalusi, Zsolt | Fehrenbach, Heinz | Jensen-Jarolim, Erika | Hartmann, Anton | Pali-Schöll, Isabella | Untersmayr, Eva | Wille, Soren | Meyer, Peter | Klingebiel, Caroline | Lidholm, Jonas | Ehrenberg, Angelica | Östling, Jonas | Cleach, Isabelle | Mège, Jean-Louis | Vitte, Joana | Aina, Roberta | Dubiela, Pawel | Pfeifer, Sabine | Bublin, Merima | Radauer, Christian | Humeniuk, Piotr | Kabasser, Stefan | Asero, Riccardo | Bogas, Gador | Gomez, Francisca | Campo, Paloma | Salas, Maria | Doña, Inmaculada | Barrionuevo, Esther | Guerrero, Maria Auxiliadora | Mayorga, Cristobalina | Prieto, Ana | Barber, Domingo | Torres, Maria Jose | Jamin, Annette | Wangorsch, Andrea | Ballmer, Barbara | Vieths, Stefan | Scheurer, Stephan | Apostolovic, Danijela | Mihailovic, Jelena | Krstic, Maja | Starkhammar, Maria | Velickovic, Tanja Cirkovic | Hamsten, Carl | van Hage, Marianne | van Erp, Francine C. | Knol, Edward F. | Kansen, Hannah M. | Pontoppidan, Bo | Meijer, Yolanda | van der Ent, Cornelis K. | Knulst, André C. | Sayers, Rebekah | Brown, Helen | Custovic, Adnan | Simpson, Angela | Mills, Claire | Schulz, Juliane | Akkerdaas, Jaap | Totis, Muriel | Capt, Annabelle | Herouet-Guicheney, Corinne | van Ree, Ronald | Banerjee, Tushar | Banerjee, Antima | Claude, Mathilde | Bouchaud, Grégory | Lupi, Roberta | Castan, Laure | Tranquet, Olivier | Denery-Papini, Sandra | Bodinier, Marie | Brossard, Chantal | De Poi, Rosella | Gritti, Elisa | De Dominicis, Emiliano | Popping, Bert | de Laureto, Patrizia Polverino | Palosuo, Kati | Kukkonen, Anna Kaarina | Pelkonen, Anna | Mäkelä, Mika | Lee, Nanju Alice | Rost, Johanna | Muralidharan, Sridevi | Campbell, Dianne | Mehr, Sam | Nock, Catherine | Baumert, Joseph | Taylor, Steve | Mastrorilli, Carla | Tripodi, Salvatore | Caffarelli, Carlo | Perna, Serena | Di Rienzo Businco, Andrea | Sfika, Ifigenia | Dondi, Arianna | Bianchi, Annamaria | Dascola, Carlotta Povesi | Ricci, Giampaolo | Cipriani, Francesca | Maiello, Nunzia | del Giudice, Michele Miraglia | Frediani, Tullio | Frediani, Simone | Macrì, Francesco | Pistoletti, Chiara | Iacono, Iride Dello | Patria, Maria Francesca | Varin, Elena | Peroni, Diego | Comberiati, Pasquale | Chini, Loredana | Moschese, Viviana | Lucarelli, Sandra | Bernardini, Roberto | Pingitore, Giuseppe | Pelosi, Umberto | Olcese, Roberta | Moretti, Matteo | Cirisano, Anastasia | Faggian, Diego | Travaglini, Alessandro | Plebani, Mario | Verga, Maria Carmen | Calvani, Mauro | Giordani, Paolo | Matricardi, Paolo Maria | Ontiveros, Noe | Cabrera-Chavez, Francisco | Galand, Julie | Beaudouin, Etienne | Pineau, Florence | Sakai, Shinobu | Matsunaga, Kayoko | Teshima, Reiko | Larré, Colette | Denery, Sandra | Tschirner, Sebastian | Trendelenburg, Valérie | Schulz, Gabriele | Niggemann, Bodo | Beyer, Kirsten | Bouferkas, Youcef | Belabbas, Younes | Saidi, Djamel | Kheroua, Omar | Mecherfi, Kamel Eddine El | Guendouz, Malika | Haddi, Abir | Kaddouri, Hanane | Amaral, Luis | Pereira, Ana | Rodrigues, Susana | Datema, Mareen | Jongejan, Laurian | Clausen, Michael | Knulst, Andre | Papadopoulos, Nikolaos | Kowalski, Marek | de Blay, Frédéric | Zwinderman, Aeilko | Hoffman-Sommergruber, Karin | Ballmer-Weber, Barbara | Fernandez-Rivas, Montserrat | Deng, Shan | Yin, Jia | Eisenmann, Charlotte | Nassiri, Maria | Reinert, Rabea | van der Valk, Johanna P. M. | van Wijk, Roy Gerth | Vergouwe, Yvonne | Steyerberg, Ewout W. | Reitsma, Marit | Wichers, Harry J. | Savelkoul, Huub F. J. | Vlieg-Boerstra, Berber | Dubois, Anthony E. J. | de Jong, Nicolette W. | Carolino, Fabrícia | Rodolfo, Ana | Cernadas, Josefina | Roa-Medellín, Dasha | Rodriguez-Fernandez, Ana | Navarro, Joaquín | Albendiz, Vicente | Baeza, María Luisa | Intente-Herrero, Sonsoles | Mikkelsen, Andrea | Mehlig, Kirsten | Lissner, Lauren | Verrill, Linda | Luccioli, Stefano | van Bilsen, Jolanda | Kuper, Frieke | Wolterbeek, André | Rankouhi, Tanja Rouhani | Verschuren, Lars | Cnossen, Hilde | Jeurink, Prescilla | Garssen, Johan | Knippels, Léon | Garthoff, Jossie | Houben, Geert | Leeman, Winfried | Eleonore Pettersson, M. | Schins, Afke M. M. | Koppelman, Gerard H. | Kollen, Boudewjin J. | Zubchenko, Svitlana | Kuntz, Sarah | Mérida, Pablo | Álvaro, Montserrat | Piquer, Monica | Riggioni, Carmen | Castellanos, Juan Heber | Jimenez, Rosa | Cap, Melanie | Drumez, Elodie | Lejeune, Stéphanie | Thumerelle, Caroline | Mordacq, Clémence | Nève, Véronique | Ricò, Sonia | Varini, Margherita | Nocerino, Rita | Cosenza, Linda | Amoroso, Antonio | Di Costanzo, Margherita | Di Scala, Carmen | Bedogni, Giorgio | Canani, Roberto Berni | Turner, Paul J. | Poza-Guedes, Paloma | González-Pérez, Ruperto | Sánchez-Machín, Inmaculada | Matheu-Delgado, Victor | Wambre, Erik | Ballegaard, Anne-Sofie | Madsen, Charlotte | Gregersen, Juliane | Bøgh, Katrine Lindholm | Aubert, Philippe | Neunlist, Michel | Magnan, Antoine | Lozano-Ojalvo, Daniel | Pablos-Tanarro, Alba | Pérez-Rodríguez, Leticia | Molina, Elena | López-Fandiño, Rosina | Rekima, Akila | Macchiaverni, Patricia | Turfkruyer, Mathilde | Holvoet, Sebastien | Dupuis, Lénaïck | Baiz, Nour | Annesi-Maesano, Isabella | Mercenier, Annick | Nutten, Sophie | Verhasselt, Valérie | Mrakovcic-Sutic, Ines | Banac, Srdan | Sutic, Ivana | Baricev-Novakovic, Zdenka | Sutic, Ingrid | Pavisic, Valentino | Muñoz-Cano, Rosa | Jiménez-Rodríguez, Teodoríkez | Corbacho, Daniel | Roca-Ferrer, Jordi | Bartra, Joan | Bulog, Aleksandar | Micovic, Vladimir | Markiewicz, Lidia | Szymkiewicz, Agata | Szyc, Anna | Wróblewska, Barbara | Harvey, Bryan M. | Harthoorn, Lucien F. | Wesley Burks, A. | Rentzos, Georgios | Björk, Anna-Lena Bramstång | Bengtsson, Ulf | Barber, Colin | Kalicinsky, Chrystyna | Breynaert, Christine | Coorevits, Lieve | Jansen, Cornelia | Van Hoeyveld, Erna | Verbeke, Kristin | Kochuyt, Anne-Marie | Schrijvers, Rik | Deleanu, Diana | Muntean, Adriana | Konstantakopoulou, Maria | Pasioti, Maria | Papadopoulou, Anastasia | Iliopoulou, Anna | Mikos, Nikolaos | Kompoti, Evangelia | de Castro, Eunice Dias | Bartalomé, Borja | Ue, Kok Loong | Griffiths, Elizabeth | Till, Stephen | Grimshaw, Kate | Roberts, Graham | Selby, Anna | Butiene, Indre | Larco, Jose Ignacio | Dubakiene, Ruta | Fiandor, Ana | Fiocchi, Alessandro | Papadopoulos, Nikos | Sigurdardottir, Sigurveig | Sprikkelman, Aline | Schoemaker, Anne-Fleur | Xepapadaki, Paraskevi | Keil, Thomas | Cojocariu, Zizi | Barbado, Beatriz Secades | Iancu, Vasti | Arroabarren, Esozia | Esarte, Marta Goñi | Arteaga, Miren | Andrade, Mayra Coutinho | Borges, Denise | Kalil, Jorge | Bianchi, Pedro Giavina | Agondi, Rosana Camara | Gupta, Rinkesh Kumar | Sharma, Akanksha | Gupta, Kriti | Das, Mukul | Dwivedi, Premendra | Karseladze, Rusudan | Jorjoliani, Liana | Saginadze, Lali | Tskhakaia, Mariam | Basello, Katia | Piuri, Gabriele | Speciani, Attilio Francesco | Speciani, Michela Carola | Camerotto, Carla | Zinno, Francesco | Pakholchuk, Olga | Nedelska, Svitlana | Pattini, Stefano | Costantino, Maria Teresa | Peveri, Silvia | Villalta, Danilo | Savi, Eleonora | Costanzi, Andrea | Revyakina, Vera A. | Kiseleva, Marina A. | Kuvshinova, Elena D. | Larkova, Inna A. | Shekhetov, Anton A. | Silva, Diana | Moreira, André | Plácido, José | van der Kleij, Hanneke | van Twuijver, Esther | Sutorius, Robbert | de Kam, Pieter-Jan | van Odijk, Jenny | Lindqvist, Helen | Lustig, Elin | Jácome, Amyra Ali Azamar | Aguilar, Karla Leversia Borjas | Domínguez, Miguel García | Hernández, David Alejandro Mendoza | Caruso, Cristiano | Casale, Cono | Rapaccini, Gian Lodovico | Romano, Antonino | De Vitis, Italo | Cocco, Renata R. | Aranda, Carolina | Mallozi, Marcia C. | Motta, Jackeline F. | Moraes, Lilian | Pastorino, Antonio | Rosario, Nelson | Goudouris, Ekaterini | Porto, Arnaldo | Wandalsen, Neusa F. | Sarinho, Emanuel | Sano, Flavio | Solé, Dirceu | Pitsios, Constantinos | Petrodimopoulou, Maria | Papadopoulou, Ekaterini | Passioti, Maria | Kontogianni, Meropi | Adamia, Nino | Khaleva, Ekaterina | del Prado, Ana Prieto | Du Toit, George | Krzych, Edyta | Samolinska-Zawisza, Urszula | Furmanczyk, Konrad | Tomaszewska, Aneta | Raciborski, Filip | Lipiec, Agnieszka | Samel-Kowalik, Piotr | Walkiewicz, Artur | Borowicz, Jacek | Samolinski, Boleslaw | Nano, Aimee Lou | Recto, Marysia | Somoza, Maria Luisa | López, Natalia Blanca | Alzate, Diana Pérez | Ruano, Francisco Javier | Garcimartín, Maria Isabel | Haroun, Elisa | de la Torre, Maria Vázquez | Rojas, Antonia | Onieva, Montserrat López | Canto, Gabriela | Rodrigues, Alexandra | Forno, Andreia | Cabral, António Jorge | Gonçalves, Rute | Vorozhko, Ilya | Sentsova, Tatyana | Chernyak, Olga | Denisova, Svetlana | Ilènko, Lidia | Muhortnich, Valery | Zimmermann, Caroline | Rohrbach, Alexander | Bakhsh, Faisal R. | Boudewijn, Kollen | Oomkes-Pilon, Anne-Marie | Van Ginkle, Dorien | Šilar, Mira | Jeverica, Anja | Vesel, Tina | Avčin, Tadej | Korošec, Peter | van der Valk, Johanna | Berends, Irene | Arends, Nicolette | van Maaren, Maurits | Wichers, Harry | Emons, Joyce | Dubois, Anthony | de Jong, Nicolette | Matsyura, Oksana | Besh, Lesya | Huang, Chung-Hsiung | Jan, Tong-Rong | Stiefel, Gary | Tratt, Jean | Kirk, Kerrie | Carolino, Fabricia | Arasi, Stefania | Caminiti, Lucia | Crisafulli, Giuseppe | Fiamingo, Chiara | Fresta, Jlenia | Pajno, Giovanni | Remington, Ben | Kruizinga, Astrid | Marty Blom, W. | Westerhout, Joost | Bijlsma, Sabina | Baumert, Joe | Blankestijn, Mark | Otten, Henny | Klemans, Rob | Michelsen-Huisman, Anouska D. | van Os-Medendorp, Harmieke | Kruizinga, Astrid G. | Versluis, Astrid | van Duijn, Gert | de Zeeuw-Brouwer, H. Mary-Lene | Castenmiller, Jacqueline J. M. | Noteborn, Hub P. J. M. | Houben, Geert F. | Bravin, Kristian | Luyt, David | Javed, Bushra | Couch, Phil | Munro, Christopher | Padfield, Phil | Sperrin, Matt | Byrne, Aideen | Oosthuizen, Lizalet | Kelleher, Carina | Ward, Fiona | Brosnan, Niamh | King, Graham | Corbet, Eva | Guzmán, Josué Alejandro Huertas | García, Montserrat Bosque | Asensio, Oscar | Navarrete, Laura Valdesoiro | Larramona, Helena | Miró, Xavier Domingo | Pyrz, Katarzyna | Austin, Moira | Boloh, Yanne | Couch, Philip | Galloway, Deirdre | Hernandez, Pilar | Hourihane, Jonathan O’B. | Kenna, Fiona | Majkowska-Wojciechowska, Barbara | Regent, Lynne | Themisb, Marina | Schnadt, Sabine | Semic-Jusufagic, Aida | Galvin, Audrey Dunn | Kauppila, Tiina | Kuitunen, Mikael | Kitsioulis, Nikolaos A. | Douladiris, Nikolaos | Kostoudi, Sofia | Manolaraki, Ioanna | Mitsias, Dimitris | Manousakis, Emmanouil | Papadopoulos, Nikolaos G. | Knibb, Rebecca | Hammond, Jennifer | Cooke, Richard | Yrjänä, Jaakko | Hanni, Anna-Maija | Vähäsarja, Päivi | Mustonen, Oona | Dunder, Teija | Kulmala, Petri | Lasa, Eva | D’Amelio, Carmen | Martínez, Sara | Joral, Alejandro | Gastaminza, Gabriel | Goikoetxea, Maria Jose | Candy, David C. A. | Van Ampting, Marleen T. J. | Oude Nijhuis, Manon M. | Butt, Assad M. | Peroni, Diego G. | Fox, Adam T. | Knol, Jan | Michaelis, Louise J. | Padua, Ines | Padrao, Patricia | Moreira, Pedro | Barros, Renata | Sharif, Hanan | Ahmed, Manzoor | Gomaa, Nehad | Mens, Joris | Smit, Koen | Timmermans, Frans | Poredoš, Tomaž | Jeverica, Anja Koren | Sedmak, Marjeta | Benedik, Evgen | Accetto, Meta | Zupančič, Mirjana | Yonamine, Glauce | Soldateli, Gustavo | Aquilante, Bruna | Pastorino, Antonio Carlos | de Moraes Beck, Cleonir Lui | Gushken, Andrea Keiko | de Barros Dorna, Mayra | dos Santos, Cristiane Nunes | Castro, Ana Paula Moschione | Al-Qahtani, Abdulhadi | Arnaout, Rand | Khaliq, Agha Rehan | Amin, Rashid | Sheikh, Farrukh | Alvarez, Jorge | Anda, Marta | Palacios, Miriam | De Prada, Montserrat | Ponce, Carmen | Balbino, Bianca | Sibilano, Riccardo | Marichal, Thomas | Gaudenzio, Nicolas | Karasuyama, Hajime | Bruhns, Pierre | Tsai, Mindy | Reber, Laurent L. | Galli, Stephen J. | Ferreira, Ana Reis | Cernadas, Josefina R. | del Campo García, Aida | Fernández, Sara Pereiro | Carrera, Nerea Sarmiento | Sánchez-Cruz, Fernando Bandrés | Lorenzo, José Ramón Fernández | Claus, Stephanie | Pföhler, Claudia | Ruëff, Franziska | Treudler, Regina | Jaume, Mercedes Escarrer | Madroñero, Agustin | Perez, Maria Teresa Guerra | Julia, Juan Carlos | Plovdiv, Charlotte Hands | Gethings, Lee | Langridge, Jim | Adel-Patient, Karine | Bernard, Hervé | Barcievic-Jones, Ivona | Sokolova, Raditsa | Yankova, Rumyana | Ivanovska, Mariya | Murdjeva, Marianna | Popova, Tatyana | Dermendzhiev, Svetlan | Karjalainen, Martin | Lehnigk, Ulrike | Brown, Duncan | Locklear, Julie C. | Locklear, Julie | Maris, Ioana | Hourihane, Jonathan | Ornelas, Cristina | Caiado, Joana | Ferreira, Manuel Branco | Pereira-Barbosa, Manuel | Puente, Yolanda | Daza, Juan Carlos | Monteseirin, Francisco Javier | Ukleja-Sokolowska, Natalia | Gawronska-Ukleja, Ewa | Zbikowska-Gotz, Magdalena | Bartuzi, Zbigniew | Sokolowski, Lukasz | Adams, Aine | Mahon, Bernard | English, Karen | Gourdon-Dubois, Nelly | Sellam, Laetitia | Pereira, Bruno | Michaud, Elodie | Messaoudi, Khaled | Evrard, Bertrand | Fauquert, Jean-Luc | Palomares, Francisca | Gomez, Gador | Rodriguez, Maria Jose | Galindo, Luisa | Molina, Ana | Paparo, Lorella | Mennini, Maurizio | Aitoro, Rosita | Wawrzeńczyk, Adam | Przybyszewski, Michał | Wawrzeńczyk, Anna | Sarıcoban, Hulya Ercan | Ugras, Meltem | Yalvac, Zerrin | Flokstra-de Blok, Bertine M. J. | van der Velde, J. L. | Vereda, Andrea | Ippolito, Clara | Traversa, Amaranta | Adriano, Daniela | Bianchi, Daniela Manila | Gallina, Silvia | Decastelli, Lucia | Makatsori, Melina | Miles, Anne | Devetak, Sonja Posega | Devetak, Iztok | Tabet, Soraya Ainad | Trandbohus, Jeanette Fisker | Winther, Pernille | Malling, Hans-Jørgen | Hansen, Kirsten Skamstrup | Garvey, Lene Heise | Wang, Chia-Chi | Cheng, Yin-Hua | Tung, Chun-Wei | Dietrich, Mariola | Marenholz, Ingo | Kalb, Birgit | Grosche, Sarah | Blümchen, Katharina | Schlags, Rupert | Price, Mareike | Rietz, Sylke | Esparza-Gordillo, Jorge | Lau, Susanne | Lee, Young-Ae | Almontasheri, Ali | Bahkali, Mohammad Al | Elshorbagi, Sahar | Alfhaid, Abdullah | Altamimi, Mashary | Madbouly, Eman | Al-Dhekri, Hassan | Arnaout, Rand K. | Basagaña, Maria | Miquel, Sira | Bartolomé, Borja | Brix, Bettina | Rohwer, Stefanie | Brandhoff, Sandra | Berger, Alena | Suer, Waltraud | Weimann, Alf | Bueno, Cristina | Martín-Pedraza, Laura | Abián, Sara | Segundo-Acosta, Pablo San | López-Rodríguez, Juan Carlos | Barderas, Rodrigo | Batanero, Eva | Cuesta-Herranz, Javier | Villalba, María Teresa | Correia, Magna | Benito-Garcia, Filipe | Arêde, Cristina | Piedade, Susana | Morais-Almeida, Mário | Hindley, James | Yarham, Ross | Kuklinska-Pijanka, Anna | Gillick, David | Patient, Karine | Chapman, Martin D. | Bøgh, Katrine L. | Miranda, Ana | Matos, Eugénia | Sokolova, Anna | Rao, Huan | Baricevic-Jones, Ivona | Smith, Frances | Xue, Wentong | Magnusdottir, Helga | Vidarsdottir, Anna G. | Lund, Sigrun | Jensen, Anders Blom | Ludviksson, Bjorn R. | Simon, Reyna | Elfont, Robert | Bennett, Sean | Voyksner, Robert | de Lurdes Torre, Maria | Yürek, Songül | Faber, Margaretha A. | Bastiaensen, Annick | Mangodt, Evelyne | van Gasse, Athina | Decuyper, Ine | Sabato, Vito | Hagendorens, Margo M. | Bridts, Chris H. | De Clerck, Luc S. | Ebo, Didier | Schwarz, Susanne | Ziegert, Mandy | Albroscheit, Saskia | Schwager, Christian | Kull, Skadi | Behrends, Jochen | Röckendorf, Niels | Schocker, Frauke | Frey, Andreas | Homann, Arne | Becker, Wolf-Meinhard | Jappe, Uta | Zaabat, Nesrine | Osscini, Sylvia | Agabriel, Chantal | Sterling, Benoît | Carsin, Ania | Liabeuf, Valérie | Maćków, Monica | Zbróg, Alina | Bronkowska, Monica | Courtois, Justine | Gadisseur, Romy | Bertholet, Catherine | Lukas, Pierre | Cavalier, Etienne | Delahaut, Philippe | Quinting, Birgit | Gertmo, Margareta Brandt | Hasseus, Ewa Ternesten | Barzylovych, Vladyslava | Oliveira, Júlio | Ensina, Luis F. | Aranda, Carolina S. | Dopazo, Leire | Lopez, Rebeca | Perez, Raquel | Santos-Diez, Laura | Bilbao, Agurtzane | Garcia, Juan Miguel | Núñez, Ignacio García | Mármol, María Ángeles Algaba | Villarejo, María José Barasona | Martos, José Antonio Bácter | Vergara, Marina Suárez | García, José María Ignacio | Michalska, Agata | Sergiejko, Grzegorz | Zacniewski, Robert | Ghiordanescu, Ileana-Maria | Deaconu, Cristina | Popescu, Mihaela | Bumbacea, Roxana Silvia | Ibranji, Alkerta | Nikolla, Elida | Loloci, Gjustina | Juel-Berg, Nanna | Larsen, Lau Fabricius | Poulsen, Lars Kjaergaard | Marcelino, João | Prata, Ricardo | Costa, Ana Célia | Duarte, Fátima | Neto, Marta | Santos, Jennifer | Pestana, Luís Câmara | Sampaio, Daniel | Minale, Paola | Dignetti, Paola | Bignardi, Donatella | Nedelea, Irena | Popescu, Florin-Dan | Vieru, Mariana | Secureanu, Florin-Adrian | Ganea, Carmen Saviana | Vieira, Miguel | Silva, José Pedro Moreira | Watts, Timothy | Watts, Sophia | Lomikovska, Marta | Peredelskaya, Marina | Nenasheva, Natalia | Filipovic, Ivana | Zivkovic, Zorica | Filipovic, Djordje | Higgs, Jennette | Warner, Amena | Jones, Carla
doi:10.1186/s13601-017-0142-2
PMCID: PMC5384531
3.  Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis 
Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMP). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels have been shown to distinguish active from latent as well as successfully treated Mycobacterium tuberculosis (Mtb) infection. MMP-1 expression is also associated with active TB. Here, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other non-tuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied expression of HO-1 and MMP-1 in Mtb-infected human and murine macrophages. We found that infection of macrophages with live virulent Mtb is required for robust induction of high levels of HO-1, but not MMP-1. In addition, we observed that carbon monoxide, a product of Mtb induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients.
