TY  - JOUR
A1  - Couch, Fergus J.
A1  - Wang, Xianshu
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Olswold, Curtis
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Fredericksen, Zachary
A1  - Barrowdale, Daniel
A1  - Dennis, Joe
A1  - Gaudet, Mia M.
A1  - Dicks, Ed
A1  - Kosel, Matthew
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Lee, Adam
A1  - Bacot, Françios
A1  - Vincent, Daniel
A1  - Hogervorst, Frans B. L.
A1  - Peock, Susan
A1  - Stoppa-Lyonnet, Dominique
A1  - Jakubowska, Anna
A1  - Radice, Paolo
A1  - Schmutzler, Rita Katharina
A1  - Domchek, Susan M.
A1  - Piedmonte, Marion
A1  - Singer, Christian F.
A1  - Friedman, Eitan
A1  - Thomassen, Mads
A1  - Hansen, Thomas V. O.
A1  - Neuhausen, Susan L.
A1  - Szabo, Csilla I.
A1  - Blanco, Ingnacio
A1  - Greene, Mark H.
A1  - Karlan, Beth Y.
A1  - Garber, Judy
A1  - Phelan, Catherine M.
A1  - Weitzel, Jeffrey N.
A1  - Montagna, Marco
A1  - Olah, Edith
A1  - Andrulis, Irene L.
A1  - Godwin, Andrew K.
A1  - Yannoukakos, Drakoulis
A1  - Goldgar, David E.
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Osorio, Ana
A1  - Terry, Mary Beth
A1  - Daly, Mary B.
A1  - van Rensburg, Elisabeth J.
A1  - Hamann, Ute
A1  - Ramus, Susan J.
A1  - Toland, Amanda Ewart
A1  - Caligo, Maria A.
A1  - Olopade, Olufunmilayo I.
A1  - Tung, Nadine
A1  - Claes, Kathleen
A1  - Beattie, Mary S.
A1  - Southey, Melissa C.
A1  - Imyanitov, Evgeny N.
A1  - Tischkowitz, Marc
A1  - Janavicius, Ramunas
A1  - John, Esther M.
A1  - Kwong, Ava
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Balmaña, Judith
A1  - Barkardottir, Rosa B.
A1  - Arun, Banu K.
A1  - Rennert, Gad
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Campbell, Ian
A1  - van der Hout, Annemarie H.
A1  - van Deurzen, Carolien H. M.
A1  - Seynaeve, Caroline
A1  - Garcia, Encarna B. Gómez
A1  - van Leeuwen, Flora E.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Gille, Johannes J. P.
A1  - Ausems, Magreet G. E. M.
A1  - Blok, Marinus J.
A1  - Ligtenberg, Marjolinjin J. L.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - Verhoef, Senno
A1  - van Os, Theo A. M.
A1  - Wijnen, Juul T.
A1  - Frost, Debra
A1  - Ellis, Steve
A1  - Fineberg, Elena
A1  - Platte, Radke
A1  - Evans, D. Gareth
A1  - Izatt, Luise
A1  - Eeles, Rosalind A.
A1  - Adlard, Julian
A1  - Eccles, Diana M.
A1  - Cook, Jackie
A1  - Brewer, Carole
A1  - Douglas, Fiona
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Side, Lucy E.
A1  - Donaldson, Alan
A1  - Houghton, Catherine
A1  - Rogers, Mark T.
A1  - Dorkins, Huw
A1  - Eason, Jacqueline
A1  - Gregory, Helen
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Calender, Alain
A1  - Hardouin, Agnès
A1  - Berthet, Pascaline
A1  - Delnatte, Capucine
A1  - Nogues, Catherine
A1  - Lasset, Christine
A1  - Houdayer, Claude
A1  - Leroux,, Dominique
A1  - Rouleau, Etienne
A1  - Prieur, Fabienne
A1  - Damiola, Francesca
A1  - Sobol, Hagay
A1  - Coupier, Isabelle
A1  - Venat-Bouvet, Laurence
A1  - Castera, Laurent
A1  - Gauthier-Villars, Marion
A1  - Léoné, Mélanie
A1  - Pujol, Pascal
A1  - Mazoyer, Sylvie
A1  - Bignon, Yves-Jean
A1  - Zlowocka-Perlowska, Elzbieta
A1  - Gronwald, Jacek
A1  - Lubinski,, Jan
A1  - Durda, Katarzyna
A1  - Jaworska, Katarzyna
A1  - Huzarski, Tomasz
A1  - Spurdle, Amanda B.
A1  - Viel, Alessandra
A1  - Peissel, Bernhard
A1  - Bonanni, Bernardo
A1  - Melloni, Guilia
A1  - Ottini, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Tibiletti, Maria Grazia
A1  - Peterlongo, Paolo
A1  - Volorio, Sara
A1  - Manoukian, Siranoush
A1  - Pensotti, Valeria
A1  - Arnold, Norbert
A1  - Engel, Christoph
A1  - Deissler, Helmut
A1  - Gadzicki, Dorothea
A1  - Gehrig, Andrea
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Ditsch, Nina
A1  - Plendl, Hansjoerg
A1  - Preisler-Adams, Sabine
A1  - Engert, Stefanie
A1  - Sutter, Christian
A1  - Varon-Mateeva, Raymenda
A1  - Wappenschmidt, Barbara
A1  - Weber, Bernhard H. F.
A1  - Arver, Brita
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Einbeigi, Zakaria
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Blank, Stephanie V.
A1  - Cohn, David E.
A1  - Rodriguez, Gustavo C.
A1  - Small, Laurie
A1  - Friedlander, Michael
A1  - Bae-Jump, Victoria L.
A1  - Fink-Retter, Anneliese
A1  - Rappaport, Christine
A1  - Gschwantler-Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Lindor, Noralane M.
A1  - Kaufman, Bella
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Skytte, Anne-Bine
A1  - Gerdes, Anne-Marie
A1  - Pedersen, Inge Sokilde
A1  - Moeller, Sanne Traasdahl
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Vijai, Joseph
A1  - Sarrel, Kara
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Ozcelik, Hilmi
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Jønson, Lars
A1  - Andersen, Mette K.
A1  - Ding, Yuan Chun
A1  - Steele, Linda
A1  - Foretova, Lenka
A1  - Teulé, Alex
A1  - Lazaro, Conxi
A1  - Brunet, Joan
A1  - Pujana, Miquel Angel
A1  - Mai, Phuong L.
A1  - Loud, Jennifer T.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Narod, Steven A.
A1  - Herzog, Josef
A1  - Sand, Sharon R.
A1  - Tognazzo, Silvia
A1  - Agata, Simona
A1  - Vaszko, Tibor
A1  - Weaver, Joellen
A1  - Stravropoulou, Alexandra V.
A1  - Buys, Saundra S.
A1  - Romero, Atocha
A1  - de la Hoya, Miguel
A1  - Aittomäki, Kristiina
A1  - Muranen, Taru A.
A1  - Duran, Mercedes
A1  - Chung, Wendy K.
A1  - Lasa, Adriana
A1  - Dorfling, Cecilia M.
A1  - Miron, Alexander
A1  - Benitez, Javier
A1  - Senter, Leigha
A1  - Huo, Dezheng
A1  - Chan, Salina B.
A1  - Sokolenko, Anna P.
A1  - Chiquette, Jocelyne
A1  - Tihomirova, Laima
A1  - Friebel, Tara M.
A1  - Agnarsson, Bjarne A.
A1  - Lu, Karen H.
A1  - Lejbkowicz, Flavio
A1  - James, Paul A.
A1  - Hall, Per
A1  - Dunning, Alison M.
A1  - Tessier, Daniel
A1  - Cunningham, Julie
A1  - Slager, Susan L.
A1  - Chen, Wang
A1  - Hart, Steven
A1  - Stevens, Kristen
A1  - Simard, Jacques
A1  - Pastinen, Tomi
A1  - Pankratz, Vernon S.
A1  - Offit, Kenneth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
JF  - PLOS Genetics
N2  - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
KW  - common variants
KW  - susceptibility alleles
KW  - genetic variants
KW  - modifiers
KW  - ZNF365
KW  - investigators
KW  - population
KW  - consortium
KW  - selection
KW  - subtypes
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947
SN  - 1553-7404
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Dörk, Thilo
A1  - Peterlongo, Peter
A1  - Mannermaa, Arto
A1  - Bolla, Manjeet K.
A1  - Wang, Qin
A1  - Dennis, Joe
A1  - Ahearn, Thomas
A1  - Andrulis, Irene L.
A1  - Anton-Culver, Hoda
A1  - Arndt, Volker
A1  - Aronson, Kristan J.
A1  - Augustinsson, Annelie
A1  - Beane Freeman, Laura E.
A1  - Beckmann, Matthias W.
A1  - Beeghly-Fadiel, Alicia
A1  - Behrens, Sabine
A1  - Bermisheva, Marina
A1  - Blomqvist, Carl
A1  - Bogdanova, Natalia V.
A1  - Bojesen, Stig E.
A1  - Brauch, Hiltrud
A1  - Brenner, Hermann
A1  - Burwinkel, Barbara
A1  - Canzian, Federico
A1  - Chan, Tsun L.
A1  - Chang-Claude, Jenny
A1  - Chanock, Stephen J.
A1  - Choi, Ji-Yeob
A1  - Christiansen, Hans
A1  - Clarke, Christine L.
A1  - Couch, Fergus J.
A1  - Czene, Kamila
A1  - Daly, Mary B.
A1  - dos-Santos-Silva, Isabel
A1  - Dwek, Miriam
A1  - Eccles, Diana M.
A1  - Ekici, Arif B.
A1  - Eriksson, Mikael
A1  - Evans, D. Gareth
A1  - Fasching, Peter A.
A1  - Figueroa, Jonine
A1  - Flyger, Henrik
A1  - Fritschi, Lin
A1  - Gabrielson, Marike
A1  - Gago-Dominguez, Manuela
A1  - Gao, Chi
A1  - Gapstur, Susan M.
A1  - García-Closas, Montserrat
A1  - García-Sáenz, José A.
A1  - Gaudet, Mia M.
A1  - Giles, Graham G.
A1  - Goldberg, Mark S.
A1  - Goldgar, David E.
A1  - Guenél, Pascal
A1  - Haeberle, Lothar
A1  - Haimann, Christopher A.
A1  - Håkansson, Niclas
A1  - Hall, Per
A1  - Hamann, Ute
A1  - Hartman, Mikael
A1  - Hauke, Jan
A1  - Hein, Alexander
A1  - Hillemanns, Peter
A1  - Hogervorst, Frans B. L.
A1  - Hooning, Maartje J.
A1  - Hopper, John L.
A1  - Howell, Tony
A1  - Huo, Dezheng
A1  - Ito, Hidemi
A1  - Iwasaki, Motoki
A1  - Jakubowska, Anna
A1  - Janni, Wolfgang
A1  - John, Esther M.
A1  - Jung, Audrey
A1  - Kaaks, Rudolf
A1  - Kang, Daehee
A1  - Kapoor, Pooja Middha
A1  - Khusnutdinova, Elza
A1  - Kim, Sung-Won
A1  - Kitahara, Cari M.
A1  - Koutros, Stella
A1  - Kraft, Peter
A1  - Kristensen, Vessela N.
A1  - Kwong, Ava
A1  - Lambrechts, Diether
A1  - Le Marchand, Loic
A1  - Li, Jingmei
A1  - Lindström, Sara
A1  - Linet, Martha
A1  - Lo, Wing-Yee
A1  - Long, Jirong
A1  - Lophatananon, Artitaya
A1  - Lubiński, Jan
A1  - Manoochehri, Mehdi
A1  - Manoukian, Siranoush
A1  - Margolin, Sara
A1  - Martinez, Elena
A1  - Matsuo, Keitaro
A1  - Mavroudis, Dimitris
A1  - Meindl, Alfons
A1  - Menon, Usha
A1  - Milne, Roger L.
A1  - Mohd Taib, Nur Aishah
A1  - Muir, Kenneth
A1  - Mulligan, Anna Marie
A1  - Neuhausen, Susan L.
A1  - Nevanlinna, Heli
A1  - Neven, Patrick
