34 results on '"Janssen U"'
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2. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
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Reaich R., Schouten D., Rashid H., Birtcher K., Cantu J., Tait C., Taun W., Fadem S., Das D., Khosla U., Brown C., Brown T., Buquing J., Cromwell H., Dickson N., Najimipour B., Robeson J., Tabibi W., Mulloy L., Bailey K., Burton B., Fall P., Jagadeesan M., Paulson W., Szerlip H., White J., Faulkner M., Adeleye O., Boatright D., Mensah D., Nwankwo U., Crutcher L., Cummings C., Floyd M., Putatunda B., Ross J., Sanford V., Thadani U., Haragsim L., Parker B., Rogan L., Thresher M., Turner J., Dworkin L., Mignano D., O'Mara A., Shemin D., Bakris G., Basta E., Chua D., Neri G., Ahmed I., Elliott W., Fondren L., Hasabou N., Khosla N., Mazin A., Riehle J., Kovesdy C., Mendoza J., Ahmadzadeh S., Iranmanesh A., Lewis M., Lu J., Benabe J., Gonzalez-Melendez E., Padilla B., Serrano J., Russ T., Athmann L., Funke L., Larson P., Roach D., Salveson B., Nogueira J., Hanes D., Hise M., Light P., Copland E., Fink J., Hakim M., Hough K., McMinn S., Weir M., Young C., Kershaw G., Hill I., White B., Plumb T., Florescu M., Groggel G., Martin M., Rao V., Denu-Ciocca C., Candiani C., Cooper J., Gordon B., Joy M., Kiser M., Lambeth C., Rosas S., Cochetti P., Robinson J., Schankel K., Teng H., Weise W., Geneidy A., Murray P., Solomon R., De Waal D., LaPointe S., Schoenknecht A., Campese V., Habashy M., Ananthakrisna R., Bedwani D., Fazli U., Fetrat M., Frampton Q., Kaldas B., Kazarian V., Pitts L., Sadeghi A., Yeasmin N., Young E., Fissell R., Belanger K., Ricci N., Farwell W., Bowman T., Dhingra R., Pesenson A., Ambrosino J., Chittamooru S., Kaufman J., Ramos M., Yap C., Nakhle S., Aligaen L., Duren D., Laine B., Moore S., Tuazon H., Coyne D., Audrain J., Bryant B., Dombek S., Freeman S., Klein P., Germain M., Berkowitz A., Bokhari A., Braden G., Diaz A., Greco B., Mulhern J., O'Shea M., Poindexter A., Poppel D., Ryan M., Sweet S., Ye J., Osterman J., Lin T., Mays B., Rizvi A., Sonnier C., Twining C., Wang S., Hix M., Schenck J., Baigent C., Landray M., Reith C., Dasgupta T., Emberson J., Herrington W., Lewis D., Mafham M., Collins R., Bray C., Chen Y., Baxter A., Young A., Hill M., Knott C., Cass A., Feldt-Rasmussen B., Fellstrom B., Grobbee R., Gronhagen-Riska C., Haas M., Holdaas H., Hooi L.S., Jiang L., Kasiske B., Krairittichai U., Levin A., Massy Z., Tesar V., Walker R., Wanner C., Wheeler D., Wiecek A., Majoni W., Simpson D., Strony J., Musliner T., Agodoa L., Armitage J., Chen Z., Craig J., De Zeeuw D., Gaziano M., Grimm R., Krane V., Neal B., Ophascharoensuk V., Pedersen T., Sleight P., Tobert J., Tomson C., Sandercock P., Keech A., Whelton P., Yusuf S., Peto R., Parish S., Dolph L., Bahu T., Booth-Davey E., Brewster A., Yau F., Denis E., Frederick K., Haywood D., Heineman J., Howard S., Jayne K., Madgwick Z., Michell S., Murphy K., Ning L., Nolan J., Nunn M., Roberts J., Wickman M., Bowman L., Bulbulia R., Haynes R., Rahimi K., Rahman N., Ait-Sadi R., Barton I., Zhu W., Clark S., Kourellias K., Radley M., Brown K., Worthing D., Coates G., Goodenough B., Lucas N., Carreras A., Currie R., Donaldson O., Fjalling E., Gallagher M., Gibson K., Goddard J., Healy J., Hones L., Jardine M., Kwong I., Merai M., Murray S., Perkovic V., Rendina A., Gallo K., Caron S., Carlson K., Foley K., Matzek S., Mewhort L., O'Donoghue S., Perel-Winkler A., Terins T., Nie Q., Yu H., Ge L., Hao D., Li L., Pang X., Wei X., Yan G., Certikova Chabova V., Holst H., Molvadgaard T., Munksgaard D., Peltonen Y., Liabeuf S., Lebel C., Ouabou L., Bauer B., Bergmann K., Beusch M., Cavitt D., Drechsler C., Dulau I., Hugen K., Kempf S., Kuchenmeister B., Pscheidl V., Schmiedeke D., Schwarz M., Speerschneider K., Stahl B., Lim B.C., Nadia H., Zishareena M.F., Vasuthavan S., Ganesapillai A.T., Yuen S., Grobbee D., Bobbink I., Groot K., Sikking I., Raley J., Colban M., Smerud K., Trygg N., Waagaard E., Westad H., Rotkegel S., Spiechowicz U., Domoradzka M., Gawlowska M., Flygar A., Odmark I., Pettersson A., Blackwood S., Barclay J., Benham J., Brown R., Cureton L., Jackson D., Kennedy I., Leaper C., Taylor A., Winter C., Wise C., Nash M., Taylor Bennett A., Donaldson D., Chalmers K., Corderoy H., Bartkoske M., Bjerk C., Camarena A., Herskovitz L., Heuer C., Levin J., Robinson R., Wicklund B., Bentzel D., Cohen S., Costa C., Scranton R., Auwardt R., Boyer M., Cogdell P., Menahem S., Sheldrake J., Mount P., Fraenkel M., Bisscheroux P., Dempester J., Gleeson P., Harris G., Holmes C., Hyett K., Linton A., Miach P., Booth D., Druce L., Mantha M., Borg E., Green S., Killen J., Lynch Y., Colquhoun D., Herzig K., Row G., Addison J., Asa J., Beatson G., Calvird D., Edmunds J., Ferreira-Jardim A., Gwynne A., Mackay D., McLoughlin L., Wightwick C., Williams L., Ferrari P., Barry J., Hodson S., Zakrzewska W., Meagher E., Mulcahy M., Parnham A., Carney S., Garvey L., Gillies A., Hayes S., Mathew M., Fassett R., Anderson L., Clingeleffer C., Curnock A., Mayne L., Richardson D., Smith M., Smith S., Suranyi M., Howlin K., Chow J., Cleland B., Rayment G., Spicer T., Wong J., Wong M., Packham D., Alison C., Fraser I., Mitchell J., Nagle J., Brown F., Ellery C., Monkhouse J., Nandkumar J., Reith-Myers L., Gray N., Cocks C., Courtney M., Hollett P., Johnston C., Larsen H., Pollock A., Stewart S., Styles G., Wyndham R., Fanning M., Gibson W., Jackson S., Mannering M., Mercado E., Oliphant R., Sud K., Ubera N., Wood C., Karrasch J., Brinkley T., Estensen K., Moroney A., Sutton J., Warren R., Saltissi D., Jahke H., Roach H., Saltissi J., Wiederroth O'Brien M., Johnson D., Bali V., Evans M., Franzen K., Halbish S., Helyar J., Martin A., Mudge D., Sonnenburg K., Sudak J., Roger S., Almeida S., Andrews H., Bohringer L., Bouwhuis L., Brady L., Carpenter A., Warren S., Elias T., Bannister K., Chew G., Clarke J., Faull R., Hooper A., Jeffs L., Napier A., Peh C., Pirone K., Skilton F., Ranganathan D., Best J., Hart L., Healy H., Morgan C., Ratanjee S., Salisbury A., Jose M., Freeman J., Hamilton R., Kirkland G., Read G., Anderson H., Boekel K., Farrell M., Foreman A., Iliev K., Pedagogos E., Raspudic T., Pollock C., Cooper B., Kesselhut J., Macadam C., Pearse J., Rowland C., Tully H., Irish A., Dogra G., Coutts P., Hayes L., Khoo D., Nathoo B., Shakespeare K., Warger A., Gillin A., Burman J., George C., Sherwood S., Snelling P., Stevens C., Hutchison B., Luxton G., Devenny N., Herson H., Pellicano S., Kelly J., Coutelas J., Garlinge C., McClelland A., Pirabhahar S., Saleh H., Langham R., Englebright B., Giang M., Lanteri M., Mullins K., Turner C., Collett P., Stokoe S., Sutherland K., Talafua D., Talaulikar G., Clarkson A., Rees C., Carney G., Falk M., Gracey D., Jadeer A., Johnson P., Karpe K., Singer R., Walters G., McDonald S., Burgess J., Fischer K., Gentgall M., Hockley M., Veitch D., De Jersey P., Gillam A., Hartig V., Holland K., McArdle J., Washington W., Rangan G., Mikaheal M., Murie P., Perez N., Punnoose N., Smolonogov T., Taler N., Williams G., Wen C., Kohlhagen J., Wessels J., Johnson S., Reid A., Ryan J., Taprell D., Auinger M., Eigner M., Kodras K., Leithner C., Magpantay L., Marterer C., Prager R., Prinz C., Seiringer E., Kramar R., Mitter E., Stummvoll H., Dieplinger G., Wenzel R., Stolz G., Drose S., Edlinger E., Headlam-Leitner E., Miska H., Then M., Weninger S., Lhotta K., Neyer U., Dickie H., Smodek S., Sprenger-Mahr H., Rosenkranz A., Zitt E., Mayr B., Schinner A., Soltys G., Begin V., Brunet S., Cournoyer S., Gelinas M., Giroux C., Martineau J., Roy M., Savoie L., Agharazii M., Blouin J., Desmeules S., Langlois S., Samson F., Wong G., Constantini L., Jing J., Malko J., Rivers C., Rochester D., Skilling C., Wadgymar A., Wu G., Kates D., Husch J., Mantle M., Turri L., Barrett B., Curtis B., Greeley B., Hannaford M., Harnett J., Kelly M., Langille E., Morgan J., Murphy S., Karim M., Arbo T., Carpenito G., Chan V., DaRoza G., Friesen M., Kraus D., Lam S., Lange B., Minhas S., Starko R., Torng S., Vela K., Madore F., Roy P., Troyanov S., Bonnardeaux A., Lauzon L., Pichette V., Yeates K., Mahoney K., Myers C., Pilkey R., Moist L., Edgar M., House A., Kortas C., Mindorff S., Tam P., Chow S., Fung J., Nagai G., Ng P., Sikaneta T., Ting R., Forzley B., Clouatre Y., Cooper S., DaCosta H., Granger S., Valley S., Karunakaran S., Abdulhadi M., Altwasser C., Anderson S., Bergquist L., Wijeyesinghe C., Berst L., Horgan K., Coles K., Lotter T., Robson L., Barre P., Golden J., Golden M., Tanguay N., Rigatto C., Armstrong S., Fine A., Fontaine B., Friesen D., Henry S., Kraushar M., Reslerova M., Verrelli M., Rabbat C., Clase C., Suva G., Winegard N., Goldstein M., Curvelo S., Donnelly S., Huckle J., Marticorena R., Chan-Yan C., Chiu A., DeLuca L., Flamer D., Gill J., Jamal A., Jung B., Kiaii M., Landsberg D., Rozen N., Taylor P., Werb R., Pylypchuk G., Ahmed A., Barton J., Hundseth M., Kappel J., Keindel I., Klassen J., Pylypchuk S., Rindall M., Tobe S., Naimark D., Agelopoulos M., Chessman M., Hladunewich M., Perkins N., Sainsbury S., McCready W., Adams B., Tonelli M., Caldwell S., Kumar U., McMahon A., Nikitin S., Restall J., Treit S., Wysocki Y., Duncan J., Copland M., Jastrzebski J., Keown P., Kwan S., Rogers D., Shapiro J., Singh S., Sioson L., Yee K., Yeung C., Zacharias J., Bueti J., Dizon B., Lam H., Miller L., Ross M., Zarrillo M., Li Z., Wang C., Liu L., Hong M., Zheng H., Zuo W., Ge Z., Liu Q., Li Y., Sun K., Zhao R., Sun G., Wang F., Cui Z., Lou F., Du Y., Song L., Huang H., Song Z., Wang J., Zhou L., Wu R., Xiao R., Zhang Q., Duan N., Ju N., Wang A., Xu Z., Lu Z., Zhang Y., Zhao L., Zhang C., Mo Z., Xie Y., Xiong J., Chen J., Guo L., Zhao S., Peiskerova M., Jancova E., Kazderova M., Kobrova L., Gorun P., Kmentova T., Burgelova M., Lyerova L., Viklicky O., Berdych M., Nydlova Z., Jelinkova G., Moltas J., Pauzar T., Knetl P., Cahova J., Simkova J., Zakova M., Vankova S., Safarova R., Hruby M., Karlova R., Prikaska V., Sellenberg P., Vesela E., Malanova L., Vlasak J., Kaprova P., Novakova D., Kotherova K., Studenovska M., Christensen J., Solling J., Jepsen M., Kristensen V., Aerenlund H., Braemer-Jensen M., Kamper A., Raaschou S., Heaf J., Dreyer J., Freese P., Holm M., Munch M., Gade-Rasmussen E., Bredmose K., Daugaard H., Nielsen J., Friedberg M., Jensen