doi:10.4049/jimmunol.1500942
PMCID: PMC4561190  PMID: 26268658
6.  Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk 
Nature  2014;511(7507):99-103.
Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent1. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria2–5. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality6. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target7. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.
doi:10.1038/nature13489
PMCID: PMC4809146  PMID: 24990750
7.  Data discipline in electronic medical records 
Canadian Family Physician  2015;61(12):e570-e576.
Objective
To evaluate the transformation in smoking status documentation after implementing a standardized intake tool as part of a primary care smoking cessation program.
Design
A before-and-after evaluation of smoking status documentation was conducted following implementation of a smoking assessment tool. To evaluate the effect of the intervention, the Canadian Primary Care Sentinel Surveillance Network was used to extract aggregate smoking data on the study cohort.
Setting
Academic primary care clinic in Kingston, Ont.
Participants
A total of 7312 primary care patients.
Interventions
As the first phase in a primary care smoking cessation program, a standardized intake tool was developed as part of a vital signs screening process.
Main outcome measures
Documented smoking status of patients before implementation of the intake tool and documented smoking status of patients in the 6 months after its implementation.
Results
Following the implementation of the standardized intake tool, there was a 55% (P < .001; 95% CI 0.53 to 0.56) increase in the proportion of patients with a completed smoking status; more than 1100 former smokers were identified and the documented smoking rate in this cohort increased from 4.4% to 16.2%.
Conclusion
This study shows that the implementation of an intake tool, integrated into existing clinical operational structures, is an effective way to standardize clinical documentation and promotes the optimization of electronic medical records.
PMCID: PMC4677960  PMID: 27035007
8.  Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis 
PLoS Pathogens  2015;11(8):e1005040.
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6Chigh monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses.
Author Summary
Meningoencephalitis due to Cryptococcus neoformans is the leading cause of mortality in AIDS patients in the developing world. It has been known that depletion of CD4 T cells is the most critical predisposing factor to cryptococcosis in HIV infected patients. What has not been clear is the effect of HIV-induced innate inflammation in susceptibility to cryptococcosis. We treated C. neoformans infected mice with poly-ICLC (pICLC), a dsRNA virus mimic, to study the role of virus-induced type I IFN in host defense against cryptococcosis. PICLC treatment induced type I IFN in C. neoformans infected mice via MDA5 and significantly prolonged the survival of mice with reduced fungal burden in the brain. PICLC also protected mice from cryptococcosis caused by C. gattii. PICLC treatment recruited large numbers of neutrophils and Ly6Chigh monocytes into the lung parenchyma and suppressed eosinophilia. PICLC-mediated protection against C. neoformans required CD4 T cells and was associated with suppressed Th2 and enhanced Th17 responses. IFNγ and IL-17A were also important for pICLC-induced protection of infected mice. Our study demonstrates that induction of type I IFN dramatically improves host resistance against cryptococci by beneficial alterations in both innate and adaptive immune responses as long as CD4 cells are not depleted.
doi:10.1371/journal.ppat.1005040
PMCID: PMC4529209  PMID: 26252005
9.  Defining Features of Protective CD4 T cell responses to Mycobacterium tuberculosis 
CD4 T cells are critical for control of Mycobacterium tuberculosis (Mtb) infection and represent the best hope for vaccine-elicited protection. However, little is understood about the properties of Mtb-specific CD4 T cells that mediate control, and the lack of correlates of protection present a significant barrier to the rational development of new vaccination and therapeutic strategies which are sorely needed. Here we discuss the features of protective CD4 T cells including recent evidence for IFN-γ dependent and independent mechanisms of protection, poor protection by terminally differentiated cells and the importance of T cell migratory capacity for the control of Mtb infection.
doi:10.1016/j.coi.2014.06.003
PMCID: PMC4122329  PMID: 25000593
10.  Intravascular staining for discrimination of vascular and tissue leukocytes 
Nature protocols  2014;9(1):209-222.