A1  - Newman, William G.
A1  - Offit, Kenneth
A1  - Olopade, Olufunmilayo I.
A1  - Olshan, Andrew F.
A1  - Olson, Janet E.
A1  - Olsson, Håkan
A1  - Park, Sue K.
A1  - Park-Simon, Tjoung-Won
A1  - Peto, Julian
A1  - Plaseska-Karanfilska, Dijana
A1  - Pohl-Rescigno, Esther
A1  - Presneau, Nadege
A1  - Rack, Brigitte
A1  - Radice, Paolo
A1  - Rashid, Muhammad U.
A1  - Rennert, Gad
A1  - Rennert, Hedy S.
A1  - Romero, Atocha
A1  - Ruebner, Matthias
A1  - Saloustros, Emmanouil
A1  - Schmidt, Marjanka K.
A1  - Schmutzler, Rita K.
A1  - Schneider, Michael O.
A1  - Schoemaker, Minouk J.
A1  - Scott, Christopher
A1  - Shen, Chen-Yang
A1  - Shu, Xiao-Ou
A1  - Simard, Jaques
A1  - Slager, Susan
A1  - Smichkoska, Snezhana
A1  - Southey, Melissa C.
A1  - Spinelli, John J.
A1  - Stone, Jennifer
A1  - Surowy, Harald
A1  - Swerdlow, Anthony J.
A1  - Tamimi, Rulla M.
A1  - Tapper, William J.
A1  - Teo, Soo H.
A1  - Terry, Mary Beth
A1  - Toland, Amanda E.
A1  - Tollenaar, Rob A. E. M.
A1  - Torres, Diana
A1  - Torres-Mejía, Gabriela
A1  - Troester, Melissa A.
A1  - Truong, Thérèse
A1  - Tsugane, Shoichiro
A1  - Untch, Michael
A1  - Vachon, Celine M.
A1  - van den Ouweland, Ans M. W.
A1  - van Veen, Elke M.
A1  - Vijai, Joseph
A1  - Wendt, Camilla
A1  - Wolk, Alicja
A1  - Yu, Jyh-Cherng
A1  - Zheng, Wei
A1  - Ziogas, Argyrios
A1  - Ziv, Elad
A1  - Dunnig, Alison
A1  - Pharaoh, Paul D. P.
A1  - Schindler, Detlev
A1  - Devilee, Peter
A1  - Easton, Douglas F.
T1  - Two truncating variants in FANCC and breast cancer risk
JF  - Scientific Reports
N2  - Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
KW  - oncology
KW  - risk factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222838
VL  - 9
ER  - 
TY  - JOUR
A1  - Antoniou, Antonis C.
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Beesley, Jonathan
A1  - Chen, Xiaoqing
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Barrowdale, Daniel
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Caligo, Maria A.
A1  - Loman, Niklas
A1  - Harbst, Katja
A1  - Lindblom, Annika
A1  - Arver, Brita
A1  - Rosenquist, Richard
A1  - Karlsson, Per
A1  - Nathanson, Kate
A1  - Domchek, Susan
A1  - Rebbeck, Tim
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Jaworska, Katarzyna
A1  - Durda, Katarzyna
A1  - Zlowowcka-Perłowska, Elżbieta
A1  - Osorio, Ana
A1  - Durán, Mercedes
A1  - Andrés, Raquel
A1  - Benítez, Javier
A1  - Hamann, Ute
A1  - Hogervorst, Frans B.
A1  - van Os, Theo A.
A1  - Verhoef, Senno
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Wijnen, Juul
A1  - Garcia, Encarna B. Gómez
A1  - Ligtenberg, Marjolijn J.
A1  - Kriege, Mieke
A1  - Collée, Margriet
A1  - Ausems, Margreet G. E. M.
A1  - Oosterwijk, Jan C.
A1  - Peock, Susan
A1  - Frost, Debra
A1  - Ellis, Steve D.
A1  - Platte, Radka
A1  - Fineberg, Elena
A1  - Evans, D. Gareth
A1  - Lalloo, Fiona
A1  - Jacobs, Chris
A1  - Eeles, Ros
A1  - Adlard, Julian
A1  - Davidson, Rosemarie
A1  - Cole, Trevor
A1  - Cook, Jackie
A1  - Paterson, Joan
A1  - Douglas, Fiona
A1  - Brewer, Carole
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Walker, Lisa
A1  - Rogers, Mark T.
A1  - Donaldson, Alan
A1  - Dorkins, Huw
A1  - Godwin, Andrew K.
A1  - Bove, Betsy
A1  - Stoppa-Lyonnet, Dominique
A1  - Houdayer, Claude
A1  - Buecher, Bruno
A1  - de Pauw, Antoine
A1  - Mazoyer, Sylvie
A1  - Calender, Alain
A1  - Léoné, Mélanie
A1  - Bressac-de Paillerets, Brigitte
A1  - Caron, Olivier
A1  - Sobol, Hagay
A1  - Frenay, Marc
A1  - Prieur, Fabienne
A1  - Ferrer, Sandra Fert
A1  - Mortemousque, Isabelle
A1  - Buys, Saundra
A1  - Daly, Mary
A1  - Miron, Alexander
A1  - Terry, Mary Beth
A1  - Hopper, John L.
A1  - John, Esther M.
A1  - Southey, Melissa
A1  - Goldgar, David
A1  - Singer, Christian F.
A1  - Fink-Retter, Anneliese
A1  - Muy-Kheng, Tea
A1  - Geschwantler Kaulich, Daphne
A1  - Hansen, Thomas V. O.
A1  - Nielsen, Finn C.
A1  - Barkardottir, Rosa B.
A1  - Gaudet, Mia
A1  - Kirchhoff, Tomas
A1  - Joseph, Vijai
A1  - Dutra-Clarke, Ana
A1  - Offit, Kenneth
A1  - Piedmonte, Marion
A1  - Kirk, Judy
A1  - Cohn, David
A1  - Hurteau, Jean
A1  - Byron, John
A1  - Fiorica, James
A1  - Toland, Amanda E.
A1  - Montagna, Marco
A1  - Oliani, Cristina
A1  - Imyanitov, Evgeny
A1  - Isaacs, Claudine
A1  - Tihomirova, Laima
A1  - Blanco, Ignacio
A1  - Lazaro, Conxi
A1  - Teulé, Alex
A1  - Del Valle, J.
A1  - Gayther, Simon A.
A1  - Odunsi, Kunle
A1  - Gross, Jenny
A1  - Karlan, Beth Y.
A1  - Olah, Edith
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Beattie, Mary S.
A1  - Dorfling, Cecelia M.
A1  - Jansen van Rensburg, Elizabeth
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Schmutzler, Rita K.
A1  - Wappenschmidt, Barbara
A1  - Engel, Christoph
A1  - Meindl, Alfons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Heidemann, Simone
A1  - Niederacher, Dieter
A1  - Preisler-Adams, Sabine
A1  - Gadzicki, Dorothea
A1  - Varon-Mateeva, Raymonda
A1  - Deissler, Helmut
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Kast, Karin
A1  - Fiebig, Britta
A1  - Schäfer, Dieter
A1  - Caldes, Trinidad
A1  - de la Hoya, Miguel
A1  - Nevanlinna, Heli
A1  - Muranen, Taru A.
A1  - Lespérance, Bernard
A1  - Spurdle, Amanda B.
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan C.
A1  - Wang, Xianshu
A1  - Fredericksen, Zachary
A1  - Pankratz, Vernon S.
A1  - Lindor, Noralane M.
A1  - Peterlongo, Paulo
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Bonanni, Bernardo
A1  - Bernard, Loris
A1  - Dolcetti, Riccardo
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Radice, Paolo
A1  - Greene, Mark H.
A1  - Loud, Jennifer T.
A1  - Andrulis, Irene L.
A1  - Ozcelik, Hilmi
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Thomassen, Mads
A1  - Gerdes, Anne-Marie
A1  - Jensen, Uffe B.
A1  - Skytte, Anne-Bine
A1  - Kruse, Torben A.
A1  - Chenevix-Trench, Georgia
A1  - Couch, Fergus J.
A1  - Simard, Jacques
A1  - Easton, Douglas F.
T1  - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
JF  - Breast Cancer Research
N2  - Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). 
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. 
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). 
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
KW  - investigators
KW  - genetic modifiers
KW  - mammographic density
KW  - susceptibility loci
KW  - ovarian cancer
KW  - hormone-related protein
KW  - genome-wide association
KW  - tumor subtypes
KW  - alleles
KW  - consortium
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130449
VL  - 14
IS  - R33
ER  - 
TY  - JOUR
A1  - Dumont, Martine
A1  - Weber-Lassalle, Nana
A1  - Joly-Beauparlant, Charles
A1  - Ernst, Corinna
A1  - Droit, Arnaud
A1  - Feng, Bing-Jian
A1  - Dubois, Stéphane
A1  - Collin-Deschesnes, Annie-Claude
A1  - Soucy, Penny
A1  - Vallée, Maxime
A1  - Fournier, Frédéric
A1  - Lemaçon, Audrey
A1  - Adank, Muriel A.
A1  - Allen, Jamie
A1  - Altmüller, Janine
A1  - Arnold, Norbert
A1  - Ausems, Margreet G. E. M.
A1  - Berutti, Riccardo
A1  - Bolla, Manjeet K.
A1  - Bull, Shelley
A1  - Carvalho, Sara
A1  - Cornelissen, Sten
A1  - Dufault, Michael R.
A1  - Dunning, Alison M.
A1  - Engel, Christoph
A1  - Gehrig, Andrea
A1  - Geurts-Giele, Willemina R. R.
A1  - Gieger, Christian
A1  - Green, Jessica
A1  - Hackmann, Karl
A1  - Helmy, Mohamed
A1  - Hentschel, Julia
A1  - Hogervorst, Frans B. L.
A1  - Hollestelle, Antoinette
A1  - Hooning, Maartje J.
A1  - Horváth, Judit
A1  - Ikram, M. Arfan
A1  - Kaulfuß, Silke
A1  - Keeman, Renske
A1  - Kuang, Da
A1  - Luccarini, Craig
A1  - Maier, Wolfgang
A1  - Martens, John W. M.
A1  - Niederacher, Dieter
A1  - Nürnberg, Peter
A1  - Ott, Claus-Eric
A1  - Peters, Annette
A1  - Pharoah, Paul D. P.
A1  - Ramirez, Alfredo
A1  - Ramser, Juliane
A1  - Riedel-Heller, Steffi
A1  - Schmidt, Gunnar
A1  - Shah, Mitul
A1  - Scherer, Martin
A1  - Stäbler, Antje
A1  - Strom, Tim M.
A1  - Sutter, Christian
A1  - Thiele, Holger
A1  - van Asperen, Christi J.
A1  - van der Kolk, Lizet
A1  - van der Luijt, Rob B.
A1  - Volk, Alexander E.
A1  - Wagner, Michael
A1  - Waisfisz, Quinten
A1  - Wang, Qin
A1  - Wang-Gohrke, Shan
A1  - Weber, Bernhard H. F.
A1  - Devilee, Peter
A1  - Tavtigian, Sean
A1  - Bader, Gary D.
A1  - Meindl, Alfons
A1  - Goldgar, David E.
A1  - Andrulis, Irene L.
A1  - Schmutzler, Rita K.
A1  - Easton, Douglas F.
A1  - Schmidt, Marjanka K.
A1  - Hahnen, Eric
A1  - Simard, Jacques
T1  - Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry
JF  - Cancers
N2  - Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
KW  - breast cancer
KW  - genetic susceptibility
KW  - whole-exome sequencing
KW  - moderate-penetrance genes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Farmer, Adam D.
A1  - Strzelczyk, Adam
A1  - Finisguerra, Alessandra
A1  - Gourine, Alexander V.
A1  - Gharabaghi, Alireza
A1  - Hasan, Alkomiet
A1  - Burger, Andreas M.
A1  - Jaramillo, Andrés M.