D., Munk Plum M., Solling K., Dieperink H., Arp Nielsen L., Friborg E., Gloe-Jakobsen A., Thye Ronn P., Rasmussen K., Andersen C., Johansen A., Odum L., Ostergaard O., Pedersen L., Lykkegaard S., Aundal M., Faureholm Huess S., Danielsen H., Madsen J., Nyvang M., Ekstrand A., Boman H., Hartman J., Lipponen A., Lithovius R., Rauta V., Salmela A., Saloranta K., Forslund T., Koskiaho P., Jaaskelainen K., Kanninen M., Laine K., Asola M., Huhti J., Pentti M., Metsarinne K., Heiro M., Koivuviita N., Saarinen M., Tertti R., Choukroun G., Fournier A., Ducloux D., Marechal F., Simula Faivre D., Combe C., Douillet M., Lamblot T., Nardi H., Vendrely B., Bourbigot B., Ferlandin S., Zaoui P., Jouet C., Geffroy-Guiberteau S., Bugnazet L., Aldigier J., El Hamel-Belili C., Giraud S., Dussol B., Berland Y., Chollet M., Sichez H., Cristol J., Canaud B., Morena M., Rodriguez A., Kessler M., Mizejewski B., Risse B., Urena Torres P., Bou-Bekr M.A., Arezki C., Ras El Qdim P., Vela C., Borsato F., Talairach A., Normand M., Normand V., Rieu P., Gauthier B., Vigneron-Foy C., Wolak A., Menoyo V., Alos L., Caillette-Beaudoin A., Berger V., Al-Sarraf S., Konnerth I., Urban C., Weiner S., Boesken W., Jochum E., Kiefer C., Wagner A., Krumme B., Bohler J., Bonow B., Hohenstatt U., Mettang T., Rockel A., Langanke J., Lipponer H., Dunschen-Weimar G., Dunst R., Hubel E., Petrik R., Rengel R., Schmidgen M., Mayr H., Garschhammer C., Weirauch S., Anger H., Goock T., Mai A., Bast I., Suptitz C., Iwig B., Florschutz K., Hasselbacher R., Sauerbrey G., Delrieux S., Rau S., Poley M., Laux R., Schonfelder O., Kunowski G., Fuchs G., Hoffmann K., Schurger R., Brensing K., Guven Z., Immenkamp C., Kottmann C., Schmitt H., Schulz M., Arnold P., Knaup R., Schneider H., Siemsen H., Pyriki P., Korkemeyer F., Pyriki R., Siebrecht A., Schulz E., Krumwiede A., Kruse D., Lucke S., Keim H., Fink H., Fischer S., Klingbeil A., Kuhlmei K., Ortwein-Horn N., Merker L., Bayer B., Benamar K., Emmert S., Floten E., Holzheuer K., Lummer M., Ossendorf E., Scholz M., Oppitz M., Georgiew L., Tripps C., Wendehake M., Lange D., Pingel V., Brause M., Schanze W., Duygulu E., Dellanna F., Heinemann-Nieberding S., Sturmer C., Wieczorek K., Zarga O., Kullmer B., Kullmer S., Akin M., Gondolf M., Schutterle S., Walker G., Bertsch R., Seul M., Allendorff J., Siehler R., Stemmler S., Baldus M., Adler A., Harter S., Wurmell W., Moller M., Hame C., Muller M., Schreiber M., Schurfeld C., Millington-Herrmann M., Benschneider A., Gaffal J., Sprunken U., Bohling M., Wunderlich S., Schramm L., Kollenbrath C., Netzer K., Sieber T., Zimmermann J., Bellersen M., Uerkvitz M., David-Walek T., Hauschildt B., Leimenstoll G., Lonnemann G., Hilfenhaus M., Benedetto C., Stockmann S., Ichtiaris P., Jungmann A., Neumeier K., Stoof A., Bohmer K., Kirpal A., Knogl A., Flege F., Franke K., Groth P., Parensen E., Bockmann M., Przyklenk P., Piazolo L., Thinius-Jaudas L., Versen A., Hettich R., Arendt R., Geiger K., Hoppe H., Schwarting A., Beyer T., Faust J., Hazenbiller A., Tschirner S., Grupp C., Dorsch O., Eigner-Schmidtchen M., Michler K., Roth J., Schramm S., Waldmuller G., Riedl B., Vogele-Dirks H., Linz J., Biggar P., Hennemann H., Bauer G., Buchholz J., Fischer P., Bihlmaier W., Baumann A., Peichl B., Roser S., Ludewig S., Ricksgers M., Szendzielorz M., Baus A., Baust K., Schaller P., Schnellbacher G., Sorensen S., Buschges-Seraphin B., Hauenstein L., Hofmann B., Nikolay J., Merkel F., Nebel M., Petersen J., Schweb S., Zeissler H., Baumhackel K., Krauss A., Schafer R., Pastor A., Zielinski B., Strauss H., Theis H., Burkhardt K., Heckel M., Hussendorfer K., Bahner U., Brandl M., Hammerl-Kraus B., Herrmann D., Kramer H., Baudenbacher H., Blaser C., Buschmann G., Eckert G., Ehrich H., Hofmann K., Huller U., Geiger H., Becker B., Hoischen S., Bartel C., Hennig J., Obermuller N., Schulte C., Fischereder M., Burchardi F., Rupprecht H., Weidner S., Anders H., Andriaccio L., Lederer S., Ricken G., Strasser C., Lammert A., Schmitt W., Van Der Woude F., Langhauser B., Markau S., Osten B., Thiemicke D., Dorligschaw O., Weickert M., Breunig F., Denninger G., Osiek S., Rebstock W., Schulz P., Swoboda F., De Cicco D., Harlos J., Lebert A., Riegel M., Schmiedeke T., Hoffmann U., Nolle M., Jankrift P., Pfleiderer H., Witta J., Wittler B., Luth J., Dumann H., Habel U., Torp A., Sehland D., Tiess M., Etzold C., Friederiszik A., Morgenroth A., Dybala A., Suffel A., Leimbach T., Kron J., Sauer S., Meyer T., Meyer M., Lammers U., Bekman J., Holtz S., Kausler-Book B., Stobbe S., Hohage H., Heck M., Schulte F., Welling U., Zeh M., Seyfried J., De Heij T., Menzinger A., Weinreich T., Hopf M., Groll J., Kammholz K., Peters K., Schwietzer G., Kreft B., Weibchen U., Vosskuhler A., Hollenbeck M., Klaue K., Rzepucha E., Sperling K., Seeger W., Weyer J., Heine C., Kirste P., Zemann B., Alscher D., Rumpf D., Wullen B., Bengel A., Friedrich B., Kirschner T., Knodler U., Machleidt C., Niederstrasser K., Noack E., Wilhelm J., Heuer H., Dulea J., Piolot R., Rudke M., Treinen G., Elberg B., Hanke J., Nitschke T., Rosendahl C., Schmitz A., Schrader J., Kulschewski A., Lubcke C., Hammersen F., Luders S., Venneklaas U., Muhlfeld A., Arabi Al-Khanne F., Ketteler M., Politt D., Schuster C., Eitner F., Goretz U., Heidenreich S., Janssen U., Kranz A., Moormann E., Schneider B., Weber W., Frei U., Jovanovic T., Asmus H., Canaan-Kuhl S., Pannier L., Petersen S., Pluer M., Schaeffner E., Schafer C., Warncke S., Schmieder R., Donhauser C., Schulze B., Koziolek M., Bechtel W., Kurz B., Strutz F., Bramlage C., Dreyer S., Mommeyer E., Niemann J., Scheel A., Troche-Polzien I., Weber F., Heine G., Girndt M., Lizzi F., Rogacev K., Lindner T., Achenbach H., Peschel K., Beige J., Jentho S., Kreyssig C., Prill K., Renders L., Walcher J., Cerny S., Fulbier A., Kristen H., Nitschke M., Kramer J., Marek P., Meier M., Schlieter J., Heyne N., Bachmann F., Faber M., Klipp K., Kustner U., Risler T., Rath T., Ruf T., Budiman D., Seidel C., Weik S., Teo S.M., Lee L.Y., Azizah H., Faridunishah S.A., Foo S.M., Go K.W., Ghazali A., Koh K.H., Zaki M., Wong H.S., Bavanandan S., Boey L.M., Lily M., Wong S.L., Rosnawati Y., Zawawi N., Azimawati A., Hindun A., Hasnah J., Korina R., Yunaidah A., Noraidah P., Ong L.M., Noor Asma A., Liew Y.F., Rozina G., Cheong Y.H., Ang A.H., Dayang J., Lim L.S., Sukeri M., Ramli S., Zulkifli M., Wan Mahmood W.K., Goh B.L., Sarifah B., Bee B.C., Ramasamy C., Ruszarimah S., Liu W.J., Razali O., Haslinah S., Vaithilingam I., Jaaini A., Faridah L., Ng K.H., Krishnan P., Rosnah A.A., Nor Azizah A.S., Tam C.C., Tan S.H., Tan C.C., Shahnaz F.K., Wazir H., Munusamy P., Wan Shaariah M.Y., Chew T.F., Fuziah Z., Tan C.H.H., Maria L., Javelin P., Lim S.K., Nazatul S.B., Engkasan L.P., Tan S.Y., Wong M.G., Julita A.A., Ang B.B., Krishnan S., Seet W.W.T., Liew S.K., Keng T.C., Tobe T., Deelen M., Klaassen I., Grave W., Emmen M., Janssen W., Bossen W., Elzinga B., Van Der Velden A., Hemmelder M., Slagman M., Waanders F., Viergever P., Boerema I., Potter Van Loon B., Muthert B., Geers T., Schollaert N., Van Weverwijk I., Veen P., Woittiez A., Krikken J., Kwakernaak A., Visser F., Navis G., Hoekstra F., Hawkins S., McGregor D., Usher J., MacGinley R., Schollum J., Ellis G., Voss D., Rosman J., Upjohn M., Panlilio N., Madhan K., Naicker V., Anderson E., Bushell M., Lumb N., Pepperell B., Sizeland P., Hayett S., Sullivan N., Tuffery C., Macdonald A., Ostapowicz T., Wessel-Aas T., Wessel-Aas H., Bjorbaek E., Bjorbaek R., Simso I., Oien C., Bergrem H., Espedal S., Kronborg J., Solbakken K., Rocke J., Aakervik O., Haugen V., Eide T., Berglund J., Loland W., Schei T., Stromsaether C., Willadsen H., Lyngdal P., Vad A., Waldum B., Froslid G., Roaldsnes C., Rustad D., Soderblom P., Eriksen B., Hanssen E., Julsrud J., Mathisen U., Pedersen M., Rumsfeld M., Toft I., Berget K., Landsverk K., Tveiten G., Wamstad H., Klinger M., Krajewska M., Golebiowski T., Kusztal M., Spiechowicz-Zaton U., Rutkowski B., Renke M., Tylicki L., Czekalski S., Koziol L., Wanic-Kossowska M., Wasik-Olejnik A., Nowicki M., Dryja P., Kurnatowska I., Zawiasa A., Ciszek M., Gomolka M., Mysliwiec M., Brzosko S., Mazerska M., Hruby Z., Koscielniak K., Stanek-Piotrowska M., Mesjasz J., Rudka R., Baranski M., Jupowiecki J., Klein D., Switalski M., Kuriga M., Ostrowski M., Lidman A., Linde T., Waltersson K., Weiss L., Andersson G., Lindell C., Welander G., Jacobson S., Edensjo P., Wallin J., Linder M., Karsberg M., Hellgren K., Lonn I., Frisenette-Fich C., Johansson A., Lundstrom A., Mauritz N., Stahl-Nilsson A., Tobafard N., Hellberg O., Ejemar E., Von Schmalensee N., Gunne T., Eriksson A., Ostberg S., Svensson C., Mulec H., Jacobsson A., Karlsson M., Onnermalm L., Osagie S., Ekengren U., Larsson M., Lindberger K., Olofsson A., Samuelsson O., Beagan L., Dezfoolian H., Just M., Ortegren L., Saeed A., Strand U., Ramsauer B., Hultstrom D., Nordlinder K., Sundberg I., Oqvist B., Green C., Fernstrom A., Cassel A., Goransson I., Gylling M., Jorgensen A., Sterner G., Christensson A., Hjelmstedt P., Nystrom A., Sundin P., Samuelsson I., Tidman M., Johansson M., Lofgren Andersson M., Ohman M., Andersson P., Hallberg Karlsson A., Ringstad L., Chittinandana A., Chailimpamontree W., Gojaseni P., Singprasert R., Tungsanga K., Amphun W., Intim P., Kanjanabuch T., Poowarattanakul D., Treratha C., Wongvan P., Jittikanont S., Suriya T., Indrasthitya P., Sumethkul V., Ingsathit A., Jansomwong J., Lertchalorarn K., Phachiyanukul V., Phiromkit T., Saengsri S., Vareesangthip K., Chawanasuntorapoj R., Kiattisunthorn K., Larpkitkachorn R., Webster J., Henderson J., Jayne D., Hollis J., Townsend K., Harron C., Bleakley N., Hanley N., Morgan S., Brittney L., Brown H., Maxwell P., Murtagh H., Thomas M., Burke E., Carmody M., Cox G., Dasgin J., Ali G., Whitehouse L., Williams V., Brown E., Dlelana G., Esson A., Fagerbrink S., Marshall F., Mazibuko B., Nelson C., Russell E., Williams R., Altmann P., McNichols-Thomas C., Parsons K., MacGregor M., McGowan J., Mead P., Gilbanks K., Sanderson M., Fluck R., Chandler G., Hulme L., Smith J., Tse Y., West C., Taylor J., Breakspear S., Burgess B., Isles C., Bell J., Duignan J., Gorman J., Swainson C., Beveridge C., Cairns A., Miller D., Paterson F., Smith L., Kumwenda M., Glover R., Geddes C., Gemmell C., Grieve I., Matthews E., McLaren