Characterization of the cellular participants in tissue immune responses is crucial to understanding infection, cancer, autoimmunity, allergy, graft rejection and other immunological processes. previous reports indicate that leukocytes in lung vasculature fail to be completely removed by perfusion. several studies suggest that intravascular staining may discriminate between tissue-localized and blood-borne cells in the mouse lung. Here we outline a protocol for the validation and use of intravascular staining to define innate and adaptive immune cells in mice. We demonstrate application of this protocol to leukocyte analyses in many tissues and we describe its use in the contexts of lymphocytic choriomeningitis virus and Mycobacterium tuberculosis infections or solid tumors. Intravascular staining and organ isolation usually takes 5–30 min per mouse, with additional time required for any subsequent leukocyte isolation, staining and analysis. In summary, this simple protocol should help enable interpretable analyses of tissue immune responses.
doi:10.1038/nprot.2014.005
PMCID: PMC4428344  PMID: 24385150
11.  Control of Mycobacterium tuberculosis infection by a subset of lung parenchyma homing CD4 T cells 
Summary
Th1 cells are critical for containment of Mycobacterium tuberculosis (Mtb) infection, but little else is known about the properties of protective CD4 T cell responses. Here we show that pulmonary Th1 response against Mtb is composed of two populations that are either CXCR3hi and localize to lung parenchyma or are CX3CR1hiKLRG1hi and retained within lung blood vasculature. Mtb-specific parenchymal CD4 T cells rapidly migrate back into the lung parenchyma upon adoptive transfer, while the intravascular effectors produce the highest levels of IFNγ in vivo. Importantly, parenchymal T cells displayed greater control of infection compared to the intravascular counterparts upon transfer into susceptible T cell deficient hosts. Thus, we have identified a subset of naturally generated Mtb-specific CD4 T cells with enhanced protective capacity, and show that control of Mtb correlates with the ability of CD4 T cells to efficiently enter the lung parenchyma rather than produce high levels of IFNγ.
doi:10.4049/jimmunol.1400019
PMCID: PMC4010124  PMID: 24591367
12.  CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1–Mediated Inhibition 
Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection.
doi:10.4049/jimmunol.1003304
PMCID: PMC4059388  PMID: 21172867
13.  Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through Mincle/CARD9 signaling and the inflammasome 
Although adjuvants are critical vaccine components, their modes of action are poorly understood. Here, we investigated the mechanisms by which the heat-killed mycobacteria in complete Freund’s adjuvant (CFA) promote T helper 17 (Th17) CD4+ T cell responses. We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1 receptor (IL-1R) signaling. Through measurement of antigen-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase 1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule CARD9 plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase 1-and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.
doi:10.4049/jimmunol.1203343
PMCID: PMC3719989  PMID: 23630357
14.  Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease 
PLoS ONE  2013;8(5):e62618.
Background
Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB.
Methods
Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India.
Results
Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α.
Conclusion
These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins.
doi:10.1371/journal.pone.0062618
PMCID: PMC3646008  PMID: 23671613
15.  Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection 
Immunity  2011;35(6):1023-1034.
SUMMARY
Interleukin-1 (IL-1) receptor signaling is required for control of Mycobacterium tuberculosis (Mtb) infection, yet the role of its two ligands, IL-1α and IL-1β, and the regulation of their expression in vivo are poorly understood. Here we show that in addition to IL-1β, IL-1α was independently required for host resistance. We identified two multifunctional inflammatory monocyte-macrophage and DC populations that co-expressed both IL-1 species at the single cell level in lungs of Mtb infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in fine-tuning IL-1 production by these cell populations in vivo. Type I IFNs inhibited IL-1 production by both subsets while CD4+ T cell derived IFNγ suppressed IL-1 expression selectively in inflammatory monocytes. These data provide a cellular basis for the anti-inflammatory effects of IFNs as well as pro-bacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 induction by specialized cellular sources as an additional layer of complexity in the activity of IL-1 in vivo.
doi:10.1016/j.immuni.2011.12.002
PMCID: PMC3246221  PMID: 22195750
16.  Cutting Edge: Caspase-1 Independent IL-1β Production Is Critical for Host Resistance to Mycobacterium tuberculosis and Does Not Require TLR Signaling In Vivo 
To investigate the respective contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1β-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1β signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88-deficient mice, rather than being defective in IL-1β expression, displayed increased cytokine levels relative to wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome-mediated IL-1β maturation, showed unimpaired IL-1β production and importantly, were considerably less susceptible to infection than IL-1β deficient mice. Together our findings reveal a major role for IL-1β in host resistance to M. tuberculosis and indicate that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1. The Journal of Immunology, 2010, 184: 3326–3330.
doi:10.4049/jimmunol.0904189
PMCID: PMC3420351  PMID: 20200276
17.  TRPC3 Activation by Erythropoietin Is Modulated by TRPC6* 
The Journal of Biological Chemistry  2009;284(7):4567-4581.
Regulation of intracellular calcium ([Ca2+]i) by erythropoietin (Epo) is an essential part of signaling pathways controlling proliferation and differentiation of erythroid progenitors, but regulatory mechanisms are largely unknown. TRPC3 and the homologous TRPC6 are two members of the transient receptor potential channel (TRPC) superfamily that are expressed on normal human erythroid precursors. Here we show that TRPC3 expression increases but TRPC6 decreases during erythroid differentiation. This is associated with a significantly greater increase in [Ca2+]i in response to Epo stimulation, suggesting that the ratio of TRPC3/TRPC6 is physiologically important. In HEK 293T cells heterologously expressing TRPC and erythropoietin receptor (Epo-R), Epo stimulated an increase in [Ca2+]i through TRPC3 but not TRPC6. Replacement of the C terminus of TRPC3 with the TRPC6 C terminus (TRPC3-C6C) resulted in loss of activation by Epo. In contrast, substitution of the C terminus of TRPC6 with that of TRPC3 (TRPC6-C3C) resulted in an increase in [Ca2+]i in response to Epo. Substitution of the N termini had no effect. Domains in the TRPC3 C terminus between amino acids 671 and 746 are critical for the response to Epo. Epo-R and phospholipase Cγ associated with TRPC3, and these interactions were significantly reduced with TRPC6 and TRPC3-C6C chimeras. TRPC3 and TRPC6 form heterotetramers. Coexpression of TRPC6 or C3/C6 chimeras with TRPC3 and Epo-R inhibited the Epo-stimulated increase in [Ca2+]i. In a heterologous expression system, Epo stimulation increased cell surface expression of TRPC3, which was inhibited by TRPC6. However, in primary erythroblasts, an increase in TRPC3 cell surface expression was not observed in erythroblasts in which Epo stimulated an increase in [Ca2+]i, demonstrating that increased membrane insertion of TRPC3 is not required. These data demonstrate that TRPC6 regulates TRPC3 activation by Epo. Endogenously, regulation of TRPC3 by TRPC6 may primarily be through modulation of signaling mechanisms, including reduced interaction of TRPC6 with phospholipase Cγ and Epo-R.