A1  - Mertens, Ann
A1  - Majid, Arshad
A1  - Verkuil, Bart
A1  - Badran, Bashar W.
A1  - Ventura-Bort, Carlos
A1  - Gaul, Charly
A1  - Beste, Christian
A1  - Warren, Christopher M.
A1  - Quintana, Daniel S.
A1  - Hämmerer, Dorothea
A1  - Freri, Elena
A1  - Frangos, Eleni
A1  - Tobaldini, Eleonora
A1  - Kaniusas, Eugenijus
A1  - Rosenow, Felix
A1  - Capone, Fioravante
A1  - Panetsos, Fivos
A1  - Ackland, Gareth L.
A1  - Kaithwas, Gaurav
A1  - O'Leary, Georgia H.
A1  - Genheimer, Hannah
A1  - Jacobs, Heidi I. L.
A1  - Van Diest, Ilse
A1  - Schoenen, Jean
A1  - Redgrave, Jessica
A1  - Fang, Jiliang
A1  - Deuchars, Jim
A1  - Széles, Jozsef C.
A1  - Thayer, Julian F.
A1  - More, Kaushik
A1  - Vonck, Kristl
A1  - Steenbergen, Laura
A1  - Vianna, Lauro C.
A1  - McTeague, Lisa M.
A1  - Ludwig, Mareike
A1  - Veldhuizen, Maria G.
A1  - De Couck, Marijke
A1  - Casazza, Marina
A1  - Keute, Marius
A1  - Bikson, Marom
A1  - Andreatta, Marta
A1  - D'Agostini, Martina
A1  - Weymar, Mathias
A1  - Betts, Matthew
A1  - Prigge, Matthias
A1  - Kaess, Michael
A1  - Roden, Michael
A1  - Thai, Michelle
A1  - Schuster, Nathaniel M.
A1  - Montano, Nicola
A1  - Hansen, Niels
A1  - Kroemer, Nils B.
A1  - Rong, Peijing
A1  - Fischer, Rico
A1  - Howland, Robert H.
A1  - Sclocco, Roberta
A1  - Sellaro, Roberta
A1  - Garcia, Ronald G.
A1  - Bauer, Sebastian
A1  - Gancheva, Sofiya
A1  - Stavrakis, Stavros
A1  - Kampusch, Stefan
A1  - Deuchars, Susan A.
A1  - Wehner, Sven
A1  - Laborde, Sylvain
A1  - Usichenko, Taras
A1  - Polak, Thomas
A1  - Zaehle, Tino
A1  - Borges, Uirassu
A1  - Teckentrup, Vanessa
A1  - Jandackova, Vera K.
A1  - Napadow, Vitaly
A1  - Koenig, Julian
T1  - International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)
JF  - Frontiers in Human Neuroscience
N2  - Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
KW  - transcutaneous vagus nerve stimulation
KW  - minimum reporting standards
KW  - guidelines & recommendations
KW  - transcutaneous auricular vagus nerve stimulation
KW  - transcutaneous cervical vagus nerve stimulation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234346
SN  - 1662-5161
VL  - 14
ER  - 
TY  - JOUR
A1  - Ludwig, K. U.
A1  - Sämann, P.
A1  - Alexander, M.
A1  - Becker, J.
A1  - Bruder, J.
A1  - Moll, K.
A1  - Spieler, D.
A1  - Czisch, M.
A1  - Warnke, A.
A1  - Docherty, S. J.
A1  - Davis, O. S. P.
A1  - Plomin, R.
A1  - Nöthen, M. M.
A1  - Landerl, K.
A1  - Müller-Myhsok, B.
A1  - Hoffmann, P.
A1  - Schumacher, J.
A1  - Schulte-Körne, G.
A1  - Czamara, D.
T1  - A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults
JF  - Translational Psychiatry
N2  - The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities\((P_{comb}=7.71 x 10^{-10}, n=699)\), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.
KW  - disability
KW  - sulcal morphology
KW  - prelevance
KW  - identification
KW  - brain
KW  - cancer
KW  - association
KW  - developmental dyscalculia
KW  - tumor-suppressor gene
KW  - correlate
KW  - disorders
KW  - dyscalculia
KW  - dyslexia
KW  - genomic imaging
KW  - mathematics
KW  - quantitative trait
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131513
N1  - Supplementary Information accompanies the paper on the Translational Psychiatry website (http://www.nature.com/tp).
VL  - 3
IS  - e229
ER  - 
TY  - JOUR
A1  - Sadovnick, A. Dessa
A1  - Traboulsee, Anthony L.
A1  - Bernales, Cecily Q.
A1  - Ross, Jay P.
A1  - Forwell, Amanda L.
A1  - Yee, Irene M.
A1  - Guillot-Noel, Lena
A1  - Fontaine, Bertrand
A1  - Cournu-Rebeix, Isabelle
A1  - Alcina, Antonio
A1  - Fedetz, Maria
A1  - Izquierdo, Guillermo
A1  - Matesanz, Fuencisla
A1  - Hilven, Kelly
A1  - Dubois, Bénédicte
A1  - Goris, An
A1  - Astobiza, Ianire
A1  - Alloza, Iraide
A1  - Antigüedad, Alfredo
A1  - Vandenbroeck, Koen
A1  - Akkad, Denis A.
A1  - Aktas, Orhan
A1  - Blaschke, Paul
A1  - Buttmann, Mathias
A1  - Chan, Andrew
A1  - Epplen, Joerg T.
A1  - Gerdes, Lisa-Ann
A1  - Kroner, Antje
A1  - Kubisch, Christian
A1  - Kümpfel, Tania
A1  - Lohse, Peter
A1  - Rieckmann, Peter
A1  - Zettl, Uwe K.
A1  - Zipp, Frauke
A1  - Bertram, Lars
A1  - Lill, Christina M.
A1  - Fernandez, Oscar
A1  - Urbaneja, Patricia
A1  - Leyva, Laura
A1  - Alvarez-Cermeño, Jose Carlos
A1  - Arroyo, Rafael
A1  - Garagorri, Aroa M.
A1  - García-Martínez, Angel
A1  - Villar, Luisa M.
A1  - Urcelay, Elena
A1  - Malhotra, Sunny
A1  - Montalban, Xavier
A1  - Comabella, Manuel
A1  - Berger, Thomas
A1  - Fazekas, Franz
A1  - Reindl, Markus
A1  - Schmied, Mascha C.
A1  - Zimprich, Alexander
A1  - Vilariño-Güell, Carles
T1  - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
JF  - G3: Genes Genomes Genetics
N2  - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
KW  - multiple sclerosis
KW  - genetics
KW  - linkage
KW  - association
KW  - plasminogen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405
VL  - 6
IS  - 7
ER  - 
TY  - JOUR
A1  - Bielaszewska, Martina
A1  - Schiller, Roswitha
A1  - Lammers, Lydia
A1  - Bauwens, Andreas
A1  - Fruth, Angelika
A1  - Middendorf, Barbara
A1  - Schmidt, M. Alexander
A1  - Tarr, Phillip I.
A1  - Dobrindt, Ulrich
A1  - Karch, Helge
A1  - Mellmann, Alexander
T1  - Heteropathogenic virulence and phylogeny reveal phased pathogenic metamorphosis in Escherichia coli O2:H6
JF  - EMBO Molecular Medicine
N2  - Extraintestinal pathogenic and intestinal pathogenic (diarrheagenic) Escherichia coli differ phylogenetically and by virulence profiles. Classic theory teaches simple linear descent in this species, where non-pathogens acquire virulence traits and emerge as pathogens. However, diarrheagenic Shiga toxin-producing E.coli (STEC) O2:H6 not only possess and express virulence factors associated with diarrheagenic and uropathogenic E.coli but also cause diarrhea and urinary tract infections. These organisms are phylogenetically positioned between members of an intestinal pathogenic group (STEC) and extraintestinal pathogenic E.coli. STEC O2:H6 is, therefore, a 'heteropathogen,' and the first such hybrid virulent E.coli identified. The phylogeny of these E.coli and the repertoire of virulence traits they possess compel consideration of an alternate view of pathogen emergence, whereby one pathogroup of E.coli undergoes phased metamorphosis into another. By understanding the evolutionary mechanisms of bacterial pathogens, rational strategies for counteracting their detrimental effects on humans can be developed.
KW  - phased metamorphosis
KW  - phylogeny
KW  - heteropathogenicity
KW  - Shiga toxin-producing Escherichia coli
KW  - hemolytic-uremic syndrome
KW  - urinary-tract-infection
KW  - cytolethal distending toxin
KW  - shiga toxin
KW  - Crohns-disease
KW  - outbreak
KW  - genes
KW  - island
KW  - strains
KW  - parallel evolution
KW  - uropathogenic Escherichia coli
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117254
SN  - 1757-4684
VL  - 6
IS  - 3
ER  - 
TY  - JOUR
A1  - Vogt, Marius L.
A1  - Kollikowski, Alexander M.
A1  - Weidner, Franziska
A1  - Strinitz, Marc
A1  - Feick, Jörn
A1  - Essig, Fabian
A1  - Neugebauer, Herrmann
A1  - Haeusler, Karl Georg
A1  - Pham, Mirko
A1  - Maerz, Alexander
T1  - Safety and Effectiveness of the New Generation APERIO® Hybrid Stent-retriever Device in Large Vessel Occlusion Stroke
JF  - Clinical Neuroradiology
N2  - Background
It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness.
Methods
Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019–09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result.
Results
A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7%) treated with AP vs. 150 patients (50.3%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7% for AP vs. 79.3% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7% for AP and 16.0% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups.
Conclusion
In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness.
KW  - APERIO Hybrid
KW  - mechanical thrombectomy
KW  - stent-retriever device
KW  - stroke
KW  - APERIO
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264817
VL  - 32
IS  - 1
ER  - 
TY  - JOUR
A1  - Hautmann, Christopher
A1  - Döpfner, Manfred
A1  - Katzmann, Josepha
A1  - Schürmann, Stephanie
A1  - Wolff Metternich-Kaizman, Tanja
A1  - Jaite, Charlotte
A1  - Kappel, Viola
A1  - Geissler, Julia
A1  - Warnke, Andreas
A1  - Jacob, Christian
A1  - Hennighausen, Klaus
A1  - Haack-Dees, Barbara
A1  - Schneider-Momm, Katja
A1  - Philipsen, Alexandra
A1  - Matthies, Swantje
A1  - Rösler, Michael
A1  - Retz, Wolfgang
A1  - Gontard, Alexander von
A1  - Sobanski, Esther
A1  - Alm, Barbara
A1  - Hohmann, Sarah
A1  - Häge, Alexander
A1  - Poustka, Luise
A1  - Colla, Michael
A1  - Gentschow, Laura
A1  - Freitag, Christine M.
A1  - Becker, Katja
A1  - Jans, Thomas
T1  - Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial
JF  - BMC Psychiatry
N2  - Background
The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment.