B., Meyer B., Spiers A., Banks R., Apperley P., Patterson T., Paynter H., Scoble J., Thom D., Watkins J., Kalra P., Gowland S., Haydock L., Smart I., Bhandari S., Gillett P., James K., Lewis R., Melville H., Tamimi A., Williams P., Heath T., Small S., Paterson A., Gibson N., Laven C., Wilson T., Cairns H., Casley-Ready K., Warwick G., Fentum B., James J., Kumar T., Marshall R., Ratcliffe F., Shenton A., Warwicker P., Bowser M., Mumford C., Mitra S., Woolfson R., Yang R., Williams A., Richards K., Turner A., Odum J., Rylance P., Smallwood A., Ward J., Henderson I., McMahon M., Ross C., Burrows M., Morais J., Rajan S., Tindall H., Barrett C., Kelly F., El-Nahas M., Bartholomew J., Edwards L., Okhuoya F., Bebb C., Cassidy M., Brand S., Quashie-Howard M., Taggart C., Capps N., Tonks L., Mason J., Powell S., Watkins L., Ball S., Dutton M., Fifer L., McGlynn F., Wood M., Jenkins D., Allan N., Fahal I., Elhag-Ali H., King J., Peel R., Potts L., Logie I., McGhie F., Naik R., Parry R., Andain K., Durkin S., D'Souza R., Harrison D., Cooke J., Kinyanjui R., Harper J., Algate K., McCarthy M., Van Eker D., Thuraisingham R., Chinodya M., Deelchand V., Garcia R., Ngango R., Rolfe C., Williams K., Solomon L., Heap T., MacDowall P., Saunderson Smith L., MacDiarmaid-Gordon A., Harman W., Smithson H., Robertson D., Gammon B., O'Grady D., Verow C., Rogerson M., Berry L., Gough C., Hayward E., Jones C., Payne T., Rowe L., Sibley C., Szymanski J., Almond M., Bourton L., Bromwich C., Dawson S., Mason S., Oliveira D., Ramkhelawon R., Tuazon J., Andrews P., Archer K., Moore A., Thomas G., Velazquez C., Mumtaz R., Roberts R., Farquhar F., Ott J., Fenwick S., Callaway A., Garrett P., Dees L., McDonagh U., Garner S., Zehnder D., Aldridge N., Dyer C., Gomez M., Hewins S., McCarthy K., Rush J., Spencer S., Harvey M., Mills H., Drew P., Henry M., Wilberforce S., Worth D., Adair Z., Hartley J., Jibani M., Jones D., Swan S., Shamp T., Alcorn H., Bookey J., Cannon C., Jarvis K., Muesing C., Murphy M., Muster H., Planting M., Strand C., Middleton J., Gitter K., Mace N., Schumm D., Pogue V., Alimohammadi B., Arora P., Herbert L., Cheng J., Dowie D., Mohan S., Peters G., Tuttle K., Albritton S., Benedetti R., Joshi S., Lund B., Shuler L., Trevino M., Mai K., Osborn T., Parekh R., Eustace J., Novak G., Patterson S., Lindsey C., Hill T., Liston M., Wiegmann T., Nagaria A., Hurd C., Hurst A., Omoscharka E., Parks S., Price V., Reaich R., Schouten D., Rashid H., Birtcher K., Cantu J., Tait C., Taun W., Fadem S., Das D., Khosla U., Brown C., Brown T., Buquing J., Cromwell H., Dickson N., Najimipour B., Robeson J., Tabibi W., Mulloy L., Bailey K., Burton B., Fall P., Jagadeesan M., Paulson W., Szerlip H., White J., Faulkner M., Adeleye O., Boatright D., Mensah D., Nwankwo U., Crutcher L., Cummings C., Floyd M., Putatunda B., Ross J., Sanford V., Thadani U., Haragsim L., Parker B., Rogan L., Thresher M., Turner J., Dworkin L., Mignano D., O'Mara A., Shemin D., Bakris G., Basta E., Chua D., Neri G., Ahmed I., Elliott W., Fondren L., Hasabou N., Khosla N., Mazin A., Riehle J., Kovesdy C., Mendoza J., Ahmadzadeh S., Iranmanesh A., Lewis M., Lu J., Benabe J., Gonzalez-Melendez E., Padilla B., Serrano J., Russ T., Athmann L., Funke L., Larson P., Roach D., Salveson B., Nogueira J., Hanes D., Hise M., Light P., Copland E., Fink J., Hakim M., Hough K., McMinn S., Weir M., Young C., Kershaw G., Hill I., White B., Plumb 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Herrington W., Lewis D., Mafham M., Collins R., Bray C., Chen Y., Baxter A., Young A., Hill M., Knott C., Cass A., Feldt-Rasmussen B., Fellstrom B., Grobbee R., Gronhagen-Riska C., Haas M., Holdaas H., Hooi L.S., Jiang L., Kasiske B., Krairittichai U., Levin A., Massy Z., Tesar V., Walker R., Wanner C., Wheeler D., Wiecek A., Majoni W., Simpson D., Strony J., Musliner T., Agodoa L., Armitage J., Chen Z., Craig J., De Zeeuw D., Gaziano M., Grimm R., Krane V., Neal B., Ophascharoensuk V., Pedersen T., Sleight P., Tobert J., Tomson C., Sandercock P., Keech A., Whelton P., Yusuf S., Peto R., Parish S., Dolph L., Bahu T., Booth-Davey E., Brewster A., Yau F., Denis E., Frederick K., Haywood D., Heineman J., Howard S., Jayne K., Madgwick Z., Michell S., Murphy K., Ning L., Nolan J., Nunn M., Roberts J., Wickman M., Bowman L., Bulbulia R., Haynes R., Rahimi K., Rahman N., Ait-Sadi R., Barton I., Zhu W., Clark S., Kourellias K., Radley M., Brown K., Worthing D., Coates G., Goodenough B., Lucas N., Carreras A., Currie R., Donaldson O., Fjalling E., Gallagher M., Gibson K., Goddard J., Healy J., Hones L., Jardine M., Kwong I., Merai M., Murray S., Perkovic V., Rendina A., Gallo K., Caron S., Carlson K., Foley K., Matzek S., Mewhort L., O'Donoghue S., Perel-Winkler A., Terins T., Nie Q., Yu H., Ge L., Hao D., Li L., Pang X., Wei X., Yan G., Certikova Chabova V., Holst H., Molvadgaard T., Munksgaard D., Peltonen Y., Liabeuf S., Lebel C., Ouabou L., Bauer B., Bergmann K., Beusch M., Cavitt D., Drechsler C., Dulau I., Hugen K., Kempf S., Kuchenmeister B., Pscheidl V., Schmiedeke D., Schwarz M., Speerschneider K., Stahl B., Lim B.C., Nadia H., Zishareena M.F., Vasuthavan S., Ganesapillai A.T., Yuen S., Grobbee D., Bobbink I., Groot K., Sikking I., Raley J., Colban M., Smerud K., Trygg N., Waagaard E., Westad H., Rotkegel S., Spiechowicz U., Domoradzka M., Gawlowska M., Flygar A., Odmark I., Pettersson A., Blackwood S., Barclay J., Benham J., Brown R., Cureton L., Jackson D., Kennedy I., Leaper C., Taylor A., Winter C., Wise C., Nash M., Taylor Bennett A., Donaldson D., Chalmers K., Corderoy H., Bartkoske M., Bjerk C., Camarena A., Herskovitz L., Heuer C., Levin J., Robinson R., Wicklund B., Bentzel D., Cohen S., Costa C., Scranton R., Auwardt R., Boyer M., Cogdell P., Menahem S., Sheldrake J., Mount P., Fraenkel M., Bisscheroux P., Dempester J., Gleeson P., Harris G., Holmes C., Hyett K., Linton A., Miach P., Booth D., Druce L., Mantha M., Borg E., Green S., Killen J., Lynch Y., Colquhoun D., Herzig K., Row G., Addison J., Asa J., Beatson G., Calvird D., Edmunds J., Ferreira-Jardim A., Gwynne A., Mackay D., McLoughlin L., Wightwick C., Williams L., Ferrari P., Barry J., Hodson S., Zakrzewska W., Meagher E., Mulcahy M., Parnham A., Carney S., Garvey L., Gillies A., Hayes S., Mathew M., Fassett R., Anderson L., Clingeleffer C., Curnock A., Mayne L., Richardson D., Smith M., Smith S., Suranyi M., Howlin K., Chow J., Cleland B., Rayment G., Spicer T., Wong J., Wong M., Packham D., Alison C., Fraser I., Mitchell J., Nagle J., Brown F., Ellery C., Monkhouse J., Nandkumar J., Reith-Myers L., Gray N., Cocks C., Courtney M., Hollett P., Johnston C., Larsen H., Pollock A., Stewart S., Styles G., Wyndham R., Fanning M., Gibson W., Jackson S., Mannering M., Mercado E., Oliphant R., Sud K., Ubera N., Wood C., Karrasch J., Brinkley T., Estensen K., Moroney A., Sutton J., Warren R., Saltissi D., Jahke H., Roach H., Saltissi J., Wiederroth O'Brien M., Johnson D., Bali V., Evans M., Franzen K., Halbish S., Helyar J., Martin A., Mudge D., Sonnenburg K., Sudak J., Roger S., Almeida S., Andrews H., Bohringer L., Bouwhuis L., Brady L., Carpenter A., Warren S., Elias T., Bannister K., Chew G., Clarke J., Faull R., Hooper A., Jeffs L., Napier A., Peh C., Pirone K., Skilton F., Ranganathan D., Best J., Hart L., Healy H., Morgan C., Ratanjee S., Salisbury A., Jose M., Freeman J., Hamilton R., Kirkland G., Read G., Anderson H., Boekel K., Farrell M., Foreman A., 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M., Kodras K., Leithner C., Magpantay L., Marterer C., Prager R., Prinz C., Seiringer E., Kramar R., Mitter E., Stummvoll H., Dieplinger G., Wenzel R., Stolz G., Drose S., Edlinger E., Headlam-Leitner E., Miska H., Then M., Weninger S., Lhotta K., Neyer U., Dickie H., Smodek S., Sprenger-Mahr H., Rosenkranz A., Zitt E., Mayr B., Schinner A., Soltys G., Begin V., Brunet S., Cournoyer S., Gelinas M., Giroux C., Martineau J., Roy M., Savoie L., Agharazii M., Blouin J., Desmeules S., Langlois S., Samson F., Wong G., Constantini L., Jing J., Malko J., Rivers C., Rochester D., Skilling C., Wadgymar A., Wu G., Kates D., Husch J., Mantle M., Turri L., Barrett B., Curtis B., Greeley B., Hannaford M., Harnett J., Kelly M., Langille E., Morgan J., Murphy S., Karim M., Arbo T., Carpenito G., Chan V., DaRoza G., Friesen M., Kraus D., Lam S., Lange B., Minhas S., Starko R., Torng S., Vela K., Madore F., Roy P., Troyanov S., Bonnardeaux A., Lauzon L., Pichette V., Yeates K., Mahoney K., Myers C., Pilkey R., Moist L., Edgar M., House A., Kortas C., Mindorff S., Tam P., Chow S., Fung J., Nagai G., Ng P., Sikaneta T., Ting R., Forzley B., Clouatre Y., Cooper S., DaCosta H., Granger S., Valley S., Karunakaran S., Abdulhadi M., Altwasser C., Anderson S., Bergquist L., Wijeyesinghe C., Berst L., Horgan K., Coles K., Lotter T., Robson L., Barre P., Golden J., Golden M., Tanguay N., Rigatto C., Armstrong S., Fine A., Fontaine B., Friesen D., Henry S., Kraushar M., Reslerova M., Verrelli M., Rabbat C., Clase C., Suva G., Winegard N., Goldstein M., Curvelo S., Donnelly S., Huckle J., Marticorena R., Chan-Yan C., Chiu A., DeLuca L., Flamer D., Gill J., Jamal A., Jung B., Kiaii M., Landsberg D., Rozen N., Taylor P., Werb R., Pylypchuk G., Ahmed A., Barton J., Hundseth M., Kappel J., Keindel I., Klassen J., Pylypchuk S., Rindall M., Tobe S., Naimark D., Agelopoulos M., Chessman M., Hladunewich M., Perkins N., Sainsbury S., McCready W., Adams B., Tonelli M., Caldwell S., Kumar U., McMahon A., Nikitin S., Restall J., Treit S., Wysocki Y., Duncan J., Copland M., Jastrzebski J., Keown P., Kwan S., Rogers D., Shapiro J., Singh S., Sioson L., Yee K., Yeung C., Zacharias J., Bueti J., Dizon B., Lam H., Miller L., Ross M., Zarrillo M., Li Z., Wang C., Liu L., Hong M., Zheng H., Zuo W., Ge Z., Liu Q., Li Y., Sun K., Zhao R., Sun G., Wang F., Cui Z., Lou F., Du Y., Song L., Huang H., Song Z., Wang J., Zhou L., Wu R., Xiao R., Zhang Q., Duan N., Ju N., Wang A., Xu Z., Lu Z., Zhang Y., Zhao L., Zhang C., Mo Z., Xie Y., Xiong J., Chen J., Guo L., Zhao S., Peiskerova M., Jancova E., Kazderova M., Kobrova L., Gorun P., Kmentova T., Burgelova M., Lyerova L., Viklicky O., Berdych M., Nydlova Z., Jelinkova G., Moltas J., Pauzar T., Knetl P., Cahova J., Simkova J., Zakova M., Vankova S., Safarova R., Hruby M., Karlova R., Prikaska