doi:10.1074/jbc.M804734200
PMCID: PMC2640975  PMID: 19074769
18.  An in vitro screening cascade to identify neuroprotective antioxidants in ALS 
Free Radical Biology & Medicine  2009;46(8):1127-1138.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, characterized by progressive dysfunction and death of motor neurons. Although evidence for oxidative stress in ALS pathogenesis is well described, antioxidants have generally shown poor efficacy in animal models and human clinical trials. We have developed an in vitro screening cascade to identify antioxidant molecules capable of rescuing NSC34 motor neuron cells expressing an ALS-associated mutation of superoxide dismutase 1. We have tested known antioxidants and screened a library of 2000 small molecules. The library screen identified 164 antioxidant molecules, which were refined to the 9 most promising molecules in subsequent experiments. Analysis of the in silico properties of hit compounds and a review of published literature on their in vivo effectiveness have enabled us to systematically identify molecules with antioxidant activity combined with chemical properties necessary to penetrate the central nervous system. The top-performing molecules identified include caffeic acid phenethyl ester, esculetin, and resveratrol. These compounds were tested for their ability to rescue primary motor neuron cultures after trophic factor withdrawal, and the mechanisms of action of their antioxidant effects were investigated. Subsequent in vivo studies can be targeted using molecules with the greatest probability of success.
doi:10.1016/j.freeradbiomed.2009.01.019
PMCID: PMC2742740  PMID: 19439221
5-LOX, 5-lipoxygenase; AAPH, 2,2′-azobis(2-methylpropionamidine) dihydrochloride; ALS, amyotrophic lateral sclerosis; ARE, antioxidant response element; BBB, blood–brain barrier; CAPE, caffeic acid phenethyl ester; CNS, central nervous system; DCF, dichlorofluorescein; DMSO, dimethyl sulfoxide; Esc, esculetin; EthD1, ethidium homodimer-1; EGFP, enhanced green fluorescent protein; LTB4, leukotriene B4; MN, motor neuron; MTT, methylthiazolyldiphenyl tetrazolium bromide; NDGA, nordihydroguaiaretic acid; Nrf2, nuclear factor erythroid 2-related factor 2; OTCA, 2-oxo-l-thiazolidine-4-carboxylic acid; PBS, phosphate-buffered saline; PI, prediction interval; PSA, polar surface area; Res, resveratrol; R-PE, R-phycoerythrin; SOD1, superoxide dismutase 1; TK, thymidine kinase promoter; TRAP, total radical-trapping antioxidant parameter.; Antioxidant; Amyotrophic lateral sclerosis; Mouse; NSC34; Superoxide dismutase; Free radicals
19.  Prevention of renal injury after induction of ozone tolerance in rats submitted to warm ischaemia. 
Mediators of Inflammation  1999;8(1):37-41.
On the basis that ozone (O3) can upregulate cellular antioxidant enzymes, a morphological, biochemical and functional renal study was performed in rats undergoing a prolonged treatment with O3 before renal ischaemia. Rats were divided into four groups: (1) control, a medial abdominal incision was performed to expose the kidneys; (2) ischaemia, in animals undergoing a bilateral renal ischaemia (30 min), with subsequent reperfusion (3 h); (3) O3 + ischaemia, as group 2, but with previous treatment with O3 (0.5 mg/kg per day given in 2.5 ml O2) via rectal administration for 15 treatments; (4) O2 + ischaemia, as group 3, but using oxygen (O2) alone. Biochemical parameters as fructosamine level, phospholipase A, and superoxide dismutases (SOD) activities, as well as renal plasma flow (RPF) and glomerular filtration rate (GFR), were measured by means of plasma clearance of p-amino-hippurate and inulin, respectively. In comparison with groups 1 and 3, the RPF and GFR were significantly decreased in groups 2 and 4. Interestingly, renal homogenates of the latter groups yielded significantly higher values of phospholipase A activity and fructosamine level in comparison with either the control (1) and the O3 (3) treated groups. Moreover renal SOD activity showed a significant increase in group 3 without significant differences among groups 1, 2 and 4. Morphological alterations of the kidney were present in 100%, 88% and 30% of the animals in groups 2, 4 and 3, respectively. It is proposed that the O3 protective effect can be ascribed to the substantial possibility of upregulating the antioxidant defence system capable of counteracting the damaging effect of ischaemia. These findings suggest that, whenever possible, ozone preconditioning may represent a prophylactic approach for minimizing renal damage before transplantation.
PMCID: PMC1781776  PMID: 10704088
20.  Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice 
Nature microbiology  2016;1(11):16140.
The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.
doi:10.1038/nmicrobiol.2016.140
PMCID: PMC5808443  PMID: 27782139
21.  Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study 
The Lancet. Neurology  2017;17(1):64-74.
Summary
Background
Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.
Methods
In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.
Findings
This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.
Interpretation
Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
doi:10.1016/S1474-4422(17)30400-3
PMCID: PMC5805394  PMID: 29263008
22.  The glycolytic enzyme phosphofructokinase-1 assembles into filaments 
The Journal of Cell Biology  2017;216(8):2305-2313.
Phosphofructokinase-1 (PFK1) is an essential glycolysis enzyme as it catalyzes the step committing glucose to breakdown. Webb et al. show that the liver PFK1 isoform assembles into filaments in a tetramer- and substrate-dependent manner, providing insights into the spatial organization of isoform-specific glucose metabolism in cells.