Methods
The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher).

Results
Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2).

Conclusions
Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand.

Trial registration
ISRCTN registry ISRCTN73911400. Registered 29 March 2007.
KW  - mothers
KW  - children
KW  - adult treatment
KW  - parent training
KW  - efficacy
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227930
VL  - 18
ER  - 
TY  - JOUR
A1  - Kollikowski, Alexander M.
A1  - Pham, Mirko
A1  - März, Alexander G.
A1  - Papp, Lena
A1  - Nieswandt, Bernhard
A1  - Stoll, Guido
A1  - Schuhmann, Michael K.
T1  - Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke
JF  - Translational Stroke Research
N2  - Experimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018-05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (- 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r =  - 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization.
KW  - chemokines
KW  - CXCL4
KW  - PF4
KW  - CXCL7
KW  - NAP-2
KW  - ischemic stroke
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270194
SN  - 1868-601X
VL  - 13
IS  - 3
ER  - 
TY  - JOUR
A1  - Strinitz, Marc
A1  - Pham, Mirko
A1  - März, Alexander G.
A1  - Feick, Jörn
A1  - Weidner, Franziska
A1  - Vogt, Marius L.
A1  - Essig, Fabian
A1  - Neugebauer, Hermann
A1  - Stoll, Guido
A1  - Schuhmann, Michael K.
A1  - Kollikowski, Alexander M.
T1  - Immune cells invade the collateral circulation during human stroke: prospective replication and extension
JF  - International Journal of Molecular Sciences
N2  - It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R\(^2\) = 0.09696, p = 0.0373) and (4) greater infarct extent (R\(^2\) = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.
KW  - ischemic stroke
KW  - cerebral ischemia
KW  - mechanical thrombectomy
KW  - large vessel occlusion
KW  - leukocytes
KW  - neutrophils
KW  - collateral circulation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284281
SN  - 1422-0067
VL  - 22
IS  - 17
ER  - 
TY  - JOUR
A1  - Mencacci, Niccoló E.
A1  - Isaias, Ioannis U.
A1  - Reich, Martin M.
A1  - Ganos, Christos
A1  - Plagnol, Vincent
A1  - Polke, James M.
A1  - Bras, Jose
A1  - Hersheson, Joshua
A1  - Stamelou, Maria
A1  - Pittman, Alan M.
A1  - Noyce, Alastair J.
A1  - Mok, Kin Y.
A1  - Opladen, Thomas
A1  - Kunstmann, Erdmute
A1  - Hodecker, Sybille
A1  - Münchau, Alexander
A1  - Volkmann, Jens
A1  - Samnick, Samuel
A1  - Sidle, Katie
A1  - Nanji, Tina
A1  - Sweeney, Mary G.
A1  - Houlden, Henry
A1  - Batla, Amit
A1  - Zecchinelli, Anna L.
A1  - Pezzoli, Gianni
A1  - Marotta, Giorgio
A1  - Lees, Andrew
A1  - Alegria, Paulo
A1  - Krack, Paul
A1  - Cormier-Dequaire, Florence
A1  - Lesage, Suzanne
A1  - Brice, Alexis
A1  - Heutink, Peter
A1  - Gasser, Thomas
A1  - Lubbe, Steven J.
A1  - Morris, Huw R.
A1  - Taba, Pille
A1  - Koks, Sulev
A1  - Majounie, Elisa
A1  - Gibbs, J. Raphael
A1  - Singleton, Andrew
A1  - Hardy, John
A1  - Klebe, Stephan
A1  - Bhatia, Kailash P.
A1  - Wood, Nicholas W.
T1  - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
JF  - Brain
N2  - GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
KW  - DOPA-responsive-dystonia
KW  - GCH1
KW  - Parkinson's disease
KW  - dopamine
KW  - exome sequencing
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268
VL  - 137
IS  - 9
ER  - 
TY  - JOUR
A1  - Carsten A., Böger
A1  - Gorski, Mathias
A1  - Li, Man
A1  - Hoffmann, Michael M.
A1  - Huang, Chunmei
A1  - Yang, Qiong
A1  - Teumer, Alexander
A1  - Krane, Vera
A1  - O'Seaghdha, Conall M.
A1  - Kutalik, Zoltán
A1  - Wichmann, H.-Erich
A1  - Haak, Thomas
A1  - Boes, Eva
A1  - Coassin, Stefan
A1  - Coresh, Josef
A1  - Kollerits, Barbara
A1  - Haun, Margot
A1  - Paulweber, Bernhard
A1  - Köttgen, Anna
A1  - Li, Guo
A1  - Shlipak, Michael G.
A1  - Powe, Neil
A1  - Hwang, Shih-Jen
A1  - Dehghan, Abbas
A1  - Rivadeneira, Fernando
A1  - Uitterlinden, André
A1  - Hofman, Albert
A1  - Beckmann, Jacques S.
A1  - Krämer, Bernhard K.
A1  - Witteman, Jacqueline
A1  - Bochud, Murielle
A1  - Siscovick, David
A1  - Rettig, Rainer
A1  - Kronenberg, Florian
A1  - Wanner, Christoph
A1  - Thadhani, Ravi I.
A1  - Heid, Iris M.
A1  - Fox, Caroline S.
A1  - Kao, W.H.
T1  - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD
JF  - PLoS Genetics
N2  - Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
KW  - Chronic Kidney-disease
KW  - Stage renal-disease
KW  - Glomerular-filtration-rate
KW  - Diabetic-nephropathy
KW  - General-population
KW  - African-americans
KW  - Risk
KW  - Progression
KW  - Mortality
KW  - Variants
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133758
VL  - 7
IS  - 9
ER  - 
TY  - JOUR
A1  - Leyh, Catherine
A1  - Ehmer, Ursula
A1  - Roessler, Daniel
A1  - Philipp, Alexander B.
A1  - Reiter, Florian P.
A1  - Jeliazkova, Petia
A1  - Jochheim, Leonie S.
A1  - Jeschke, Matthias
A1  - Hammig, Janina
A1  - Ludwig, Johannes M.
A1  - Theysohn, Jens M.
A1  - Geier, Andreas
A1  - Lange, Christian M.
T1  - Sorafenib versus lenvatinib-based sequential systemic therapy for advanced hepatocellular carcinoma: a real-world analysis
JF  - Cancers
N2  - The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.
KW  - hepatocellular carcinoma
KW  - systemic therapy
KW  - tyrosine-kinase inhibitor
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270765
SN  - 2072-6694
VL  - 14
IS  - 8
ER  - 
TY  - JOUR
A1  - Kleinschnitz, Christoph
A1  - Grund, Henrike
A1  - Wingler, Kirstin
A1  - Armitage, Melanie E.
A1  - Jones, Emma
A1  - Mittal, Manish
A1  - Barit, David
A1  - Schwarz, Tobias
A1  - Geis, Christian
A1  - Kraft, Peter
A1  - Barthel, Konstanze
A1  - Schuhmann, Michael K.
A1  - Herrmann, Alexander M.
A1  - Meuth, Sven G.
A1  - Stoll, Guido
A1  - Meurer, Sabine
A1  - Schrewe, Anja
A1  - Becker, Lore
A1  - Gailus-Durner, Valerie
A1  - Fuchs, Helmut
A1  - Klopstock, Thomas
A1  - de Angelis, Martin Hrabe
A1  - Jandeleit-Dahm, Karin
A1  - Shah, Ajay M.
A1  - Weissmann, Norbert
A1  - Schmidt, Harald H. H. W.
T1  - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration
N2  - Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
KW  - Schlaganfall
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416
ER  - 
TY  - JOUR
A1  - Fiedler, Mascha O.
A1  - Muellenbach, Ralf M.
A1  - Rolfes, Caroline
A1  - Lotz, Christopher
A1  - Nickel, Felix
A1  - Müller-Stich, Beat P.
A1  - Supady, Alexander
A1  - Lepper, Philipp M.
A1  - Weigand, Markus A.
A1  - Meybohm, Patrick
A1  - Kalenka, Armin
A1  - Reyher, Christian
T1  - Pumpless extracorporeal hemadsorption technique (pEHAT): a proof-of-concept animal study
JF  - Journal of Clinical Medicine
N2  - Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb\(^®\) and four Oxiris\(^®\) hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45–85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb\(^®\) blood flow [mL/min] = 4.226 × MAP [mmHg] − 3.496 (R-square 0.8133) and Oxiris\(^®\) blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb\(^®\) and Oxiris\(^®\) devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.
KW  - blood purification
KW  - extracorporeal hemadsorption
KW  - cytokines
KW  - adsorption
KW  - animal model
KW  - immunosorbents
KW  - septic shock
KW  - endotoxin
KW  - extracorporeal techniques in hemadsorption therapy
KW  - arteriovenous extracorporeal hemadsorption technique
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297347
SN  - 2077-0383
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Mambretti, Egle M.
A1  - Kistner, Katrin
A1  - Mayer, Stefanie
A1  - Massotte, Dominique
A1  - Kieffer, Brigitte L.
A1  - Hoffmann, Carsten
A1  - Reeh, Peter W.
A1  - Brack, Alexander
A1  - Asan, Esther
A1  - Rittner, Heike L.
T1  - Functional and structural characterization of axonal opioid receptors as targets for analgesia
JF  - Molecular Pain
N2  - Background
Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. µ-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in naïve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function.

Results
Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\(^2\), N-MePhe\(^4\), Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in naïve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In vitro, using β-arrestin-2/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization.