V., Sellenberg P., Vesela E., Malanova L., Vlasak J., Kaprova P., Novakova D., Kotherova K., Studenovska M., Christensen J., Solling J., Jepsen M., Kristensen V., Aerenlund H., Braemer-Jensen M., Kamper A., Raaschou S., Heaf J., Dreyer J., Freese P., Holm M., Munch M., Gade-Rasmussen E., Bredmose K., Daugaard H., Nielsen J., Friedberg M., Jensen D., Munk Plum M., Solling K., Dieperink H., Arp Nielsen L., Friborg E., Gloe-Jakobsen A., Thye Ronn P., Rasmussen K., Andersen C., Johansen A., Odum L., Ostergaard O., Pedersen L., Lykkegaard S., Aundal M., Faureholm Huess S., Danielsen H., Madsen J., Nyvang M., Ekstrand A., Boman H., Hartman J., Lipponen A., Lithovius R., Rauta V., Salmela A., Saloranta K., Forslund T., Koskiaho P., Jaaskelainen K., Kanninen M., Laine K., Asola M., Huhti J., Pentti M., Metsarinne K., Heiro M., Koivuviita N., Saarinen M., Tertti R., Choukroun G., Fournier A., Ducloux D., Marechal F., Simula Faivre D., Combe C., Douillet M., Lamblot T., Nardi H., Vendrely B., Bourbigot B., Ferlandin S., Zaoui P., Jouet C., Geffroy-Guiberteau S., Bugnazet L., Aldigier J., El Hamel-Belili C., Giraud S., Dussol B., Berland Y., Chollet M., Sichez H., Cristol J., Canaud B., Morena M., Rodriguez A., Kessler M., Mizejewski B., Risse B., Urena Torres P., Bou-Bekr M.A., Arezki C., Ras El Qdim P., Vela C., Borsato F., Talairach A., Normand M., Normand V., Rieu P., Gauthier B., Vigneron-Foy C., Wolak A., Menoyo V., Alos L., Caillette-Beaudoin A., Berger V., Al-Sarraf S., Konnerth I., Urban C., Weiner S., Boesken W., Jochum E., Kiefer C., Wagner A., Krumme B., Bohler J., Bonow B., Hohenstatt U., Mettang T., Rockel A., Langanke J., Lipponer H., Dunschen-Weimar G., Dunst R., Hubel E., Petrik R., Rengel R., Schmidgen M., Mayr H., Garschhammer C., Weirauch S., Anger H., Goock T., Mai A., Bast I., Suptitz C., Iwig B., Florschutz K., Hasselbacher R., Sauerbrey G., Delrieux S., Rau S., Poley M., Laux R., Schonfelder O., Kunowski G., Fuchs G., Hoffmann K., Schurger R., Brensing K., Guven Z., Immenkamp C., Kottmann C., Schmitt H., Schulz M., Arnold P., Knaup R., Schneider H., Siemsen H., Pyriki P., Korkemeyer F., Pyriki R., Siebrecht A., Schulz E., Krumwiede A., Kruse D., Lucke S., Keim H., Fink H., Fischer S., Klingbeil A., Kuhlmei K., Ortwein-Horn N., Merker L., Bayer B., Benamar K., Emmert S., Floten E., Holzheuer K., Lummer M., Ossendorf E., Scholz M., Oppitz M., Georgiew L., Tripps C., Wendehake M., Lange D., Pingel V., Brause M., Schanze W., Duygulu E., Dellanna F., Heinemann-Nieberding S., Sturmer C., Wieczorek K., Zarga O., Kullmer B., Kullmer S., Akin M., Gondolf M., Schutterle S., Walker G., Bertsch R., Seul M., Allendorff J., Siehler R., Stemmler S., Baldus M., Adler A., Harter S., Wurmell W., Moller M., Hame C., Muller M., Schreiber M., Schurfeld C., Millington-Herrmann M., Benschneider A., Gaffal J., Sprunken U., Bohling M., Wunderlich S., Schramm L., Kollenbrath C., Netzer K., Sieber T., Zimmermann J., Bellersen M., Uerkvitz M., David-Walek T., Hauschildt B., Leimenstoll G., Lonnemann G., Hilfenhaus M., Benedetto C., Stockmann S., Ichtiaris P., Jungmann A., Neumeier K., Stoof A., Bohmer K., Kirpal A., Knogl A., Flege F., Franke K., Groth P., Parensen E., Bockmann M., Przyklenk P., Piazolo L., Thinius-Jaudas L., Versen A., Hettich R., Arendt R., Geiger K., Hoppe H., Schwarting A., Beyer T., Faust J., Hazenbiller A., Tschirner S., Grupp C., Dorsch O., Eigner-Schmidtchen M., Michler K., Roth J., Schramm S., Waldmuller G., Riedl B., Vogele-Dirks H., Linz J., Biggar P., Hennemann H., Bauer G., Buchholz J., Fischer P., Bihlmaier W., Baumann A., Peichl B., Roser S., Ludewig S., Ricksgers M., Szendzielorz M., Baus A., Baust K., Schaller P., Schnellbacher G., Sorensen S., Buschges-Seraphin B., Hauenstein L., Hofmann B., Nikolay J., Merkel F., Nebel M., Petersen J., Schweb S., Zeissler H., Baumhackel K., Krauss A., Schafer R., Pastor A., Zielinski B., Strauss H., Theis H., Burkhardt K., Heckel M., Hussendorfer K., Bahner U., Brandl M., Hammerl-Kraus B., Herrmann D., Kramer H., Baudenbacher H., Blaser C., Buschmann G., Eckert G., Ehrich H., Hofmann K., Huller U., Geiger H., Becker B., Hoischen S., Bartel C., Hennig J., Obermuller N., Schulte C., Fischereder M., Burchardi F., Rupprecht H., Weidner S., Anders H., Andriaccio L., Lederer S., Ricken G., Strasser C., Lammert A., Schmitt W., Van Der Woude F., Langhauser B., Markau S., Osten B., Thiemicke D., Dorligschaw O., Weickert M., Breunig F., Denninger G., Osiek S., Rebstock W., Schulz P., Swoboda F., De Cicco D., Harlos J., Lebert A., Riegel M., Schmiedeke T., Hoffmann U., Nolle M., Jankrift P., Pfleiderer H., Witta J., Wittler B., Luth J., Dumann H., Habel U., Torp A., Sehland D., Tiess M., Etzold C., Friederiszik A., Morgenroth A., Dybala A., Suffel A., Leimbach T., Kron J., Sauer S., Meyer T., Meyer M., Lammers U., Bekman J., Holtz S., Kausler-Book B., Stobbe S., Hohage H., Heck M., Schulte F., Welling U., Zeh M., Seyfried J., De Heij T., Menzinger A., Weinreich T., Hopf M., Groll J., Kammholz K., Peters K., Schwietzer G., Kreft B., Weibchen U., Vosskuhler A., Hollenbeck M., Klaue K., Rzepucha E., Sperling K., Seeger W., Weyer J., Heine C., Kirste P., Zemann B., Alscher D., Rumpf D., Wullen B., Bengel A., Friedrich B., Kirschner T., Knodler U., Machleidt C., Niederstrasser K., Noack E., Wilhelm J., Heuer H., Dulea J., Piolot R., Rudke M., Treinen G., Elberg B., Hanke J., Nitschke T., Rosendahl C., Schmitz A., Schrader J., Kulschewski A., Lubcke C., Hammersen F., Luders S., Venneklaas U., Muhlfeld A., Arabi Al-Khanne F., Ketteler M., Politt D., Schuster C., Eitner F., Goretz U., Heidenreich S., Janssen U., Kranz A., Moormann E., Schneider B., Weber W., Frei U., Jovanovic T., Asmus H., Canaan-Kuhl S., Pannier L., Petersen S., Pluer M., Schaeffner E., Schafer C., Warncke S., Schmieder R., Donhauser C., Schulze B., Koziolek M., Bechtel W., Kurz B., Strutz F., Bramlage C., Dreyer S., Mommeyer E., Niemann J., Scheel A., Troche-Polzien I., Weber F., Heine G., Girndt M., Lizzi F., Rogacev K., Lindner T., Achenbach H., Peschel K., Beige J., Jentho S., Kreyssig C., Prill K., Renders L., Walcher J., Cerny S., Fulbier A., Kristen H., Nitschke M., Kramer J., Marek P., Meier M., Schlieter J., Heyne N., Bachmann F., Faber M., Klipp K., Kustner U., Risler T., Rath T., Ruf T., Budiman D., Seidel C., Weik S., Teo S.M., Lee L.Y., Azizah H., Faridunishah S.A., Foo S.M., Go K.W., Ghazali A., Koh K.H., Zaki M., Wong H.S., Bavanandan S., Boey L.M., Lily M., Wong S.L., Rosnawati Y., Zawawi N., Azimawati A., Hindun A., Hasnah J., Korina R., Yunaidah A., Noraidah P., Ong L.M., Noor Asma A., Liew Y.F., Rozina G., Cheong Y.H., Ang A.H., Dayang J., Lim L.S., Sukeri M., Ramli S., Zulkifli M., Wan Mahmood W.K., Goh B.L., Sarifah B., Bee B.C., Ramasamy C., Ruszarimah S., Liu W.J., Razali O., Haslinah S., Vaithilingam I., Jaaini A., Faridah L., Ng K.H., Krishnan P., Rosnah A.A., Nor Azizah A.S., Tam C.C., Tan S.H., Tan C.C., Shahnaz F.K., Wazir H., Munusamy P., Wan Shaariah M.Y., Chew T.F., Fuziah Z., Tan C.H.H., Maria L., Javelin P., Lim S.K., Nazatul S.B., Engkasan L.P., Tan S.Y., Wong M.G., Julita A.A., Ang B.B., Krishnan S., Seet W.W.T., Liew S.K., Keng T.C., Tobe T., Deelen M., Klaassen I., Grave W., Emmen M., Janssen W., Bossen W., Elzinga B., Van Der Velden A., Hemmelder M., Slagman M., Waanders F., Viergever P., Boerema I., Potter Van Loon B., Muthert B., Geers T., Schollaert N., Van Weverwijk I., Veen P., Woittiez A., Krikken J., Kwakernaak A., Visser F., Navis G., Hoekstra F., Hawkins S., McGregor D., Usher J., MacGinley R., Schollum J., Ellis G., Voss D., Rosman J., Upjohn M., Panlilio N., Madhan K., Naicker V., Anderson E., Bushell M., Lumb N., Pepperell B., Sizeland P., Hayett S., Sullivan N., Tuffery C., Macdonald A., Ostapowicz T., Wessel-Aas T., Wessel-Aas H., Bjorbaek E., Bjorbaek R., Simso I., Oien C., Bergrem H., Espedal S., Kronborg J., Solbakken K., Rocke J., Aakervik O., Haugen V., Eide T., Berglund J., Loland W., Schei T., Stromsaether C., Willadsen H., Lyngdal P., Vad A., Waldum B., Froslid G., Roaldsnes C., Rustad D., Soderblom P., Eriksen B., Hanssen E., Julsrud J., Mathisen U., Pedersen M., Rumsfeld M., Toft I., Berget K., Landsverk K., Tveiten G., Wamstad H., Klinger M., Krajewska M., Golebiowski T., Kusztal M., Spiechowicz-Zaton U., Rutkowski B., Renke M., Tylicki L., Czekalski S., Koziol L., Wanic-Kossowska M., Wasik-Olejnik A., Nowicki M., Dryja P., Kurnatowska I., Zawiasa A., Ciszek M., Gomolka M., Mysliwiec M., Brzosko S., Mazerska M., Hruby Z., Koscielniak K., Stanek-Piotrowska M., Mesjasz J., Rudka R., Baranski M., Jupowiecki J., Klein D., Switalski M., Kuriga M., Ostrowski M., Lidman A., Linde T., Waltersson K., Weiss L., Andersson G., Lindell C., Welander G., Jacobson S., Edensjo P., Wallin J., Linder M., Karsberg M., Hellgren K., Lonn I., Frisenette-Fich C., Johansson A., Lundstrom A., Mauritz N., Stahl-Nilsson A., Tobafard N., Hellberg O., Ejemar E., Von Schmalensee N., Gunne T., Eriksson A., Ostberg S., Svensson C., Mulec H., Jacobsson A., Karlsson M., Onnermalm L., Osagie S., Ekengren U., Larsson M., Lindberger K., Olofsson A., Samuelsson O., Beagan L., Dezfoolian H., Just M., Ortegren L., Saeed A., Strand U., Ramsauer B., Hultstrom D., Nordlinder K., Sundberg I., Oqvist B., Green C., Fernstrom A., Cassel A., Goransson I., Gylling M., Jorgensen A., Sterner G., Christensson A., Hjelmstedt P., Nystrom A., Sundin P., Samuelsson I., Tidman M., Johansson M., Lofgren Andersson M., Ohman M., Andersson P., Hallberg Karlsson A., Ringstad L., Chittinandana A., Chailimpamontree W., Gojaseni P., Singprasert R., Tungsanga K., Amphun W., Intim P., Kanjanabuch T., Poowarattanakul D., Treratha C., Wongvan P., Jittikanont S., Suriya T., Indrasthitya P., Sumethkul V., Ingsathit A., Jansomwong J., Lertchalorarn K., Phachiyanukul V., Phiromkit T., Saengsri S., Vareesangthip K., Chawanasuntorapoj R., Kiattisunthorn K., Larpkitkachorn R., Webster J., Henderson J., Jayne D., Hollis J., Townsend K., Harron C., Bleakley N., Hanley N., Morgan S., Brittney L., Brown H., Maxwell P., Murtagh H., Thomas M., Burke E., Carmody M., Cox G., Dasgin J., Ali G., Whitehouse L., Williams V., Brown E., Dlelana G., Esson A., Fagerbrink S., Marshall F., Mazibuko B., Nelson C., Russell E., Williams R., Altmann P., McNichols-Thomas C., Parsons K., MacGregor