Despite abundant knowledge of the regulation and biochemistry of glycolytic enzymes, we have limited understanding on how they are spatially organized in the cell. Emerging evidence indicates that nonglycolytic metabolic enzymes regulating diverse pathways can assemble into polymers. We now show tetramer- and substrate-dependent filament assembly by phosphofructokinase-1 (PFK1), which is considered the “gatekeeper” of glycolysis because it catalyzes the step committing glucose to breakdown. Recombinant liver PFK1 (PFKL) isoform, but not platelet PFK1 (PFKP) or muscle PFK1 (PFKM) isoforms, assembles into filaments. Negative-stain electron micrographs reveal that filaments are apolar and made of stacked tetramers oriented with exposed catalytic sites positioned along the edge of the polymer. Electron micrographs and biochemical data with a PFKL/PFKP chimera indicate that the PFKL regulatory domain mediates filament assembly. Quantified live-cell imaging shows dynamic properties of localized PFKL puncta that are enriched at the plasma membrane. These findings reveal a new behavior of a key glycolytic enzyme with insights on spatial organization and isoform-specific glucose metabolism in cells.
doi:10.1083/jcb.201701084
PMCID: PMC5551713  PMID: 28646105
23.  Metal worker’s lung: spatial association with Mycobacterium avium 
Thorax  2017;73(2):151-156.
Background
Outbreaks of hypersensitivity pneumonitis (HP) are not uncommon in workplaces where metal working fluid (MWF) is used to facilitate metal turning. Inhalation of microbe-contaminated MWF has been assumed to be the cause, but previous investigations have failed to establish a spatial relationship between a contaminated source and an outbreak.
Objectives
After an outbreak of five cases of HP in a UK factory, we carried out blinded, molecular-based microbiological investigation of MWF samples in order to identify potential links between specific microbial taxa and machines in the outbreak zone.
Methods
Custom-quantitative PCR assays, microscopy and phylogenetic analyses were performed on blinded MWF samples to quantify microbial burden and identify potential aetiological agents of HP in metal workers.
Measurements and main results
MWF from machines fed by a central sump, but not those with an isolated supply, was contaminated by mycobacteria. The factory sump and a single linked machine at the centre of the outbreak zone, known to be the workstation of the index cases, had very high levels of detectable organisms. Phylogenetic placement of mycobacterial taxonomic marker genes generated from these samples indicated that the contaminating organisms were closely related to Mycobacterium avium.
Conclusions
We describe, for the first time, a close spatial relationship between the abundance of a mycobacterium-like organism, most probably M. avium, and a localised outbreak of MWF-associated HP. The further development of sequence-based analytic techniques should assist in the prevention of this important occupational disease.
doi:10.1136/thoraxjnl-2017-210226
PMCID: PMC5801647  PMID: 28851756
hypersensitivity pneumonitis; occupational lung disease; allergic alveolitis
24.  Autoimmune comorbidities in patients with metastatic melanoma: a retrospective analysis of us claims data 
BMC Cancer  2018;18:145.
Background
Immunotherapies have advanced the treatment of metastatic melanoma; however, they are associated with immune-related toxicities. Patients with pre-existing autoimmune comorbidities are commonly excluded from clinical trials investigating immunotherapies in metastatic melanoma. Since information on pre-existing autoimmune comorbidities in “real-world” patients with newly diagnosed metastatic melanoma is limited, we sought to estimate the prevalence of autoimmune comorbidities and its change over time.
Methods
Data were obtained from a large US claims database, MarketScan®, from 2004 to 2014. Records of patients with newly diagnosed metastatic or non-metastatic melanoma and of general population were analyzed. Autoimmune comorbidities were defined as presence of autoimmune disorders, which were obtained from the list of diseases at the American Autoimmune-Related Diseases Association web portal (www.aarda.org). The prevalence of pre-existing autoimmune comorbidities and its change over the 11-year period were calculated. Logistic regression analyses were performed to evaluate the relationship between clinical and demographic factors and pre-existing autoimmune comorbidities in patients with metastatic melanoma.
Results
This study assessed the prevalence and change of prevalence over a period of 11 years of 147 autoimmune comorbidities. Among 12,028 patients with newly diagnosed metastatic melanoma, the prevalence rate of pre-existing autoimmune comorbidities increased from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates of autoimmune comorbidities increased from 11.7% in 2004 to 19.8% in 2014 in patients with non-metastatic melanoma and 7.9% in 2004 to 9.2% in 2014 in the general population. In addition, patients with bone or gastrointestinal melanoma metastases, those with more comorbid diseases, or female patients, were found to have a higher risk of autoimmune comorbidities.
Conclusions
The prevalence of pre-existing autoimmune comorbidities in patients with newly diagnosed metastatic melanoma was high, and increased over 11 years. In comparison, a lower prevalence of autoimmune comorbidities was seen in patients with newly diagnosed non-metastatic melanoma and in the general population. Increases in prevalence for these population groups were also observed over 11 years. Impact of autoimmune comorbidities on treatment decisions in patients with metastatic melanoma should be explored.
doi:10.1186/s12885-018-4051-0
PMCID: PMC5801837  PMID: 29409500
Autoimmune; Comorbidities; Metastatic melanoma; Retrospective analysis; Prevalence rate
25.  Prevention of Venous Thromboembolism in Gynecologic Oncology Surgery 
Gynecologic oncology  2016;144(2):420-427.
Gynecologic oncology patients are at a high-risk of postoperative venous thromboembolism and these events are a source of major morbidity and mortality. Given the availability of prophylaxis regimens, a structured comprehensive plan for prophylaxis is necessary to care for this population. There are many prophylaxis strategies and pharmacologic agents available to the practicing gynecologic oncologist. Current venous thromboembolism prophylaxis strategies include mechanical prophylaxis, preoperative pharmacologic prophylaxis, postoperative pharmacologic prophylaxis and extended duration pharmacologic prophylaxis that the patient continues at home after hospital discharge. In this review, we will summarize the available pharmacologic prophylaxis agents and discuss currently used prophylaxis strategies. When available, evidence from the gynecologic oncology patient population will be highlighted.
doi:10.1016/j.ygyno.2016.11.036
PMCID: PMC5503672  PMID: 27890280

Results 1-25 (2268)