Conclusion
MOPs are present and functional in the axonal membrane from naïve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia.
KW  - µ-Opioid receptor
KW  - hypertonic solution
KW  - fentanyl
KW  - calcitonin gene-related peptide
KW  - DAMGO
KW  - internalization
KW  - peripheral nerve
KW  - ultrastructure
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145917
IS  - 12
ER  - 
TY  - JOUR
A1  - Schneider, Eberhard
A1  - Pliushch, Galyna
A1  - El Hajj, Nady
A1  - Galetzka, Danuta
A1  - Puhl, Alexander
A1  - Schorsch, Martin
A1  - Frauenknecht, Katrin
A1  - Riepert, Thomas
A1  - Tresch, Achim
A1  - Mueller, Annette M.
A1  - Coerdt, Wiltrud
A1  - Zechner, Ulrich
A1  - Haaf, Thomas
T1  - Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns
N2  - DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.
KW  - Medizin
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68371
ER  - 
TY  - JOUR
A1  - Dörhöfer, Lena
A1  - Lammert, Alexander
A1  - Krane, Vera
A1  - Gorski, Mathias
A1  - Banas, Bernhard
A1  - Wanner, Christoph
A1  - Krämer, Bernhard K.
A1  - Heid, Iris M.
A1  - Böger, Carsten A.
T1  - Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2
JF  - BMC Medical Genetics
N2  - Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). 
Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro-and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e. g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. 
Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.
KW  - chronic kidney-disease
KW  - stage renal-disease
KW  - glomerular-filtration-rate
KW  - genome-wide association
KW  - blood-glucose control
KW  - genetics
KW  - serum creatinine
KW  - cardiovascular disease
KW  - replacement therapy
KW  - United States
KW  - risk factors
KW  - diabetes mellitus type 2
KW  - diabetic nephropathy
KW  - end stage renal disease
KW  - cardiovascular morbidity
KW  - diabetes complications
KW  - epidemiology
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122040
SN  - 1471-2350
VL  - 14
IS  - 25
ER  - 
TY  - JOUR
A1  - Schulz, Anita
A1  - Jaksch, Sebastian
A1  - Schubel, Rene
A1  - Wegener, Erik
A1  - Di, Zhenyu
A1  - Han, Yingchao
A1  - Meister, Annette
A1  - Kressler, Jörg
A1  - Kabanov, Alexander V.
A1  - Luxenhofer, Robert
A1  - Papadakis, Christine M.
A1  - Jordan, Rainer
T1  - Drug-Induced Morphology Switch in Drug Delivery Systems Based on Poly(2-oxazoline)s
JF  - ACS Nano
N2  - Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug–polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core.
KW  - amphiphilic poly(2-oxazoline)s
KW  - paclitaxel
KW  - drug delivery
KW  - rod-to-sphere transition
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120766
N1  - This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html), which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
VL  - 8
IS  - 3
ER  - 
TY  - JOUR
A1  - Kozlov, J. V.
A1  - Gorboulev, Valentin G.
A1  - Kurmanova, A. G.
A1  - Bayev, Alexander A.
A1  - Shilov, A. A.
A1  - Zhdanov, V. M.
T1  - On the origin of the H1N1 (A/USSR/90/77) influenza virus
N2  - The influenza virus H1N1 (the A/USSR/90/77 strain) that reappeared in 1977 after the H1N1 influenza viruses had disappeared from the human population, is compared with the A/FM/1/47 and the A/FW/1/50 influenza viruses by the method of oligonucleotide mapping of individual segments of the viral RNAs. Seven genes of the A/USSR/90/77 virus appear to be very similar to the corresponding genes of the A/FW/1/50 virus, whereas the gene coding for the M protein displays considerable homology to the corresponding gene of the A/FM/1/47 virus. The data demonstrate that the A/USSR/90/77 strain is a recombinant virus.
KW  - influenza virus ; virion RNA segments ; oligonucleotide mapping ; gene reassortment
Y1  - 1981
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-32556
ER  - 
TY  - JOUR
A1  - Miras, Alexander D.
A1  - Seyfried, Florian
A1  - Phinikaridou, Alkystis
A1  - Andia, Marcelo E.
A1  - Christakis, Ioannis
A1  - Spector, Alan C.
A1  - Botnar, Rene M.
A1  - le Roux, Carel W.
T1  - Rats Fed Diets with Different Energy Contribution from Fat Do Not Differ in Adiposity
JF  - OBESITY FACTS
N2  - Objective: To determine whether rats reaching the same body mass, having been fed either a low-fat (LFD) or a high-fat diet (HFD), differ in white adipose tissue (WAT) deposition. Methods: In experiment 1, 22 Sprague-Dawley rats of the same age were divided into 11 rats with body mass below the batch median and fed a HFD, and 11 above the median and fed a LFD. In experiment 2, 20 Sprague-Dawley rats of the same age and starting body mass were randomised to either a HFD or LFD. When all groups reached similar final body mass, WAT was quantified using magnetic resonance imaging (MRI), dissection, and plasma leptin. Results: In experiment 1, both groups reached similar final body mass at the same age; in experiment 2 the HFD group reached similar final body mass earlier than the LFD group. There were no significant differences in WAT as assessed by MRI or leptin between the HFD and LFD groups in both experiments. Dissection revealed a trend for higher retroperitoneal and epididymal adiposity in the HFD groups in both experiments. Conclusions: We conclude that at similar body mass, adiposity is independent of the macronutrient composition of the feeding regimen used to achieve it. (C) 2014 S Karger GmbH, Freiburg
KW  - Leptin
KW  - body fat
KW  - induced obesity
KW  - visceral fat
KW  - isocaloric intake
KW  - mass
KW  - tissue
KW  - weight-gain
KW  - metabolism
KW  - expenditure
KW  - accumulation
KW  - High-fat diet
KW  - Low-fat diet
KW  - MRI
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115249
VL  - 7
IS  - 5
ER  - 
TY  - JOUR
A1  - Sharma, Cynthia M.
A1  - Dugar, Gaurav
A1  - Herbig, Alexander
A1  - Förstner, Konrad U.
A1  - Heidrich, Nadja
A1  - Reinhardt, Richard
A1  - Nieselt, Kay
T1  - High-Resolution Transcriptome Maps Reveal Strain-Specific Regulatory Features of Multiple Campylobacter jejuni Isolates
JF  - PLoS Genetics
N2  - Campylobacter jejuni is currently the leading cause of bacterial gastroenteritis in humans. Comparison of multiple Campylobacter strains revealed a high genetic and phenotypic diversity. However, little is known about differences in transcriptome organization, gene expression, and small RNA (sRNA) repertoires. Here we present the first comparative primary transcriptome analysis based on the differential RNA–seq (dRNA–seq) of four C. jejuni isolates. Our approach includes a novel, generic method for the automated annotation of transcriptional start sites (TSS), which allowed us to provide genome-wide promoter maps in the analyzed strains. These global TSS maps are refined through the integration of a SuperGenome approach that allows for a comparative TSS annotation by mapping RNA–seq data of multiple strains into a common coordinate system derived from a whole-genome alignment. Considering the steadily increasing amount of RNA–seq studies, our automated TSS annotation will not only facilitate transcriptome annotation for a wider range of pro- and eukaryotes but can also be adapted for the analysis among different growth or stress conditions. Our comparative dRNA–seq analysis revealed conservation of most TSS, but also single-nucleotide-polymorphisms (SNP) in promoter regions, which lead to strain-specific transcriptional output. Furthermore, we identified strain-specific sRNA repertoires that could contribute to differential gene regulation among strains. In addition, we identified a novel minimal CRISPR-system in Campylobacter of the type-II CRISPR subtype, which relies on the host factor RNase III and a trans-encoded sRNA for maturation of crRNAs. This minimal system of Campylobacter, which seems active in only some strains, employs a unique maturation pathway, since the crRNAs are transcribed from individual promoters in the upstream repeats and thereby minimize the requirements for the maturation machinery. Overall, our study provides new insights into strain-specific transcriptome organization and sRNAs, and reveals genes that could modulate phenotypic variation among strains despite high conservation at the DNA level.
KW  - bacterial genomics
KW  - CRISPRs
KW  - genome annotation
KW  - campylobacter
KW  - genomic libraries
KW  - genomic library construction
KW  - sequence motif analysis
KW  - transcriptome analysis
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96610
ER  - 
TY  - JOUR
A1  - Atienza, Nieves
A1  - de Castro, Natalia
A1  - Cortés, Carmen
A1  - Garrido, M. Ángeles
A1  - Grima, Clara I.
A1  - Hernández, Gregorio
A1  - Márquez, Alberto
A1  - Moreno-González, Auxiliadora
A1  - Nöllenburg, Martin
A1  - Portillo, José Ramón
A1  - Reyes, Pedro
A1  - Valenzuela, Jesús
A1  - Trinidad Villar, Maria
A1  - Wolff, Alexander
T1  - Cover contact graphs
N2  - We study problems that arise in the context of covering certain geometric objects called seeds (e.g., points or disks) by a set of other geometric objects called cover (e.g., a set of disks or homothetic triangles). We insist that the interiors of the seeds and the cover elements are pairwise disjoint, respectively, but they can touch. We call the contact graph of a cover a cover contact graph (CCG). We are interested in three types of tasks, both in the general case and in the special case of seeds on a line: (a) deciding whether a given seed set has a connected CCG, (b) deciding whether a given graph has a realization as a CCG on a given seed set, and (c) bounding the sizes of certain classes of CCG’s. Concerning (a) we give efficient algorithms for the case that seeds are points and show that the problem becomes hard if seeds and covers are disks. Concerning (b) we show that this problem is hard even for point seeds and disk covers (given a fixed correspondence between graph vertices and seeds). Concerning (c) we obtain upper and lower bounds on the number of CCG’s for point seeds.
KW  - Informatik
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78845
ER  - 
TY  - JOUR
A1  - Essig, Fabian
A1  - Babilon, Lilith
A1  - Vollmuth, Christoph
A1  - Kollikowski, Alexander M.
A1  - Pham, Mirko
A1  - Solymosi, László
A1  - Haeusler, Karl Georg
A1  - Kraft, Peter
A1  - Stoll, Guido
A1  - Schuhmann, Michael K.
T1  - High mobility group box 1 protein in cerebral thromboemboli
JF  - International Journal of Molecular Sciences
N2  - High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.
KW  - acute ischemic stroke
KW  - thromboemboli
KW  - HMGB1
KW  - neutrophils
KW  - platelets
KW  - immunohistochemistry
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265568
SN  - 1422-0067
VL  - 22
IS  - 20
ER  - 
TY  - JOUR
A1  - Lodde, Georg
A1  - Forschner, Andrea
A1  - Hassel, Jessica
A1  - Wulfken, Lena M.
A1  - Meier, Friedegund
A1  - Mohr, Peter
A1  - Kähler, Katharina
A1  - Schilling, Bastian
A1  - Loquai, Carmen
A1  - Berking, Carola
A1  - Hüning, Svea
A1  - Schatton, Kerstin
A1  - Gebhardt, Christoffer
A1  - Eckardt, Julia
A1  - Gutzmer, Ralf
A1  - Reinhardt, Lydia
A1  - Glutsch, Valerie
A1  - Nikfarjam, Ulrike
A1  - Erdmann, Michael
A1  - Stang, Andreas
A1  - Kowall, Bernd
A1  - Roesch, Alexander
A1  - Ugurel, Selma
A1  - Zimmer, Lisa
A1  - Schadendorf, Dirk
A1  - Livingstone, Elisabeth
T1  - Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients
JF  - Cancers
N2  - Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
KW  - melanoma
KW  - adjuvant treatment
KW  - checkpoint blocker
KW  - targeted therapy
KW  - BRAF
KW  - PD-1
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239583
SN  - 2072-6694
VL  - 13
IS  - 10
ER  - 
TY  - JOUR
A1  - Jaite, Charlotte
A1  - Bühren, Katharina
A1  - Dahmen, Brigitte
A1  - Dempfle, Astrid
A1  - Becker, Katja
A1  - Correll, Christoph U.
A1  - Egberts, Karin M.
A1  - Ehrlich, Stefan
A1  - Fleischhaker, Christian
A1  - von Gontard, Alexander
A1  - Hahn, Freia
A1  - Kolar, David
A1  - Kaess, Michael
A1  - Legenbauer, Tanja
A1  - Renner, Tobias J.
A1  - Schulze, Ulrike
A1  - Sinzig, Judith
A1  - Thomae, Ellen
A1  - Weber, Linda
A1  - Wessing, Ida
A1  - Antony, Gisela
A1  - Hebebrand, Johannes
A1  - Föcker, Manuel
A1  - Herpertz-Dahlmann, Beate
T1  - Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa
JF  - Nutrients
N2  - We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.
KW  - anorexia nervosa
KW  - children
KW  - adolescents
KW  - clinical characteristics
KW  - BMI
KW  - outcome
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193160
SN  - 2072-6643
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Rayner, Christopher
A1  - Coleman, Jonathan R. I.
A1  - Purves, Kirstin L.
A1  - Hodsoll, John
A1  - Goldsmith, Kimberley
A1  - Alpers, Georg W.
A1  - Andersson, Evelyn
A1  - Arolt, Volker
A1  - Boberg, Julia
A1  - Bögels, Susan
A1  - Creswell, Cathy
A1  - Cooper, Peter
A1  - Curtis, Charles
A1  - Deckert, Jürgen
A1  - Domschke, Katharina
A1  - El Alaoui, Samir
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Grocholewski, Anja
A1  - Hahlweg, Kurt
A1  - Hamm, Alfons
A1  - Hedman, Erik
A1  - Heiervang, Einar R.
A1  - Hudson, Jennifer L.
A1  - Jöhren, Peter
A1  - Keers, Robert
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lavebratt, Catharina
A1  - Lee, Sang-hyuck
A1  - Lester, Kathryn J.
A1  - Lindefors, Nils
A1  - Margraf, Jürgen
A1  - Nauta, Maaike
A1  - Pané-Farré, Christiane A.
A1  - Pauli, Paul
A1  - Rapee, Ronald M.
A1  - Reif, Andreas
A1  - Rief, Winfried
A1  - Roberts, Susanna
A1  - Schalling, Martin
A1  - Schneider, Silvia
A1  - Silverman, Wendy K.
A1  - Ströhle, Andreas
A1  - Teismann, Tobias
A1  - Thastum, Mikael
A1  - Wannemüller, Andre
A1  - Weber, Heike
A1  - Wittchen, Hans-Ulrich
A1  - Wolf, Christiane