M., McGowan J., Mead P., Gilbanks K., Sanderson M., Fluck R., Chandler G., Hulme L., Smith J., Tse Y., West C., Taylor J., Breakspear S., Burgess B., Isles C., Bell J., Duignan J., Gorman J., Swainson C., Beveridge C., Cairns A., Miller D., Paterson F., Smith L., Kumwenda M., Glover R., Geddes C., Gemmell C., Grieve I., Matthews E., McLaren B., Meyer B., Spiers A., Banks R., Apperley P., Patterson T., Paynter H., Scoble J., Thom D., Watkins J., Kalra P., Gowland S., Haydock L., Smart I., Bhandari S., Gillett P., James K., Lewis R., Melville H., Tamimi A., Williams P., Heath T., Small S., Paterson A., Gibson N., Laven C., Wilson T., Cairns H., Casley-Ready K., Warwick G., Fentum B., James J., Kumar T., Marshall R., Ratcliffe F., Shenton A., Warwicker P., Bowser M., Mumford C., Mitra S., Woolfson R., Yang R., Williams A., Richards K., Turner A., Odum J., Rylance P., Smallwood A., Ward J., Henderson I., McMahon M., Ross C., Burrows M., Morais J., Rajan S., Tindall H., Barrett C., Kelly F., El-Nahas M., Bartholomew J., Edwards L., Okhuoya F., Bebb C., Cassidy M., Brand S., Quashie-Howard M., Taggart C., Capps N., Tonks L., Mason J., Powell S., Watkins L., Ball S., Dutton M., Fifer L., McGlynn F., Wood M., Jenkins D., Allan N., Fahal I., Elhag-Ali H., King J., Peel R., Potts L., Logie I., McGhie F., Naik R., Parry R., Andain K., Durkin S., D'Souza R., Harrison D., Cooke J., Kinyanjui R., Harper J., Algate K., McCarthy M., Van Eker D., Thuraisingham R., Chinodya M., Deelchand V., Garcia R., Ngango R., Rolfe C., Williams K., Solomon L., Heap T., MacDowall P., Saunderson Smith L., MacDiarmaid-Gordon A., Harman W., Smithson H., Robertson D., Gammon B., O'Grady D., Verow C., Rogerson M., Berry L., Gough C., Hayward E., Jones C., Payne T., Rowe L., Sibley C., Szymanski J., Almond M., Bourton L., Bromwich C., Dawson S., Mason S., Oliveira D., Ramkhelawon R., Tuazon J., Andrews P., Archer K., Moore A., Thomas G., Velazquez C., Mumtaz R., Roberts R., Farquhar F., Ott J., Fenwick S., Callaway A., Garrett P., Dees L., McDonagh U., Garner S., Zehnder D., Aldridge N., Dyer C., Gomez M., Hewins S., McCarthy K., Rush J., Spencer S., Harvey M., Mills H., Drew P., Henry M., Wilberforce S., Worth D., Adair Z., Hartley J., Jibani M., Jones D., Swan S., Shamp T., Alcorn H., Bookey J., Cannon C., Jarvis K., Muesing C., Murphy M., Muster H., Planting M., Strand C., Middleton J., Gitter K., Mace N., Schumm D., Pogue V., Alimohammadi B., Arora P., Herbert L., Cheng J., Dowie D., Mohan S., Peters G., Tuttle K., Albritton S., Benedetti R., Joshi S., Lund B., Shuler L., Trevino M., Mai K., Osborn T., Parekh R., Eustace J., Novak G., Patterson S., Lindsey C., Hill T., Liston M., Wiegmann T., Nagaria A., Hurd C., Hurst A., Omoscharka E., Parks S., and Price V.
- Abstract
Background: Lowering low-density lipoprotein (LDL) cholesterol with statin therapy has been shown to reduce the incidence of atherosclerotic events in many types of patient, but it remains uncertain whether it is of net benefit among people with chronic kidney disease (CKD). Method(s): Patients with advanced CKD (blood creatinine >=1.7 mg/dL [>= 150 mumol/L] in men or >=1.5 mg/dL [ >= 130 mumol/L] in women) with no known history of myocardial infarction or coronary revascularization were randomized in a ratio of 4:4:1 to ezetimibe 10 mg plus simvastatin 20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm rerandomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs placebo). The key outcome will be major atherosclerotic events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure. Results A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. Conclusions SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD.Copyright © 2010, Mosby, Inc. All rights reserved.
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- 2010
3. Analysis of the peripheral T-cell repertoire in kidney transplant patients
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Miqueu, P., Deguauque, N., Guillet, M., Giral, M., Ruíz, Catherine L., Pallier, A., Braudeau, C., Roussey-Kesler, G., Ashton-Chess, J., Doré, JC, Thervet, E., Legendre, Christophe, Hernandez-Fuentes, Maria P, Warrens, AN, Goldman, Michel, Volk, HD, Janssen, U., Wood, Kathryn, Lechler, RI, Bertrand, Dominique, Sebille, V., Soulillou, JP, Brouard, S., Miqueu, P., Deguauque, N., Guillet, M., Giral, M., Ruíz, Catherine L., Pallier, A., Braudeau, C., Roussey-Kesler, G., Ashton-Chess, J., Doré, JC, Thervet, E., Legendre, Christophe, Hernandez-Fuentes, Maria P, Warrens, AN, Goldman, Michel, Volk, HD, Janssen, U., Wood, Kathryn, Lechler, RI, Bertrand, Dominique, Sebille, V., Soulillou, JP, and Brouard, S.
- Abstract
The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8 +/CD4 + T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published
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- 2010
4. EPM- Standardisiertes Verfahren zur Organisation von MC-Prüfungen in der Medizin
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Beiderwieden, E, Frankewitsch, T, Janßen, U, Klockgether, S, Marschall, B, Beiderwieden, E, Frankewitsch, T, Janßen, U, Klockgether, S, and Marschall, B
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- 2009
5. CKD-MBD - A
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Stevens, K., primary, Beattie, E., additional, Delles, C., additional, Jardine, A., additional, Neumann, K., additional, Fang, L., additional, Ritz, E., additional, Gross-Weissmann, M.-L., additional, Kokeny, G., additional, Nakano, C., additional, Hamano, T., additional, Fujii, N., additional, Matsui, I., additional, Mikami, S., additional, Obi, Y., additional, Shimomura, A., additional, Rakugi, H., additional, Tsubakihara, Y., additional, Isaka, Y., additional, Torremade, N., additional, Arcidiacono, M. V., additional, Valcheva, P., additional, Bozic, M., additional, Fernandez, E., additional, Valdivielso, J. M., additional, Rotondi, S., additional, Pasquali, M., additional, Conte, C., additional, Leonangeli, C., additional, Muci, M. L., additional, Pirro, G., additional, Tartaglione, L., additional, Mazzaferro, S., additional, Janssen, U., additional, Naderi, S., additional, Hennies, M., additional, Kruger, T., additional, and Brandenburg, V., additional
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- 2013
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6. Umsetzungsorientierte Konzeption zur Stillegung oder Extensivierung landwirtschaftlicher Nutzflächenaus landschaftsökologischer Sicht
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Brahms, E., Janßen, U., Müller, C., and Pummerer, S.
- Abstract
Die $\textbf{EG-Agrarpolitik}$ war zumindest bis Mitte der 80er Jahre durch eine Markt- undPreispolitik gekennzeichnet, die sich wesentlich an landwirtschaftlichen Einkommenszielenorientierte. Die durchschnittlichen landwirtschaftlichen Einkommen sollten den Zuwachsratender Einkommensentwicklung in anderen Wirtschaftsbereichen entsprechen. Die Folge dieserpolitischen Rahmenbedingungen war ein kräftiges Wachstum der Agrarproduktion. Da derNachfragezuwachs in gleichem Maße ausblieb, entstanden strukturelle Überschüsse mitsteigenden Belastungen für den EG-Haushalt durch entsprechende Marktordnungsausgaben,Mit der Milchquotenregelung (1984) und der Festlegung von Preisregelungsmechanismen(1988) wurden Signale in Richtung einer restriktiven Mengen- und Preispolitik gesetzt.Das starke Produktionswachstum hatte gleichzeitig eine Intensivierung der landwirtschaftlichenBodennutzung zur Folge, die sich ausdrückt in- einer zunehmenden Bewirtschaftungsintensität. So hat sich z.B. (SRU 1985)$\bullet$ der Schlepperbesatz pro 100 ha landwirtschaftlich genutzter Fläche (LF) seit 1960nahezu verdoppelt und die durchschnittliche Schlepperleistung vervierfacht.$\bullet$ der Einsatz von mineralischem Stickstoffdünger zwischen 1950151 und 1982183 fastverfünffacht$\bullet$ der Absatz von herbiziden Pflanzenschutzmitteln seit 1970 um 81% erhöht- einem steigenden Anteil von Betrieben mit einer Betriebsgröße von über 50 ha (AGRARBERICHT1990, Materialband)- einer zunehmenden Schlaggröße; bundesdurchschnittlich um mehr als das Dreifache- einem Trend zur stärkeren Spezialisierung. Der Anteil von Spezialbetrieben (mehr als 75 %des Standarddeckungsbeitrages werden mit Marktfruchtanbau, Futterbau, Veredelung oderDauerkulturen erwirtschaftet) stieg zwischen 1970 und 1980 um knapp 70%- einer Zunahme des Viehbesatzes. Im Zeitraum von 1971 bis 1983 stieg allein der durchschnittlicheFlächenbesatz um knapp 20%, wobei durch die verstärkte betriebliche undregionale Konzentration z.T. sehr hohe Extremwerte auftreten. [...]
- Published
- 1992
7. Improved survival and amelioration of nephrotoxic nephritis in intercellular adhesion molecule-1 knockout mice
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Janssen, U., Ostendorf, T., Gaertner, S., Eitner, F., Hedrich, H.J., Assmann, K.J.M., Floege, J., Janssen, U., Ostendorf, T., Gaertner, S., Eitner, F., Hedrich, H.J., Assmann, K.J.M., and Floege, J.
- Abstract
Item does not contain fulltext
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- 1998
8. Ultrasonographic fata morgana
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Brandenburg, V. M., primary, Frank, R. D., additional, Janssen, U., additional, Wurth, P., additional, Floege, J., additional, and Riehl, J., additional
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- 2003
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9. Identification of a B 50-like protein in frog brain synaptosomes
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Gispen, W.H., Janssen, U., Richter-Landsberg, C., Oestreicher, A.B., Graan, P.N.E. de, Flohr, H., Gispen, W.H., Janssen, U., Richter-Landsberg, C., Oestreicher, A.B., Graan, P.N.E. de, and Flohr, H.
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- 1992
10. Possible interaction of fluoroquinolones with the benzodiazepine-GABAA- receptor complex.
- Author
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Unseld, E, primary, Ziegler, G, additional, Gemeinhardt, A, additional, Janssen, U, additional, and Klotz, U, additional
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- 1990
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11. Protein kinase C mediates transient spinule-type neurite outgrowth in the retina during light adaptation.