A1  - Rück, Christian
A1  - Breen, Gerome
A1  - Eley, Thalia C.
T1  - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders
JF  - Translational Psychiatry
N2  - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
KW  - Human behaviour
KW  - Personalized medicine
KW  - Prognostic markers
KW  - Psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048
VL  - 9
IS  - 150
ER  - 
TY  - JOUR
A1  - Röll, Alexander
A1  - Ramesha, Mundre N.
A1  - Link, Roman M.
A1  - Hertel, Dietrich
A1  - Schuldt, Bernhard
A1  - Patil, Shekhargouda L.
A1  - Hölscher, Dirk
T1  - Water availability controls the biomass increment of Melia dubia in South India
JF  - Forests
N2  - Farmland tree cultivation is considered an important option for enhancing wood production. In South India, the native leaf-deciduous tree species Melia dubia is popular for short-rotation plantations. Across a rainfall gradient from 420 to 2170 mm year\(^{–1}\), we studied 186 farmland woodlots between one and nine years in age. The objectives were to identify the main factors controlling aboveground biomass (AGB) and growth rates. A power-law growth model predicts an average stand-level AGB of 93.8 Mg ha\(^{–1}\) for nine-year-old woodlots. The resulting average annual AGB increment over the length of the rotation cycle is 10.4 Mg ha\(^{–1}\) year\(^{–1}\), which falls within the range reported for other tropical tree plantations. When expressing the parameters of the growth model as functions of management, climate and soil variables, it explains 65% of the variance in AGB. The results indicate that water availability is the main driver of the growth of M. dubia. Compared to the effects of water availability, the effects of soil nutrients are 26% to 60% smaller. We conclude that because of its high biomass accumulation rates in farm forestry, M. dubia is a promising candidate for short-rotation plantations in South India and beyond.
KW  - aboveground biomass
KW  - climatological water deficit
KW  - farm forestry
KW  - farmland woodlots
KW  - rainfall gradient
KW  - soil
KW  - wood production
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250150
SN  - 1999-4907
VL  - 12
IS  - 12
ER  - 
TY  - JOUR
A1  - Nedopil, Alexander J.
A1  - Shekhar, Adithya
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - An insert with less than spherical medial conformity causes a loss of passive internal rotation after calipered kinematically aligned TKA
JF  - Archives of Orthopaedic and Trauma Surgery
N2  - Introduction
In total knee arthroplasty (TKA), the level of conformity, a medial stabilized (MS) implant, needs to restore native (i.e., healthy) knee kinematics without over-tensioning the flexion space when the surgeon chooses to retain the posterior cruciate ligament (PCL) is unknown. Whether an insert with a medial ball-in-socket conformity and lateral flat surface like the native knee or a less than spherical medial conformity restores higher and closer to native internal tibial rotation without anterior lift-off, an over-tension indicator, when implanted with calipered kinematic alignment (KA), is unknown.
Methods and Materials
Two surgeons treated 21 patients with calipered KA and a PCL retaining MS implant. Validated verification checks that restore native tibial compartment forces in passive flexion without release of healthy ligaments were used to select the optimal insert thickness. A goniometer etched onto trial inserts with the ball-in-socket and the less than spherical medial conformity measured the tibial rotation relative to the femoral component at extension and 90° and 120° flexion. The surgeon recorded the incidence of anterior lift-off of the insert.
Results
The insert with the medial ball-in-socket and lateral flat surface restored more internal tibial rotation than the one with less than spherical medial conformity, with mean values of 19° vs. 17° from extension to 90° flexion (p < 0.01), and 23° vs. 20°-120° flexion (p < 0.002), respectively. There was no anterior lift-off of the insert at 90° and 120° flexion.
Conclusion
An MS insert with a medial ball-in-socket and lateral flat surface that matches the native knee's spherical conformity restores native tibial internal rotation when implanted with calipered KA and PCL retention without over-tensioning the flexion space.
KW  - calipered
KW  - medial stabilized
KW  - spherical
KW  - conforming
KW  - insert
KW  - rotation
KW  - total knee arthroplasty
KW  - total knee replacement
KW  - kinematic alignment
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266710
SN  - 1434-3916
VL  - 141
IS  - 12
ER  - 
TY  - JOUR
A1  - Gotschy, Alexander
A1  - Bauer, Wolfgang R.
A1  - Winter, Patrick
A1  - Nordbeck, Peter
A1  - Rommel, Eberhard
A1  - Jakob, Peter M.
A1  - Herold, Volker
T1  - Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE\(^{-/-}\) mice using ultrahigh field MRI
JF  - PLoS ONE
N2  - Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE\(^{-/-}\) and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE\(^{-/-}\) and WT mice were determined for global and local PWV measurements (global PWV: ApoE\(^{-/-}\): 2.7 ±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE\(^{-/-}\): 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R\(^2\) = 0.75, P<0.01), implying a widely uniform arterial elasticity.
In ApoE\(^{-/-}\) animals, however, no significant correlation between individual local and global PWV was present (R\(^2\) = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel
phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions.
KW  - MRI
KW  - Atherosclerosis
KW  - Aorta
KW  - Stiffness
KW  - Measurement
KW  - Time measurement
KW  - Magnetic resonance imaging
KW  - Mouse models
KW  - Systole
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171824
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Wohlfarth, Carolin
A1  - Schmitteckert, Stefanie
A1  - Härtle, Janina D.
A1  - Houghton, Lesley A.
A1  - Dweep, Harsh
A1  - Fortea, Marina
A1  - Assadi, Ghazaleh
A1  - Braun, Alexander
A1  - Mederer, Tanja
A1  - Pöhner, Sarina
A1  - Becker, Philip P.
A1  - Fischer, Christine
A1  - Granzow, Martin
A1  - Mönnikes, Hubert
A1  - Mayer, Emeran A.
A1  - Sayuk, Gregory
A1  - Boeckxstaens, Guy
A1  - Wouters, Mira M.
A1  - Simrén, Magnus
A1  - Lindberg, Greger
A1  - Ohlsson, Bodil
A1  - Schmidt, Peter Thelin
A1  - Dlugosz, Aldona
A1  - Agreus, Lars
A1  - Andreasson, Anna
A1  - D'Amato, Mauro
A1  - Burwinkel, Barbara
A1  - Bermejo, Justo Lorenzo
A1  - Röth, Ralph
A1  - Lasitschka, Felix
A1  - Vicario, Maria
A1  - Metzger, Marco
A1  - Santos, Javier
A1  - Rappold, Gudrun A.
A1  - Martinez, Cristina
A1  - Niesler, Beate
T1  - miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome
JF  - Scientific Reports
N2  - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D.
KW  - Medicine
KW  - Gene regulation
KW  - Irritable bowel syndrome
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173478
VL  - 7
ER  - 
TY  - JOUR
A1  - Göbel, Kerstin
A1  - Pankratz, Susann
A1  - Asaridou, Chloi-Magdalini
A1  - Herrmann, Alexander M.
A1  - Bittner, Stefan
A1  - Merker, Monika
A1  - Ruck, Tobias
A1  - Glumm, Sarah
A1  - Langhauser, Friederike
A1  - Kraft, Peter
A1  - Krug, Thorsten F.
A1  - Breuer, Johanna
A1  - Herold, Martin
A1  - Gross, Catharina C.
A1  - Beckmann, Denise
A1  - Korb-Pap, Adelheid
A1  - Schuhmann, Michael K.
A1  - Kuerten, Stefanie
A1  - Mitroulis, Ioannis
A1  - Ruppert, Clemens
A1  - Nolte, Marc W.
A1  - Panousis, Con
A1  - Klotz, Luisa
A1  - Kehrel, Beate
A1  - Korn, Thomas
A1  - Langer, Harald F.
A1  - Pap, Thomas
A1  - Nieswandt, Bernhard
A1  - Wiendl, Heinz
A1  - Chavakis, Triantafyllos
A1  - Kleinschnitz, Christoph
A1  - Meuth, Sven G.
T1  - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
JF  - Nature Communications
N2  - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
KW  - blood coagulation
KW  - factor XII
KW  - neuroinflammation
KW  - dendric cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165503
VL  - 7
IS  - 11626
ER  - 
TY  - JOUR
A1  - Shekhar, Adithya
A1  - Howell, Stephen M.
A1  - Nedopil, Alexander J.
A1  - Hull, Maury L.
T1  - Excellent and good results treating stiffness with early and late manipulation after unrestricted caliper-verified kinematically aligned TKA
JF  - Journal of Personalized Medicine
N2  - Manipulation under anesthesia (MUA) for stiffness within 6 to 12 weeks after mechanically aligned total knee arthroplasty (TKA) generally yields better outcome scores than an MUA performed later. However, the timing of MUA after unrestricted, caliper-verified, kinematically aligned (KA) TKA remains uncertain. A retrospective review identified 82 of 3558 (2.3%) KA TKA patients treated with an MUA between 2010 and 2017. Thirty patients treated with an MUA within 3 months of the TKA (i.e., early) and 24 in the late group (i.e., >3 months) returned a questionnaire after a mean of 6 years and 5 years, respectively. Mean outcome scores for the early vs. late group were 78 vs. 62 for the Forgotten Joint Score (FJS) (p = 0.023) and 42 vs. 39 for the Oxford Knee Score (OKS) (p = 0.037). Subjectively, the early vs. late group responses indicated that 83% vs. 67% walked without a limp, 73% vs. 54% had normal extension, and 43% vs. 25% had normal flexion. An MUA within 3 months after unrestricted KA TKA provided excellent FJS and OKS at final follow-up relative to a late MUA. A late MUA performed after 3 months is worth consideration because of the good FJS and OKS scores, albeit with a risk of a persistent limp and limitation in knee extension and flexion.
KW  - reoperation
KW  - revision
KW  - implant survival
KW  - forgotten joint score
KW  - Oxford knee score
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262094
SN  - 2075-4426
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Boes, Alexander
A1  - Spiegel, Holger
A1  - Voepel, Nadja
A1  - Edgue, Gueven
A1  - Beiss, Veronique
A1  - Kapelski, Stephanie
A1  - Fendel, Rolf
A1  - Scheuermayer, Matthias
A1  - Pradel, Gabriele
A1  - Bolscher, Judith M.
A1  - Behet, Marije C.
A1  - Dechering, Koen J.
A1  - Hermsen, Cornelus C.
A1  - Sauerwein, Robert W.
A1  - Schillberg, Stefan
A1  - Reimann, Andreas
A1  - Fischer, Rainer
T1  - Analysis of a multi-component multi-stage malaria vaccine candidate—tackling the cocktail challenge
JF  - PLoS ONE
N2  - Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total) from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80%), blood (up to 90%) and sexual parasite stages (100%). Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17–25 μg/ml), the blood stage (40–60 μg/ml) and the sexual stage (1.75 μg/ml). While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy.
KW  - malaria
KW  - vaccines
KW  - antibodies
KW  - P. falciparum
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173092
VL  - 10
IS  - 7
ER  - 
TY  - JOUR
A1  - Howell, Stephen M.
A1  - Gill, Manpreet
A1  - Shelton, Trevor J.
A1  - Nedopil, Alexander J.
T1  - Reoperations are few and confined to the most valgus phenotypes 4 years after unrestricted calipered kinematically aligned TKA
JF  - Knee Surgery, Sports Traumatology, Arthroscopy
N2  - Purpose
The present study determined the postoperative phenotypes after unrestricted calipered kinematically aligned (KA) total knee arthroplasty (TKA), whether any phenotypes were associated with reoperation, implant revision, and lower outcome scores at 4 years, and whether the proportion of TKAs within each phenotype was comparable to those of the nonarthritic contralateral limb.
Methods
From 1117 consecutive primary TKAs treated by one surgeon with unrestricted calipered KA, an observer identified all patients (N = 198) that otherwise had normal paired femora and tibiae on a long-leg CT scanogram. In both legs, the distal femur–mechanical axis angle (FMA), proximal tibia–mechanical axis angle (TMA), and the hip–knee–ankle angle (HKA) were measured. Each alignment angle was assigned to one of Hirschmann’s five FMA, five TMA, and seven HKA phenotype categories.
Results
Three TKAs (1.5%) underwent reoperation for anterior knee pain or patellofemoral instability in the subgroup of patients with the more valgus phenotypes. There were no implant revisions for component loosening, wear, or tibiofemoral instability. The median Forgotten Joint Score (FJS) was similar between phenotypes. The median Oxford Knee Score (OKS) was similar between the TMA and HKA phenotypes and greatest in the most varus FMA phenotype. The phenotype proportions after calipered KA TKA were comparable to the contralateral leg.
Conclusion
Unrestricted calipered KA’s restoration of the wide range of phenotypes did not result in implant revision or poor FJS and OKS scores at a mean follow-up of 4 years. The few reoperated patients had a more valgus setting of the prosthetic trochlea than recommended for mechanical alignment. Designing a femoral component specifically for KA that restores patellofemoral kinematics with all phenotypes, especially the more valgus ones, is a strategy for reducing reoperation risk.
KW  - phenotype
KW  - total knee arthroplasty
KW  - total knee replacement
KW  - kinematic alignment
KW  - calipered
KW  - reoperation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265291
VL  - 30
IS  - 3
ER  - 
TY  - JOUR
A1  - Thiem, Alexander
A1  - Hesbacher, Sonja
A1  - Kneitz, Hermann
A1  - di Primio, Teresa
A1  - Heppt, Markus V.
A1  - Hermanns, Heike M.
A1  - Goebeler, Matthias
A1  - Meierjohann, Svenja
A1  - Houben, Roland
A1  - Schrama, David
T1  - IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression
JF  - Journal of Experimental & Clinical Cancer Research
N2  - Background
Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.