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Weiler, R, Kohler, K, and Janssen, U
- Abstract
Light and dark adaptation of the teleost retina is accompanied by a remarkable morphological rearrangement of the synaptic connections between photoreceptors and second-order neurons: during light adaptation, numerous new neurites, the so-called spinules, arise from the terminal dendrites of horizontal cells invaginating the cone pedicle, and during dark adaptation, these spinules are retracted. The formation of these spinules is paralleled by the appearance of color opponency in horizontal and ganglion cells, which led to the suggestion that these spinules are the site of the inhibitory synapses in the negative feedback loop between cones and horizontal cells. The formation of the spinules in the light and their disappearance in darkness have a time course of minutes and are modulated by the neurotransmitters dopamine and glutamate, respectively. Neurotransmitters can modulate neuronal processing through a variety of second messengers that activate protein kinases, resulting most commonly in protein phosphorylation. Herein we report that activation of protein kinase C by phorbol esters promotes the formation of new horizontal-cell spinules in animals kept in the dark. Partial inhibition of protein kinase C activation with sphingosines prevents the formation of new spinules during light adaptation but does not affect established spinules. The spinule-forming effect of phorbol esters is not mediated by dopaminergic neurons, since the effect is also seen in retinas depleted of dopaminergic neurons. Phorbol esters also initiate the formation of spinules in synaptically isolated horizontal cells, demonstrating that they have a direct action on these cells. In addition, isolated horizontal cells have substrate proteins that are phosphorylated in a protein kinase C-dependent manner.
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- 1991
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12. Mossbauer study of hyperfine field distributions and spin canting in lithium-zinc ferrites.
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Rosenberg, M., Deppe, P., Dey, S., Janssen, U., Patton, C., and Edmondson, C.
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- 1982
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13. Invited comment. Dietary salt restriction and reduction of dialysate sodium to control hypertension in maintenance haemodialysis patients.
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Krautzig, S, Janssen, U, Koch, KM, Granolleras, C, and Shaldon, S
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- 1998
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14. Dietary salt restriction and reduction of dialysate sodium to control hypertension in maintenance haemodialysis patients.
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Krautzig, S, Janssen, U, Koch, K M, Granolleras, C, and Shaldon, S
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- 1998
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15. Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells
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Rosa eBacchetta, Barbarella eLucarelli, Claudia eSartirana, Silvia eGregori, Maria Teresa eLupo Stanghellini, Patrick eMiqueu, Stefan eTomiuk, Maria eHernandez-Fuentes, Monica Emma eGianolini, Raffaella eGreco, Massimo eBernardi, Elisabetta eZappone, Silvano eRossini, Janssen eUwe, Alessandro eAmbrosi, Monica eSalomoni, Jacopo ePeccatori, Fabio eCiceri, Maria Grazia eRoncarolo, Bacchetta, R, Lucarelli, B, Sartirana, C, Gregori, S, Stanghellini, Mtl, Miqueu, P, Tomiuk, S, Hernandez Fuentes, M, Gianolini, Me, Greco, R, Bemardi, M, Zappone, E, Rossini, S, Janssen, U, Ambrosi, Alessandro, Salomoni, M, Peccatori, J, Ciceri, Fabio, and Roncarolo, MARIA GRAZIA
- Subjects
lcsh:Immunologic diseases. Allergy ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,chemical and pharmacologic phenomena ,Haploidentical ,Cell therapy ,T regulatory type 1 cells ,Immune system ,In vivo ,Medicine ,Immunology and Allergy ,T regulatory Type 1 cells (Tr1) ,tolerance ,business.industry ,haploidentical ,Immunosuppression ,Clinical Trial ,Transplantation ,Interleukin 10 ,hematopoietic stem cell transplantation ,IL-10 ,cell therapy ,business ,lcsh:RC581-607 ,Tolerance ,Adjuvant - Abstract
T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSC transplantation (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10 anergized donor T cells (IL-10 DLI) contained T regulatory type 1 (Tr1) cell specific for the, host alloantigens, limiting donor-vs-host reactivity, and memory T cells able to respond to pathogens. IL-10 DLI were infused in 12 patients with the goal of improving immune-reconstitution after haplo-HSCT without increasing the risk of GvHD. IL-10 DLI led to fast immune-reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10 DLI. These four patients are alive, in complete disease remission and immune suppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1- specific biomarkers in vivo. Gene expression profiles of immune-reconstituted patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves the way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.
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- 2014
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16. Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron.
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Kreye J, Reincke SM, Edelburg S, Jeworowski LM, Kornau HC, Trimpert J, Hombach P, Halbe S, Nölle V, Meyer M, Kattenbach S, Sánchez-Sendin E, Schmidt ML, Schwarz T, Rose R, Krumbholz A, Merz S, Adler JM, Eschke K, Abdelgawad A, Schmitz D, Sander LE, Janssen U, Corman VM, and Prüss H
- Abstract
The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2., Competing Interests: The German Center for Neurodegenerative Diseases (DZNE) and Charité-Universitätsmedizin Berlin have filed a patent application (application number: PCT/EP2021/064,352) on antibodies for the treatment of SARS-CoV-2 infection on which J.K., S.M.R., H.-C.K., E.S.-S., L.E.S., V.M.C., and H.P. are named as inventors. V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. S.E., V.N., M.M., S.K., S.H., P.H., and U.J. are employees of Miltenyi Biotec B.V. & Co. KG., (© 2023 The Author(s).)
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- 2023
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17. Idiopathic granulomatous interstitial nephritis and isolated renal sarcoidosis: Two diagnoses of exclusion.
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Janssen U, Naderi S, and Amann K
- Abstract
Granulomatous interstitial nephritis is a rare finding in renal biopsy caused by drugs, infections, and inflammatory or autoimmune diseases. Idiopathic cases account for 18% of granulomatous interstitial nephritis in native kidneys. Sarcoidosis and drugs are the most common causes of granulomatous interstitial nephritis in Western countries, while in India tuberculosis prevails. Few cases of renal sarcoidosis without extrarenal involvement, that is, isolated renal sarcoidosis, have been reported. The diagnostic criteria of isolated renal sarcoidosis remain, however, unclear. Extrarenal sarcoidosis and other etiologies of granulomatous interstitial nephritis, in particular drug-related, have to be excluded. Some of these patients may develop extrarenal manifestations during follow-up. Changes in calcium and vitamin D metabolism are frequently observed in renal sarcoidosis and support its diagnosis. While non-necrotizing granulomas are a feature of sarcoidosis and drug-induced granulomatous interstitial nephritis, they also prevail in tuberculosis-associated granulomatous interstitial nephritis. Granulomatous interstitial nephritis caused by sarcoidosis and drugs usually responds to steroid therapy. A poor response to steroids may indicate an infectious etiology such as tuberculosis and should lead to a review of the initial diagnosis. This article gives an overview of the various etiologies of granulomatous interstitial nephritis, their frequency and histopathological characteristics, as well as potential biomarkers associated with renal sarcoidosis., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)
- Published
- 2021
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18. Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial.
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Viklicky O, Hruba P, Tomiuk S, Schmitz S, Gerstmayer B, Sawitzki B, Miqueu P, Mrazova P, Tycova I, Svobodova E, Honsova E, Janssen U, Volk HD, and Reinke P
- Subjects
- Adult, Antigens, CD, Antigens, Neoplasm, Biomarkers metabolism, CD52 Antigen, Female, Gene Expression Profiling, Graft Rejection etiology, Humans, Male, Middle Aged, Monitoring, Immunologic, Prospective Studies, Sirolimus therapeutic use, Tacrolimus therapeutic use, Young Adult, Glycoproteins antagonists & inhibitors, Graft Rejection drug therapy, Immunosuppressive Agents therapeutic use, Kidney Transplantation adverse effects, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Background: There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy., Methods: In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months., Results: TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up., Conclusions: In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings., Trial Registration: EudraCT Number: 2006-003110-18., Competing Interests: O.V. recived lecture fees from Sanofi. S.T., S.S., U.J., and B.G. were employed by Miltenyi Biotec GmbH, Germany. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
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- 2017
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19. Validation of commercially available ELISAs for the detection of circulating sclerostin in hemodialysis patients.
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Mause SF, Deck A, Hennies M, Kaesler N, Evenepoel P, Boisvert WA, Janssen U, and Brandenburg VM
- Abstract
Background: Sclerostin is an endocrine regulator in chronic kidney disease - mineral and bone disorder (CKD-MBD). Validation of assay comparability and pre-analytical handling is mandatory for establishment of sclerostin as a biomarker., Methods: Blood samples (serum, EDTA, heparin and citrate plasma) were obtained from 12 hemodialysis (HD) patients after the long dialysis interval. Passing-Bablok regression analysis and Bland-Altman difference plots were used to evaluate the agreement between sclerostin levels measured with two commercially available ELISAs from TECOmedical and Biomedica., Results: Independent of the sample type, the agreement of the two assays was poor with a strong proportional but no systematic bias. Compared to the TECOmedical assay, the Biomedica test yielded almost 2-fold higher sclerostin values throughout all sample types. Spike recovery and linear dilution studies revealed a higher accuracy of the TECOmedical assay (97% and 96%) compared to the Biomedica assay (118% and 78%). Sclerostin levels were stable within 4 hours after sample collection, in particular when analyzed in plasma. In contrast to the Biomedica assay, the TECOmedical showed a systematic but no proportional bias between serum and plasma samples with higher values for plasma samples. Among the 3 different plasma samples no systematic error could be documented., Conclusion: Careful consideration of the pre-analytical handling and comparative assay validation are necessary to facilitate a more differentiated interpretation of studies reporting circulating sclerostin levels. The presence of a proportional bias demonstrates that in HD patients the two ELISAs for measuring sclerostin should not be used interchangeably. Furthermore, caution is necessary when comparing sclerostin results obtained from different blood sample types.
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- 2016
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20. Gene expression profiling of immunomagnetically separated cells directly from stabilized whole blood for multicenter clinical trials.
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Letzkus M, Luesink E, Starck-Schwertz S, Bigaud M, Mirza F, Hartmann N, Gerstmayer B, Janssen U, Scherer A, Schumacher MM, Verles A, Vitaliti A, Nirmala N, Johnson KJ, and Staedtler F
- Abstract
Background: Clinically useful biomarkers for patient stratification and monitoring of disease progression and drug response are in big demand in drug development and for addressing potential safety concerns. Many diseases influence the frequency and phenotype of cells found in the peripheral blood and the transcriptome of blood cells. Changes in cell type composition influence whole blood gene expression analysis results and thus the discovery of true transcript level changes remains a challenge. We propose a robust and reproducible procedure, which includes whole transcriptome gene expression profiling of major subsets of immune cell cells directly sorted from whole blood., Methods: Target cells were enriched using magnetic microbeads and an autoMACS® Pro Separator (Miltenyi Biotec). Flow cytometric analysis for purity was performed before and after magnetic cell sorting. Total RNA was hybridized on HGU133 Plus 2.0 expression microarrays (Affymetrix, USA). CEL files signal intensity values were condensed using RMA and a custom CDF file (EntrezGene-based)., Results: Positive selection by use of MACS® Technology coupled to transcriptomics was assessed for eight different peripheral blood cell types, CD14+ monocytes, CD3+, CD4+, or CD8+ T cells, CD15+ granulocytes, CD19+ B cells, CD56+ NK cells, and CD45+ pan leukocytes. RNA quality from enriched cells was above a RIN of eight. GeneChip analysis confirmed cell type specific transcriptome profiles. Storing whole blood collected in an EDTA Vacutainer® tube at 4°C followed by MACS does not activate sorted cells. Gene expression analysis supports cell enrichment measurements by MACS., Conclusions: The proposed workflow generates reproducible cell-type specific transcriptome data which can be translated to clinical settings and used to identify clinically relevant gene expression biomarkers from whole blood samples. This procedure enables the integration of transcriptomics of relevant immune cell subsets sorted directly from whole blood in clinical trial protocols.
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- 2014
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21. Functional interactions between the fossa ischioanalis, levator ani and gluteus maximus muscles of the female pelvic floor: a prospective study in nulliparous women.
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Soljanik I, Janssen U, May F, Fritsch H, Stief CG, Weissenbacher ER, Friese K, and Lienemann A
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- Adolescent, Adult, Buttocks physiology, Electromyography, Female, Humans, Magnetic Resonance Imaging, Parity, Prospective Studies, Reference Values, Young Adult, Muscle, Skeletal physiology, Pelvic Floor physiology
- Abstract
Purpose: We evaluated the role of the fossa ischioanalis (FI) in functional relations between the levator ani (LA) and gluteus maximus muscles (GM) in healthy female volunteers., Methods: Twenty-three nulliparae were examined. Electromyogramms of LA and GM were simultaneously recorded during voluntary contraction of the pelvic floor muscles (PFM) and at rest in six body positions. The surface areas of LA (LAA), FI (FIA) and GM (GMA) were evaluated using MRI., Results: Simultaneous LA and GM contractions were electromyographically observed irrespectively of body position in 97.2 %. MRI revealed synchronous movement of all structures: while LAA (-7.4 %) reduced, GMA increased (+6.8 %), FIA changed significantly (+3.4 %)., Conclusions: The LA, FI and GM are morphologically and functionally connected. We recommend considering these structures as the 'LFG-Complex', emphasising the importance of this unit for functional integration of the pelvic floor. The findings of this study may contribute to understanding of urinary continence mechanism and disorders after pelvic floor surgery and obstetrical trauma.