Methods
We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.

Results
For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.

Conclusions
While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
KW  - Melanoma
KW  - PD-L1
KW  - CD274
KW  - p53
KW  - TP53
KW  - JAK2
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201016
VL  - 38
ER  - 
TY  - JOUR
A1  - Jende, Johann M. E.
A1  - Kender, Zoltan
A1  - Rother, Christian
A1  - Alvarez-Ramos, Lucia
A1  - Groener, Jan B.
A1  - Pham, Mirko
A1  - Morgenstern, Jakob
A1  - Oikonomou, Dimitrios
A1  - Hahn, Artur
A1  - Juerchott, Alexander
A1  - Kollmer, Jennifer
A1  - Heiland, Sabine
A1  - Kopf, Stefan
A1  - Nawroth, Peter P.
A1  - Bendszus, Martin
A1  - Kurz, Felix T.
T1  - Diabetic Polyneuropathy Is Associated With Pathomorphological Changes in Human Dorsal Root Ganglia: A Study Using 3T MR Neurography
JF  - Frontiers in Neuroscience
N2  - Diabetic neuropathy (DPN) is one of the most severe and yet most poorly understood complications of diabetes mellitus. In vivo imaging of dorsal root ganglia (DRG), a key structure for the understanding of DPN, has been restricted to animal studies. These have shown a correlation of decreased DRG volume with neuropathic symptom severity. Our objective was to investigate correlations of DRG morphology and signal characteristics at 3 Tesla (3T) magnetic resonance neurography (MRN) with clinical and serological data in diabetic patients with and without DPN. In this cross-sectional study, participants underwent 3T MRN of both L5 DRG using an isotropic 3D T2-weighted, fat-suppressed sequence with subsequent segmentation of DRG volume and analysis of normalized signal properties. Overall, 55 diabetes patients (66 ± 9 years; 32 men; 30 with DPN) took part in this study. DRG volume was smaller in patients with severe DPN when compared to patients with mild or moderate DPN (134.7 ± 21.86 vs 170.1 ± 49.22; p = 0.040). In DPN patients, DRG volume was negatively correlated with the neuropathy disability score (r = −0.43; 95%CI = −0.66 to −0.14; p = 0.02), a measure of neuropathy severity. DRG volume showed negative correlations with triglycerides (r = −0.40; 95%CI = −0.57 to −0.19; p = 0.006), and LDL cholesterol (r = −0.33; 95%CI = −0.51 to −0.11; p = 0.04). There was a strong positive correlation of normalized MR signal intensity (SI) with the neuropathy symptom score in the subgroup of patients with painful DPN (r = 0.80; 95%CI = 0.46 to 0.93; p = 0.005). DRG SI was positively correlated with HbA1c levels (r = 0.30; 95%CI = 0.09 to 0.50; p = 0.03) and the triglyceride/HDL ratio (r = 0.40; 95%CI = 0.19 to 0.57; p = 0.007). In this first in vivo study, we found DRG morphological degeneration and signal increase in correlation with neuropathy severity. This elucidates the potential importance of MR-based DRG assessments in studying structural and functional changes in DPN.
KW  - diabetic polyneuropathy
KW  - dorsal root ganglion
KW  - magnetic resonance neurography
KW  - neuropathic pain
KW  - peripheral nervous system
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212459
VL  - 14
ER  - 
TY  - JOUR
A1  - Huss, André M.
A1  - Halbgebauer, Steffen
A1  - Öckl, Patrick
A1  - Trebst, Corinna
A1  - Spreer, Annette
A1  - Borisow, Nadja
A1  - Harrer, Andrea
A1  - Brecht, Isabel
A1  - Balint, Bettina
A1  - Stich, Oliver
A1  - Schlegel, Sabine
A1  - Retzlaff, Nele
A1  - Winkelmann, Alexander
A1  - Roesler, Romy
A1  - Lauda, Florian
A1  - Yildiz, Özlem
A1  - Voß, Elke
A1  - Muche, Rainer
A1  - Rauer, Sebastian
A1  - Bergh, Florian Then
A1  - Otto, Markus
A1  - Paul, Friedemann
A1  - Wildemann, Brigitte
A1  - Kraus, Jörg
A1  - Ruprecht, Klemens
A1  - Stangel, Martin
A1  - Buttmann, Mathias
A1  - Zettl, Uwe K.
A1  - Tumani, Hayrettin
T1  - Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome
JF  - Journal of Neurology
N2  - The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.
KW  - multiple sklerosis
KW  - MRI criteria
KW  - conversion
KW  - MS
KW  - CSF
KW  - biomarker
KW  - OCB
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186619
VL  - 263
IS  - 12
ER  - 
TY  - JOUR
A1  - Nedopil, Alexander J.
A1  - Delman, Connor
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - Restoring the patient's pre-arthritic posterior slope is the correct target for maximizing internal tibial rotation when implanting a PCL retaining TKA with calipered kinematic alignment
JF  - Journal of Personalized Medicine
N2  - Introduction: The calipered kinematically-aligned (KA) total knee arthroplasty (TKA) strives to restore the patient's individual pre-arthritic (i.e., native) posterior tibial slope when retaining the posterior cruciate ligament (PCL). Deviations from the patient's individual pre-arthritic posterior slope tighten and slacken the PCL in flexion that drives tibial rotation, and such a change might compromise passive internal tibial rotation and coupled patellofemoral kinematics. Methods: Twenty-one patients were treated with a calipered KA TKA and a PCL retaining implant with a medial ball-in-socket and a lateral flat articular insert conformity that mimics the native (i.e., healthy) knee. The slope of the tibial resection was set parallel to the medial joint line by adjusting the plane of an angel wing inserted in the tibial guide. Three trial inserts that matched and deviated 2°> and 2°< from the patient's pre-arthritic slope were 3D printed with goniometric markings. The goniometer measured the orientation of the tibia (i.e., trial insert) relative to the femoral component. Results: There was no difference between the radiographic preoperative and postoperative tibial slope (0.7 ± 3.2°, NS). From extension to 90° flexion, the mean passive internal tibial rotation with the pre-arthritic slope insert of 19° was greater than the 15° for the 2°> slope (p < 0.000), and 15° for the 2°< slope (p < 0.000). Discussion: When performing a calipered KA TKA with PCL retention, the correct target for setting the tibial component is the patient's individual pre-arthritic slope within a tolerance of ±2°, as this target resulted in a 15–19° range of internal tibial rotation that is comparable to the 15–18° range reported for the native knee from extension to 90° flexion.
KW  - total knee replacement
KW  - total knee arthroplasty
KW  - kinematic alignment
KW  - slope
KW  - rotation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240996
SN  - 2075-4426
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Preitschopf, Tobias
A1  - Sturm, Floriane
A1  - Stroganova, Iuliia
A1  - Lemmens, Alexander K.
A1  - Rijs, Anouk M.
A1  - Fischer, Ingo
T1  - IR/UV Double Resonance Study of the 2‐Phenylallyl Radical and its Pyrolysis Products
JF  - Chemistry – A European Journal
N2  - Isolated 2‐phenylallyl radicals (2‐PA), generated by pyrolysis from a nitrite precursor, have been investigated by IR/UV ion dip spectroscopy using free electron laser radiation. 2‐PA is a resonance‐stabilized radical that is considered to be involved in the formation of polycyclic aromatic hydrocarbons (PAH) in combustion, but also in interstellar space. The radical is identified based on its gas‐phase IR spectrum. Furthermore, a number of bimolecular reaction products are identified, showing that the self‐reaction as well as reactions with unimolecular decomposition products of 2‐PA form several PAH efficiently. Possible mechanisms are discussed and the chemistry of 2‐PA is compared with the one of the related 2‐methylallyl and phenylpropargyl radicals.
KW  - free electron laser
KW  - free jet
KW  - IR spectroscopy
KW  - PAH formation
KW  - radical reactions
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312338
VL  - 29
IS  - 13
ER  - 
TY  - JOUR
A1  - Werner, Rudolf A.
A1  - Derlin, Thorsten
A1  - Lapa, Constantin
A1  - Sheikbahaei, Sara
A1  - Higuchi, Takahiro
A1  - Giesel, Frederik L.
A1  - Behr, Spencer
A1  - Drzezga, Alexander
A1  - Kimura, Hiroyuki
A1  - Buck, Andreas K.
A1  - Bengel, Frank M.
A1  - Pomper, Martin G.
A1  - Gorin, Michael A.
A1  - Rowe, Steven P.
T1  - \(^{18}\)F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging
JF  - Theranostics
N2  - Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with \(^{68}\)Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from \(^{68}\)Ga- to \(^{18}\)F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite \(^{68}\)Ge/\(^{68}\)Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, \(^{18}\)F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, \(^{18}\)F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging \(^{18}\)F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available \(^{18}\)F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.
KW  - Radiofluorine
KW  - prostate-specific membrane antigen
KW  - prostate cancer
KW  - \(^{18}\)F
KW  - PSMA
KW  - \(^{68}\)Ga
KW  - theranostics
KW  - radioligand therapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202559
SN  - 1838-7640
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Essig, Fabian
A1  - Kollikowski, Alexander M.
A1  - Pham, Mirko
A1  - Solymosi, László
A1  - Stoll, Guido
A1  - Haeusler, Karl Georg
A1  - Kraft, Peter
A1  - Schuhmann, Michael K.
T1  - Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke
JF  - International Journal of Molecular Sciences
N2  - Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.
KW  - acute ischemic stroke
KW  - thrombemboli
KW  - neutrophils
KW  - NETs
KW  - immunohistochemistry
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236192
SN  - 1422-0067
VL  - 21
IS  - 19
ER  - 
TY  - JOUR
A1  - Bolm, Louisa
A1  - Zemskov, Sergii
A1  - Zeller, Maria
A1  - Baba, Taisuke
A1  - Roldan, Jorge
A1  - Harrison, Jon M.
A1  - Petruch, Natalie
A1  - Sato, Hiroki
A1  - Petrova, Ekaterina
A1  - Lapshyn, Hryhoriy
A1  - Braun, Ruediger
A1  - Honselmann, Kim C.
A1  - Hummel, Richard
A1  - Dronov, Oleksii
A1  - Kirichenko, Alexander V.
A1  - Klinkhammer-Schalke, Monika
A1  - Kleihues-van Tol, Kees
A1  - Zeissig, Sylke R.
A1  - Rades, Dirk
A1  - Keck, Tobias
A1  - Fernandez-del Castillo, Carlos
A1  - Wellner, Ulrich F.
A1  - Wegner, Rodney E.
T1  - Concepts and outcomes of perioperative therapy in stage IA-III pancreatic cancer — a cross-validation of the National Cancer Database (NCDB) and the German Cancer Registry Group of the Society of German Tumor Centers (GCRG/ADT)
JF  - Cancers
N2  - (1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers — Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone.
KW  - pancreatic cancer
KW  - perioperative therapy
KW  - neoadjuvant therapy
KW  - pancreatic surgery
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262174
SN  - 2072-6694
VL  - 14
IS  - 4
ER  - 
TY  - JOUR
A1  - Schuhmann, Michael K.
A1  - Kraft, Peter
A1  - Bieber, Michael
A1  - Kollikowski, Alexander M.
A1  - Schulze, Harald
A1  - Nieswandt, Bernhard
A1  - Pham, Mirko
A1  - Stegner, David
A1  - Stoll, Guido
T1  - Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice
JF  - International Journal of Molecular Science
N2  - Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{−/−}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.
KW  - ischemic stroke
KW  - integrin α2
KW  - glycoprotein VI
KW  - recombinant tissue-type plasminogen activator
KW  - intracranial bleeding
KW  - transient middle cerebral artery occlusion
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201700
SN  - 1422-0067
VL  - 20
IS  - 8
ER  - 
TY  - JOUR
A1  - Eder, Andreas B.
A1  - Maas, Franzisca
A1  - Schubmann, Alexander
A1  - Krishna, Anand
A1  - Erle, Thorsten M.
T1  - Motivations underlying self-infliction of pain during thinking for pleasure
JF  - Scientific Reports
N2  - Previous research suggested that people prefer to administer unpleasant electric shocks to themselves rather than being left alone with their thoughts because engagement in thinking is an unpleasant activity. The present research examined this negative reinforcement hypothesis by giving participants a choice of distracting themselves with the generation of electric shock causing no to intense pain. Four experiments (N = 254) replicated the result that a large proportion of participants opted to administer painful shocks to themselves during the thinking period. However, they administered strong electric shocks to themselves even when an innocuous response option generating no or a mild shock was available. Furthermore, participants inflicted pain to themselves when they were assisted in the generation of pleasant thoughts during the waiting period, with no difference between pleasant versus unpleasant thought conditions. Overall, these results question that the primary motivation for the self-administration of painful shocks is avoidance of thinking. Instead, it seems that the self-infliction of pain was attractive for many participants, because they were curious about the shocks, their intensities, and the effects they would have on them.
KW  - pain
KW  - self-infliction
KW  - thinking
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301059
VL  - 12
IS  - 1
ER  - 
TY  - JOUR
A1  - Kollikowski, Alexander M.
A1  - Schuhmann, Michael K.
A1  - Nieswandt, Bernhard
A1  - Müllges, Wolfgang
A1  - Stoll, Guido
A1  - Pham, Mirko
T1  - Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke
JF  - Annals of Neurology
N2  - Objective
Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization.


Methods
We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines.


Results
Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T‐cell chemoattractant CXCL‐11. Finally, we found evidence that short‐term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation.


Interpretation
We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466–479
KW  - neurology
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212168
VL  - 87
IS  - 3
ER  - 
TY  - JOUR
A1  - Schuhmann, Michael K.
A1  - Bieber, Michael
A1  - Franke, Maximilian
A1  - Kollikowski, Alexander M.
A1  - Stegner, David
A1  - Heinze, Katrin G.
A1  - Nieswandt, Bernhard
A1  - Pham, Mirko
A1  - Stoll, Guido
T1  - Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice
JF  - Journal of Neuroinflammation
N2  - Background

In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood.

Methods

To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1\(^{−/−}\) mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion.

Results

We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion.