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- 2012
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22. Characterization of immunostimulatory components of orf virus (parapoxvirus ovis).
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Friebe A, Friederichs S, Scholz K, Janssen U, Scholz C, Schlapp T, Mercer A, Siegling A, Volk HD, and Weber O
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- Animals, Antigen-Presenting Cells immunology, Cattle, Cell Line, Ecthyma, Contagious virology, Female, Humans, Mice, Orf virus genetics, Viral Proteins genetics, Ecthyma, Contagious immunology, Orf virus immunology, Viral Proteins immunology
- Abstract
Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-γ that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.
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- 2011
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23. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.
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Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, Chapman S, Craciun L, Sergeant R, Brouard S, Rovis F, Jimenez E, Ballow A, Giral M, Rebollo-Mesa I, Le Moine A, Braudeau C, Hilton R, Gerstmayer B, Bourcier K, Sharif A, Krajewska M, Lord GM, Roberts I, Goldman M, Wood KJ, Newell K, Seyfert-Margolis V, Warrens AN, Janssen U, Volk HD, Soulillou JP, Hernandez-Fuentes MP, and Lechler RI
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- Humans, Immune Tolerance genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tissue Donors, Biomarkers metabolism, Immune Tolerance immunology, Immunosuppressive Agents immunology, Kidney Transplantation immunology
- Abstract
Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
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- 2010
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24. Identification of central venous hemodialysis catheter-related infection by a semiquantitative culture method.
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Brodersen HP, Beckers B, Clauss M, vom Dahl J, Floege J, and Janssen U
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- Aged, Bacteremia mortality, Body Temperature, Female, Humans, Leukocyte Count, Male, Middle Aged, Bacteremia diagnosis, Bacteria isolation & purification, Catheterization, Central Venous adverse effects, Catheters, Indwelling microbiology, Colony Count, Microbial methods, Renal Dialysis adverse effects
- Abstract
Background: Central venous hemodialysis catheter-related infection is a major cause of morbidity and mortality in the hemodialysis (HD) population. Due to an impaired immune response, symptoms and signs of infection may not be obvious, and thus bacteremia is often diagnosed and treated protractedly. In contrast, induction of the acute phase response is frequently observed in HD patients even without infection. Moreover, positive catheter cultures may result from contamination, asymptomatic colonization or infection. The aim of the present study was to compare the number of colonies from HD catheter tips, with symptoms and signs of infection in HD patients., Methods: In a 10-year, single-center study, 53 HD patients (29 men, 24 women; mean age 66 +/- 10 years) who had their dialysis catheters removed were divided into 3 groups according to the number of colonies growing after rolling the catheter tip across blood agar (group I: <15 colonies [n=22], II: 15-50 colonies [n=15], III: >50 colonies [n=16])., Results: The maximum white blood cell (WBC) count did not differ significantly between patients with low- and high-density colonization (group I: 11.746 +/- 9.680 WBC/microL vs. group III: 13.479 +/- 6.252 WBC/microL, p=NS) while maximum C-reactive protein (CRP) levels were higher in patients with high-density colonization (group I: 8.6 +/- 6.8 vs. group III: 19.2 +/- 12.2 mg/dL, p<0.05). Density of bacterial colonization was associated with the maximum body temperature (group I: 37.6 degrees C +/- 1.1 degrees C vs. 38.7 degrees C +/- 0.9 degrees C, p<0.05). Moreover patients with high-density colonization showed increased bacteremia (group I: 33% vs. group III: 93%, p<0.01) as well as an increased mortality due to septicemia (group I: 9% vs. group III: 50%, p<0.01). Patients of group II exhibited intermediate values in all analyses., Conclusion: The semiquantitative culture technique can help to differentiate between contamination and infection of central venous HD catheters and provides important prognostic information in dialysis patients.
- Published
- 2007
25. The quest for a model of type II diabetes with nephropathy: the Goto Kakizaki rat.
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Janssen U, Vassiliadou A, Riley SG, Phillips AO, and Floege J
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- Animals, Diabetic Nephropathies pathology, Diabetic Nephropathies physiopathology, Rats, Diabetes Mellitus, Type 2 genetics, Diabetic Nephropathies genetics, Disease Models, Animal, Rats, Wistar genetics
- Abstract
The Goto Kakakizaki (GK) rat is a moderately diabetic rat strain that was developed by repeated inbreeding of glucose-intolerant Wistar rats over several generations. In contrast to many other rodent models of non-insulin-dependent diabetes, GK rats do not exhibit hyperlipidemia or obesity. Hyperglycemia in the GK rat is associated with the development of age-dependent renal structural changes that are similar to those described in patients with prolonged non-insulin-dependent diabetes mellitus who have not developed overt renal disease. Hyperglycemia in the GK rat is, however, not associated with overt proteinuria or progressive nephropathy. In the present review the metabolic characteristics as well as renal and nonrenal changes observed in GK rats are described. Moreover the effects on renal function and morphology of secondary injurious stimuli, such as mesangioproliferative glomerulonephritis and hypertension, superimposed on type II diabetes in GK rats are discussed.
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- 2004
26. Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy.
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Janssen U, Riley SG, Vassiliadou A, Floege J, and Phillips AO
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- Animals, Blood Pressure, Desoxycorticosterone, Diabetes Mellitus, Type 2 complications, Diabetic Nephropathies pathology, Disease Progression, Hyperglycemia complications, Hyperglycemia physiopathology, Hypertension, Renal chemically induced, Hypertension, Renal pathology, Kidney physiology, Kidney Glomerulus pathology, Kidney Glomerulus physiopathology, Kidney Tubules pathology, Kidney Tubules physiopathology, Male, Rats, Rats, Wistar, Diabetes Mellitus, Type 2 physiopathology, Diabetic Nephropathies etiology, Diabetic Nephropathies physiopathology, Hypertension, Renal physiopathology
- Abstract
Background: Type II diabetes in the Goto Kakizaki (GK) rats (derived from Wistar rats) is not associated with the development of obesity, hyperlipidemia, hypertension, or pronounced renal functional changes. The aim of this study was to investigate the effect of superimposed hypertension on renal function and morphology under conditions of hyper- and normoglycemia., Methods: The evolution of biochemical and morphologic renal changes was examined in GK and Wistar rats treated with deoxycorticosterone acetate (DOCA) salt over 24 weeks., Results: Blood pressure was increased from 6 weeks on in GK and Wistar rats with no difference in blood pressure levels between both groups (week 24, 183 +/- 14 mm Hg vs. 191 +/- 13 mm Hg, P = NS, vs. 144 +/- 6 mm Hg in normal controls, P < 0.01). A progressive increase in proteinuria was observed in hypertensive GK rats from 12 weeks on (week 24, 168 +/- 62 mg/day vs. 41 +/- 30 mg/day in hypertensive Wistar rats, P = 0.002). Histologic analysis at weeks 15 and 24 showed progressive glomerulosclerosis in hypertensive GK and Wistar rats (week 24, 13 +/- 4% vs. 8 +/- 1%, P = NS) but not in nonhypertensive GK controls. This was associated with evidence of podocyte damage (de novo desmin expression) in hypertensive as compared to nonhypertensive GK rats (week 24, score 1.4 +/- 0.1 vs. 0.8 +/- 0.1, P < 0.001) while no significant increase was observed in hypertensive vs. nonhypertensive Wistar rats. Tubulointerstitial damage was increased in hypertensive GK as compared to hypertensive Wistar rats (week 24, score 1.5 +/- 0.6 vs. 0.6 +/- 0.3, P = 0.01). By immunohistochemistry, this was associated with an up-regulation of tubulointerstitial type IV collagen as well as alpha-smooth muscle actin (alpha-SMA) expression, macrophage infiltration and cell proliferation in hypertensive GK rats., Conclusion: Our data demonstrate that long-standing type II diabetes alone is not sufficient to induce progressive nephropathy unless secondary injurious mechanisms such as hypertension are present. The hypertensive GK rat provides a novel model to investigate the mechanisms involved in diabetic nephropathy.
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- 2003
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27. Disruption of mitochondrial beta -oxidation of unsaturated fatty acids in the 3,2-trans-enoyl-CoA isomerase-deficient mouse.
- Author
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Janssen U and Stoffel W
- Subjects
- Alleles, Animals, Blotting, Northern, Chromatography, Thin Layer, Dodecenoyl-CoA Isomerase, Genetic Vectors, Hepatocytes metabolism, Kidney metabolism, Lipid Metabolism, Liver metabolism, Mice, Mice, Transgenic, Phenotype, Time Factors, Tissue Distribution, Triglycerides metabolism, Carbon-Carbon Double Bond Isomerases genetics, Carbon-Carbon Double Bond Isomerases physiology, Fatty Acids metabolism, Mitochondria metabolism, Oxygen metabolism
- Abstract
Cellular energy metabolism is largely sustained by mitochondrial beta-oxidation of saturated and unsaturated fatty acids. To study the role of unsaturated fatty acids in cellular lipid and energy metabolism we generated a null allelic mouse, deficient in 3,2-trans-enoyl-CoA isomerase (ECI) (eci(-/-) mouse). ECI is the link in mitochondrial beta-oxidation of unsaturated and saturated fatty acids and essential for the complete degradation and for maximal energy yield. Mitochondrial beta-oxidation of unsaturated fatty acids is interrupted in eci(-/-)mice at the level of their respective 3-cis- or 3-trans-enoyl-CoA intermediates. Fasting eci(-/-) mice accumulate unsaturated fatty acyl groups in ester lipids and deposit large amounts of triglycerides in hepatocytes (steatosis). Gene expression studies revealed the induction of peroxisome proliferator-activated receptor activation in eci(-/-) mice together with peroxisomal beta- and microsomal omega-oxidation enzymes. Combined peroxisomal beta- and microsomal omega-oxidation of the 3-enoyl-CoA intermediates leads to a specific pattern of medium chain unsaturated dicarboxylic acids excreted in the urine in high concentration (dicarboxylic aciduria). The urinary dicarboxylate pattern is a reliable diagnostic marker of the ECI genetic defect. The eci(-/-) mouse might be a model of a yet undefined inborn mitochondrial beta-oxidation disorder lacking the enzyme link that channels the intermediates of unsaturated fatty acids into the beta-oxidation spiral of saturated fatty acids.
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- 2002
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28. Kinetics of gene expression profiling in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke.
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Bosio A, Knörr C, Janssen U, Gebel S, Haussmann HJ, and Müller T
- Subjects
- 3T3 Cells, Animals, Blotting, Northern, DNA, Complementary, Mice, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Smoke, Nicotiana chemistry
- Abstract
Previous studies from different laboratories have demonstrated that cigarette smoke (CS) harbours a strong oxidative stress potential, which broadly impacts exposed cells. Many of these studies have been devoted to identifying differentially expressed genes in exposed cells. Emerging DNA microarray techniques provide a sophisticated tool to characterize gene expression on a more comprehensive basis. Here, we report on kinetic studies performed to characterize gene expression profiles in Swiss 3T3 cells exposed to aqueous extracts of CS ('smoke-bubbled phosphate-buffered saline') up to 24 h through glass chips containing 513 different cDNA probes. The results obtained display a distinct expression pattern of up regulated and repressed genes, which was most evident after 4-8 h of exposure. The CS-related stress response involves mainly antioxidant response genes coding for, e.g. haem oxygenase-1 (HO-1), metallothionein 1/2 (MT1/2) and heat shock proteins (HSPs); genes coding for transcription factors, e.g. JunB and CAAT/enhancer binding protein (C/EBP); cell cycle-related genes, e.g. gadd34 and gadd45; and notably, genes described as mediators of an inflammatory/immune-regulatory response, e.g. st2, kc and id3. From a kinetic perspective, the stress response is characterized by the synchronized up regulation of antioxidant pathways, e.g. as reflected by the co-ordinated expression of ho-1 and ferritin. This expression pattern is obviously orchestrated by stress-responsive transcription factors, as exemplified by the early and strong expression of junB and c/ebp. Interestingly, among the 10 most up regulated genes are five which are known to counteract stress brought about by peroxynitrite. Altogether, these results demonstrate that CS induces a distinct signature of differential gene expression in exposed cells.
- Published
- 2002
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29. Expression of inter-alpha-trypsin inhibitor and tumor necrosis factor-stimulated gene 6 in renal proximal tubular epithelial cells.
- Author
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Janssen U, Thomas G, Glant T, and Phillips A
- Subjects
- Alpha-Globulins genetics, Cell Adhesion Molecules genetics, Cell Line, Cycloheximide pharmacology, Epithelial Cells metabolism, Epithelial Cells physiology, Fibrinolysin antagonists & inhibitors, Glucose pharmacology, Humans, Interleukin-1 pharmacology, Kidney Tubules, Proximal cytology, Kidney Tubules, Proximal physiology, Membrane Glycoproteins genetics, Peptide Fragments genetics, Protein Synthesis Inhibitors pharmacology, RNA, Messenger metabolism, Alpha-Globulins metabolism, Cell Adhesion Molecules metabolism, Kidney Tubules, Proximal metabolism, Trypsin Inhibitor, Kunitz Soybean
- Abstract
Background: Our previous studies have demonstrated that renal proximal tubular epithelial cells (PTCs) may contribute to renal interstitial fibrosis by the generation of transforming growth factor-beta1 (TGF-beta1). In these in vitro experiments, TGF-beta1 was, however, secreted in its latent form. Plasmin has been implicated as a potential physiological activator of TGF-beta1. The inter-alpha-trypsin inhibitor (IalphaI) family of serum protease inhibitors together with tumor necrosis factor-stimulated gene 6 (TSG-6) recently have been implicated in the regulation of this protease pathway. The aim of the current study was to examine PTC synthesis of these proteins and to relate it to alterations of plasmin-protease activity., Methods: PTCs were grown to confluence and stimulated under serum-free conditions with either interleukin-1beta (IL-1beta) or 25 mmol/L D-glucose. Alterations in IalphaI and TSG-6 generation were detected by Western analysis of both membrane extracts and supernatant samples. Alterations in gene expression were examined by reverse transcription-polymerase chain reaction. The effect of alteration in synthesis of TSG-6 on plasmin activity was determined by quantitating plasmin inhibitory activity of supernatant samples by in vitro calorimetric assay prior to and following TSG-6 immunoprecipitation., Results: The data demonstrate that human PTCs constitutively express mRNA for bikunin and heavy chain 3 (H3) of IalphaI. Neither IL-1beta (1 ng/mL) nor 25 mmol/L D-glucose influenced their mRNA expression nor protein synthesis. In contrast, the addition of either IL-1beta or 25 mmol/L D-glucose increased TSG-6 mRNA expression. This was accompanied by an early up-regulation of TSG-6 protein expression following IL-1beta stimulation (24 h) and a late up-regulation after the addition of 25 mmol/L D-glucose (96 h) in the cell culture supernatant and associated with the cell membranes. Early induction of TSG-6 mRNA by IL-1beta was unaffected by the addition of the protein synthesis inhibitor cycloheximide. In contrast, the later glucose-stimulated induction of TSG-6 mRNA was abrogated by the addition of cycloheximide. Stimulation of TSG-6 by either IL-1beta or 25 mmol/L D-glucose was associated with an inhibition of total percentage plasmin activity. Immunoprecipitation of TSG-6 in these samples returned plasmin activity to control levels., Conclusions: : The data demonstrate that human PTCs constitutively express the bikunin and H3 components of the IalphaI family of serum protease inhibitors. Moreover, the addition of IL-1beta or 25 mmol/L D-glucose up-regulates the expression of TSG-6 in these cells, resulting in an inhibition of plasmin activity.
- Published
- 2001
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30. Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes.
- Author
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Coimbra TM, Janssen U, Gröne HJ, Ostendorf T, Kunter U, Schmidt H, Brabant G, and Floege J
- Subjects
- Aging pathology, Animals, Cell Death, Cell Division, Collagen metabolism, Cytoskeletal Proteins metabolism, Diabetic Nephropathies complications, Diabetic Nephropathies metabolism, Fibronectins metabolism, Immunohistochemistry, In Situ Nick-End Labeling, Intercellular Adhesion Molecule-1 metabolism, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Kidney Glomerulus ultrastructure, Leukocytes pathology, Microscopy, Electron, Obesity complications, Rats, Rats, Zucker, Diabetes Mellitus, Type 2 pathology, Diabetic Nephropathies pathology, Obesity pathology
- Abstract
Unlabelled: Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes., Background: More than half of the new patients admitted to dialysis therapy in some centers are diagnosed with type IIb diabetes, that is, diabetes associated with obesity. This study searched for a common final pathway of renal damage in this progressive renal disease., Methods: The evolution of biochemical and morphological renal changes was examined in 6- to 60-week-old Zucker rats (fa/fa-rats), a model of obesity associated with type II diabetes., Results: fa/fa-rats exhibited pronounced hyperinsulinemia and hyperlipidemia at 6 weeks and became diabetic after 14 weeks of age. Significant focal segmental glomerulosclerosis was first noted in 18-week-old fa/fa-rats and tubulointerstitial damage and proteinuria in 40-week-old fa/fa-rats. A comparison of kidneys of six-week-old fa/fa-and lean control (Fa/?) rats by immunohistology revealed a 1.8-fold increase in glomerular monocyte/macrophage counts in fa/fa-rats and a significant increase in de novo desmin expression in podocytes. Electron microscopy demonstrated an increase in the number of podocyte mitochondria and intracytoplasmic protein and fat droplets. Podocyte desmin scores markedly increased until week 18 in fa/fa-rats, whereas glomerular monocyte/macrophage counts peaked at 3.2-fold at week 14. Podocyte desmin expression, but not glomerular macrophage infiltration, correlated with damage in adjacent tubular cells, as evidenced by their de novo expression of vimentin. Progressive glomerular hypertrophy was detected in fa/fa-rats after 10 weeks. GBM width was significantly increased in 14-week-old fa/fa-rats as compared with lean controls. Mesangial cell activation (de novo expression of alpha-smooth muscle actin) and proliferation was low to absent throughout the observation period in fa/fa-rats. Renal cell death counts (TUNEL) remained unchanged in 6- to 40-week-old fa/fa-rats. Tubulointerstitial myofibroblast formation and matrix accumulation occurred late during the study duration in fa/fa-rats., Conclusion: These data suggest that early progressive podocyte damage and macrophage infiltration is associated with hyperlipidemia and type IIb diabetes mellitus, and antedates both the development of glomerulosclerosis and tubulointerstitial damage.
- Published
- 2000
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31. Novel approach to specific growth factor inhibition in vivo: antagonism of platelet-derived growth factor in glomerulonephritis by aptamers.
- Author
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Floege J, Ostendorf T, Janssen U, Burg M, Radeke HH, Vargeese C, Gill SC, Green LS, and Janjić N
- Subjects
- Animals, Becaplermin, Cell Division drug effects, Cells, Cultured, DNA genetics, Deoxyribonucleases pharmacology, Drug Resistance, Glomerular Mesangium cytology, Humans, Nephritis pathology, Oligonucleotides pharmacokinetics, Platelet-Derived Growth Factor genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-sis, Rats, Rats, Sprague-Dawley, Glomerulonephritis metabolism, Growth Inhibitors pharmacology, Oligonucleotides pharmacology, Platelet-Derived Growth Factor antagonists & inhibitors
- Abstract
Mesangial cell proliferation and matrix accumulation, driven by platelet-derived growth factor (PDGF), contribute to many progressive renal diseases. In a novel approach to antagonize PDGF, we investigated the effects of a nuclease-resistant high-affinity oligonucleotide aptamer in vitro and in vivo. In cultured mesangial cells, the aptamer markedly suppressed PDGF-BB but not epidermal- or fibroblast-growth-factor-2-induced proliferation. In vivo effects of the aptamer were evaluated in a rat mesangioproliferative glomerulonephritis model. Twice-daily intravenous (i.v.) injections from days 3 to 8 after disease induction of 2.2 mg/kg PDGF-B aptamer, coupled to 40-kd polyethylene glycol (PEG), led to 1) a reduction of glomerular mitoses by 64% on day 6 and by 78% on day 9, 2) a reduction of proliferating mesangial cells by 95% on day 9, 3) markedly reduced glomerular expression of endogenous PDGF B-chain, 4) reduced glomerular monocyte/macrophage influx on day 6 after disease induction, and 5) a marked reduction of glomerular extracellular matrix overproduction (as assessed by analysis of fibronectin and type IV collagen) both on the protein and mRNA level. The administration of equivalent amounts of a PEG-coupled aptamer with a scrambled sequence or PEG alone had no beneficial effect on the natural course of the disease. These data show that specific inhibition of growth factors using custom-designed, high-affinity aptamers is feasible and effective.
- Published
- 1999
- Full Text
- View/download PDF
32. Human mitochondrial enoyl-CoA hydratase gene (ECHS1): structural organization and assignment to chromosome 10q26.2-q26.3.
- Author
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Janssen U, Davis EM, Le Beau MM, and Stoffel W
- Subjects
- Animals, Base Sequence, Chromosome Mapping, Cloning, Molecular, Humans, Mitochondria enzymology, Molecular Sequence Data, Rats, Sequence Analysis, Chromosomes, Human, Pair 10, Enoyl-CoA Hydratase genetics
- Abstract
The second step in mitochondrial fatty acid beta-oxidation is catalyzed by short chain enoyl-CoA hydratase (ECHS1; EC 4.2.1.17). Inherited disorders of this pathway of energy metabolism present clinical and laboratory features resembling sudden infant death syndrome and Reye-like syndrome. To investigate the role of ECHS1 further, the gene structure was analyzed and its chromosomal locus determined. A fragment of rat liver ECHS1 cDNA was employed for isolation and characterization of two overlapping genomic clones encompassing the entire human ECHS1 gene. The gene, approximately 11 kb, is composed of eight exons, with exons I and VIII containing the 5'- and 3'-untranslated regions, respectively. Two major transcription start sites, located 62 and 63 bp upstream of the translation initiation codon, were mapped by primer extension analysis. The immediate 5'-flanking region of the ECHS1 gene is GC-rich and contains several copies of the SP1 binding motive but no typical TATA or CAAT boxes are apparent. Alu repeat elements have been identified within the region -1052/-770 relative to the cap site and in intron 7. The human ECHS1 gene locus was assigned to chromosome 10q26.2-q26.3 by fluorescence in situ hybridization.
- Published
- 1997
- Full Text
- View/download PDF
33. Enoyl-CoA hydratase and isomerase form a superfamily with a common active-site glutamate residue.
- Author
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Müller-Newen G, Janssen U, and Stoffel W
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Dodecenoyl-CoA Isomerase, Enoyl-CoA Hydratase chemistry, Enoyl-CoA Hydratase isolation & purification, Escherichia coli genetics, Isomerases chemistry, Isomerases isolation & purification, Molecular Sequence Data, Rats, Recombinant Proteins metabolism, Structure-Activity Relationship, Carbon-Carbon Double Bond Isomerases, Enoyl-CoA Hydratase metabolism, Glutamic Acid metabolism, Isomerases metabolism
- Abstract
Mitochondrial 2-enoyl-CoA hydratase (mECH) and 3,2-trans-enoyl-CoA isomerase (mECI), two enzymes which catalyze totally different reactions in fatty acid beta-oxidation, belong to the low-similarity hydratase/isomerase enzyme superfamily. Their substrates and reaction mechanisms are similar [Müller-Newen, G. & Stoffel, W. (1993) Biochemistry 32, 11,405-11,412]. Glu164 of mECH is the only amino acid with a protic side chain that is conserved in these monofunctional and polyfunctional enzymes with 2-enoyl-CoA hydratase and 3,2-trans-enoyl-CoA isomerase activities. We tested our hypothesis that Glu164 of mECH is the putative active-site amino acid responsible for the base-catalyzed alpha-deprotonation in the hydratase/dehydrase and isomerase reaction. We functionally expressed rat liver mECH wild-type and [E164Q] mutant enzymes in Escherichia coli. Characterization of the purified wild-type and mutant enzymes revealed that the replacement of Glu164 by Gln lowers the kcat value more than 100,000-fold, whereas the Km value is only moderately affected. We have demonstrated in a previous study that Glu165 is indispensable for the 3,2-trans-enoyl-CoA isomerase activity. Taking these results together, we conclude that the conserved glutamic acid is the essential basic group in the active sites of 2-enoyl-CoA hydratase (Glu164) and 3,2-trans-enoyl-CoA isomerase (Glu165), and that these enzymes are not only evolutionarily but also functionally and mechanistically related.
- Published
- 1995
- Full Text
- View/download PDF
34. Human mitochondrial 3,2-trans-enoyl-CoA isomerase (DCI): gene structure and localization to chromosome 16p13.3.
- Author
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Janssen U, Fink T, Lichter P, and Stoffel W
- Subjects
- Animals, Base Sequence, Chromosome Mapping, Cricetinae, Dodecenoyl-CoA Isomerase, Exons, Genes, Humans, Hybrid Cells, Introns, Molecular Sequence Data, Carbon-Carbon Double Bond Isomerases, Chromosomes, Human, Pair 16, Isomerases genetics, Mitochondria enzymology
- Abstract
A key enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids is the 3,2-trans-enoyl-CoA isomerase (DCI; EC 5.3.3.8). It catalyzes the transformation of 3-cis and 3-trans intermediates arising during the stepwise degradation of all cis-, mono-, and polyunsaturated fatty acids to the 2-trans-enoyl-CoA intermediates. A genomic clone encoding the human DCI was isolated and characterized by use of the previously cloned human DCI cDNA. The entire gene encompasses approximately 12.5 kb, and the coding sequence is distributed over seven exons. One major and three minor transcription start sites were determined by primer extension analysis. In common with promoters of other housekeeping genes encoding mitochondrial proteins, the GC-rich, immediate 5'-flanking region of the DCI transcription initiation site lacks typical TATA and CAAT boxes; instead, two GC box consensus sequences are present. Introns 2 and 6 contain several Alu repetetive sequences. The human DCI gene locus was assigned to chromosome 16 by use of human-rodent somatic cell hybrids and to chromosome 16p13.3 by chromosomal in situ suppression hybridization studies.
- Published
- 1994
- Full Text
- View/download PDF
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