Conclusions

Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.
KW  - ischemic penumbra
KW  - glycoprotein receptor Ib
KW  - T-cells
KW  - ischemic stroke
KW  - thrombo-inflammation
KW  - middle cerebral artery occlusion
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259172
VL  - 18
IS  - 1
ER  - 
TY  - JOUR
A1  - Lange, Florian
A1  - Steigerwald, Frank
A1  - Malzacher, Tobias
A1  - Brandt, Gregor Alexander
A1  - Odorfer, Thorsten Michael
A1  - Roothans, Jonas
A1  - Reich, Martin M.
A1  - Fricke, Patrick
A1  - Volkmann, Jens
A1  - Matthies, Cordula
A1  - Capetian, Philipp D.
T1  - Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming
JF  - Frontiers in Neurology
N2  - Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model.
Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated.
Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32).
Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.
KW  - directional deep brain stimulation
KW  - image-guided programming
KW  - subthalamic nucleus
KW  - chronic stimulation
KW  - randomized controlled double-blind study
KW  - Parkinson's disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249634
SN  - 1664-2295
VL  - 12
ER  - 
TY  - JOUR
A1  - Bell, Luisa
A1  - Lenhart, Alexander
A1  - Rosenwald, Andreas
A1  - Monoranu, Camelia M.
A1  - Berberich-Siebelt, Friederike
T1  - Lymphoid aggregates in the CNS of progressive multiple sclerosis patients lack regulatory T cells
JF  - Frontiers in Immunology
N2  - In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity. Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis. Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions. GC reactions are controlled by FOXP3+ T-follicular regulatory cells (TFR), but it is unknown if they participate in autoantibody production in eLFs. Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci. CD35+ cells, parafollicular CD138+ plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs. However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells. Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3+CD27+ memory and CD4+CD69+ tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation. Intriguingly, FOXP3+ cells were almost absent in the whole brain sections and CD3+FOXP3+ TFRs were never found in the lymphoid aggregates. This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.
KW  - ectopic lymphoid follicle
KW  - lymphoid aggregate
KW  - T-follicular regulatory cell
KW  - meningeal inflammation
KW  - NFATc1
KW  - progressive multiple sclerosis
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198130
SN  - 1664-3224
VL  - 10
IS  - 3090
ER  - 
TY  - JOUR
A1  - Lübtow, Michael  M.
A1  - Marciniak, Henning
A1  - Schmiedel, Alexander
A1  - Roos, Markus
A1  - Lambert, Christoph
A1  - Luxenhofer, Robert
T1  - Ultra-high to ultra-low drug loaded micelles: Probing host-guest interactions by fluorescence spectroscopy
JF  - Chemistry - A European Journal
N2  - Polymer micelles are an attractive means to solubilize water insoluble compounds such as drugs. Drug loading, formulations stability and control over drug release are crucial factors for drug‐loaded polymer micelles. The interactions between the polymeric host and the guest molecules are considered critical to control these factors but typically barely understood. Here, we compare two isomeric polymer micelles, one of which enables ultra‐high curcumin loading exceeding 50 wt.%, while the other allows a drug loading of only 25 wt.%. In the low capacity micelles, steady‐state fluorescence revealed a very unusual feature of curcumin fluorescence, a high energy emission at 510 nm. Time‐resolved fluorescence upconversion showed that the fluorescence life time of the corresponding species is too short in the high‐capacity micelles, preventing an observable emission in steady‐state. Therefore, contrary to common perception, stronger interactions between host and guest can be detrimental to the drug loading in polymer micelles.
KW  - curcumin
KW  - drug delivery
KW  - fluorenscence
KW  - poly(2-oxazine)
KW  - pol(2-oxazoline)
KW  - Polymer-drug interaction
KW  - upconversion
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206128
VL  - 25
IS  - 54
ER  - 
TY  - JOUR
A1  - Nedopil, Alexander J.
A1  - Dhaliwal, Anand
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - A surgeon that switched to unrestricted kinematic alignment with manual instruments has a short learning curve and comparable resection accuracy and outcomes to those of an experienced surgeon
JF  - Journal of Personalized Medicine
N2  - After starting an orthopedic practice, a surgeon with a fellowship in mechanically aligned (MA) TKA initiated this study to characterize their learning curve after they switched to unrestricted kinematic alignment (KA) TKA using manual instruments. Accordingly, the present study determined for the inexperienced (IE) surgeon the number of cases required to achieve consistent femoral resections and operating times, and whether the femoral resection accuracy, patient-reported outcome measures (PROMs), and component alignment were different from an experienced (E) surgeon. This prospective cohort study analyzed the IE surgeon's first 30 TKAs, all performed with KA, and 30 consecutive KA TKAs performed by an E surgeon. The resection accuracy or deviation was the calipered thickness of the distal and posterior medial and lateral femoral resections minus the planned resection thickness, which was the thickness of the corresponding condyle of the femoral component, minus 2 mm for cartilage wear, and 1 mm for the kerf of the blade. Independent observers recorded the femoral resection thickness, operative times, PROMs, and alignment. For each femoral resection, the deviation between three groups of patients containing ten consecutive KA TKAs, was either insignificant (p = 0.695 to 1.000) or within the 0.5 mm resolution of the caliper, which indicated no learning curve. More than three groups were needed to determine the learning curve for the operative time; however, the IE surgeon's procedure dropped to 77 min for the last 10 patients, which was 20 min longer than the E surgeon. The resection deviations of the IE and E surgeon were comparable, except for the posterolateral femoral resection, which the IE surgeon under-resected by a mean of −0.8 mm (p < 0.0001). At a mean follow-up of 9 and 17 months, the Forgotten Joint Score, Oxford Knee Score, KOOS, and the alignment of the components and limbs were not different between the IE and E surgeon (p ≥ 0.6994). A surgeon that switches to unrestricted KA with manual instruments can determine their learning curve by computing the deviation of the distal and posterior femoral resections from the planned resection. Based on the present study, an IE surgeon could have resection accuracy, post-operative patient outcomes, and component alignment comparable to an E surgeon.
KW  - total knee arthroplasty
KW  - kinematic alignment
KW  - learning curve
KW  - accuracy
KW  - efficiency
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281842
SN  - 2075-4426
VL  - 12
IS  - 7
ER  - 
TY  - JOUR
A1  - Griebsch, Nora-Isabell
A1  - Kern, Johanna
A1  - Hansen, Jonas
A1  - Rullmann, Michael
A1  - Luthardt, Julia
A1  - Helfmeyer, Stephanie
A1  - Dekorsy, Franziska J.
A1  - Soeder, Marvin
A1  - Hankir, Mohammed K.
A1  - Zientek, Franziska
A1  - Becker, Georg-Alexander
A1  - Patt, Marianne
A1  - Meyer, Philipp M.
A1  - Dietrich, Arne
A1  - Blüher, Matthias
A1  - Ding, Yu-Shin
A1  - Hilbert, Anja
A1  - Sabri, Osama
A1  - Hesse, Swen
T1  - Central serotonin/noradrenaline transporter availability and treatment success in patients with obesity
JF  - Brain Sciences
N2  - Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
KW  - obesity
KW  - serotonin
KW  - noradrenaline
KW  - serotonin transporter
KW  - noradrenaline transporter
KW  - Roux-en-Y gastric bypass surgery
KW  - body mass index (BMI; kg/m\(^2\))
KW  - radiotracer
KW  - PET
KW  - PET imaging
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290294
SN  - 2076-3425
VL  - 12
IS  - 11
ER  - 
TY  - JOUR
A1  - Schmitz, Sophia M.
A1  - Storms, Sebastian
A1  - Koch, Alexander
A1  - Stier, Christine
A1  - Kroh, Andreas
A1  - Rheinwalt, Karl P.
A1  - Schipper, Sandra
A1  - Hamesch, Karim
A1  - Ulmer, Tom F.
A1  - Neumann, Ulf P.
A1  - Alizai, Patrick H.
T1  - Insulin resistance is the main characteristic of metabolically unhealthy obesity (MUO) associated with NASH in patients undergoing bariatric surgery
JF  - Biomedicines
N2  - (1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.
KW  - NAFLD
KW  - metabolically unhealthy obesity
KW  - obesity surgery
KW  - insulin resistance
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319213
SN  - 2227-9059
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Nedopil, Alexander J.
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - A TKA insert with a lateral flat articular surface maximizes external and internal tibial orientations without anterior lift-off relative to low- and ultracongruent surfaces
JF  - Journal of Personalized Medicine
N2  - Background: In total knee arthroplasty (TKA), inserts can have different levels of medial and lateral congruency determined by the acuteness of the upslopes of the anterior and posterior articular surfaces. The present study evaluated an insert with different levels of lateral congruency and a medial ball-in-socket congruency to test the hypothesis that a lateral flat (F) insert maximizes external tibial orientation at extension and internal orientation at 90° flexion and lowers the incidence of anterior lift-off relative to low-congruent (LC) and ultracongruent (UC) lateral inserts. Methods: Two surgeons treated 23 patients with unrestricted caliper-verified kinematic alignment (KA) and posterior cruciate ligament (PCL) retention. They randomly trialed inserts with a medial radial dial that functioned as a built-in goniometer by measuring the tibial orientation relative to a sagittal line on the femoral trial component. Anterior lift-off of the insert from the baseplate indicated PCL tightness. Results: The F insert’s mean of 9° of external tibial orientation was higher than that of the LC (5°, p < 0.0001) and UC inserts (2°, p < 0.0001). The −13° of internal tibial orientation at 90° flexion was higher than that of the LC (−9°, p < 0.0001) and UC inserts (−7°, p < 0.0001). The 0% incidence of anterior lift-off was less than that of the LC (26%) and UC inserts (57%) (p < 0.0001). Conclusions: Surgeons and implant manufacturers should know that adding congruency to the lateral articular surface limits external tibial orientation in extension and internal tibial orientation at 90° flexion and overtightens the PCL. These rotational limitations and flexion space tightness can adversely affect patellofemoral tracking and knee flexion.
KW  - total knee arthroplasty
KW  - kinematic alignment
KW  - implant design
KW  - PCL retention
KW  - congruency
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286142
SN  - 2075-4426
VL  - 12
IS  - 8
ER  - 
TY  - JOUR
A1  - Nedopil, Alexander J.
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - Measurement of tibial orientation helps select the optimal insert thickness to personalize PCL tension in a medial ball-in-socket TKA
JF  - Journal of Personalized Medicine
N2  - As the conformity of a medial ball-in-socket total knee arthroplasty (TKA) provides intrinsic anterior-posterior (A-P) stability, surgeons cannot rely on the manual examination of sagittal laxity to identify the optimal insert thickness. Instead, the present study determined whether measuring tibial axial orientation in extension and 90° flexion with an insert goniometer could identify the optimal thickness that, when implanted, provides high postoperative function. In twenty-two patients that underwent unrestricted caliper-verified kinematic alignment (KA) with a PCL retaining implant, two surgeons measured tibial orientation in extension and 90° flexion with 10, 11, 12, and 13 mm thick insert goniometers. Each TKA had one insert thickness that restored either the maximum external tibial orientation in extension, the maximum internal tibial orientation at 90° flexion, or both relative to 1 mm thinner and thicker inserts. In addition, the 6-month median [interquartile range] Forgotten Joint Score of 73 (54–87) and Oxford Knee Score of 42 (38–45) indicated high satisfaction and function. In conclusion, surgeons using a medial ball-in-socket TKA design can measure external tibial orientation in extension and internal tibial orientation at 90° flexion with an insert goniometer. Furthermore, implanting an insert with the thickness that provided the maximum orientation values resulted in high postoperative function, thereby personalizing PCL tension.
KW  - posterior cruciate ligament
KW  - tibial rotation
KW  - medial pivot
KW  - total knee arthroplasty
KW  - kinematic alignment
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286232
SN  - 2075-4426
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Dhaliwal, Anand
A1  - Zamora, Tomas
A1  - Nedopil, Alexander J.
A1  - Howell, Stephen M.
A1  - Hull, Maury L.
T1  - Six commonly used postoperative radiographic alignment parameters do not predict clinical outcome scores after unrestricted caliper-verified kinematically aligned TKA
JF  - Journal of Personalized Medicine
N2  - Background: Unrestricted caliper-verified kinematically aligned (KA) TKA restores patient’s prearthritic coronal and sagittal alignments, which have a wide range containing outliers that concern the surgeon practicing mechanical alignment (MA). Therefore, knowing which radiographic parameters are associated with dissatisfaction could help a surgeon decide whether to rely on them as criteria for revising an unhappy patient with a primary KA TKA using MA principles. Hence, we determined whether the femoral mechanical angle (FMA), hip–knee–ankle angle (HKAA), tibial mechanical angle (TMA), tibial slope angle (TSA), and the indicators of patellofemoral tracking, including patella tilt angle (PTA) and the lateral undercoverage of the trochlear resection (LUCTR), are associated with clinical outcome scores. Methods: Forty-three patients with a CT scan and skyline radiograph after a KA TKA with PCL retention and medial stabilized design were analyzed. Linear regression determined the strength of the association between the FMA, HKA angle, PTS, PTA, and LUCTR and the forgotten joint score (FJS), Oxford knee score (OKS), and KOOS Jr score obtained at a mean of 23 months. Results: There was no correlation between the FMA (range 2° varus to −10° valgus), HKAA (range 10° varus to −9° valgus), TMA (range 10° varus to −0° valgus), TSA (range 14° posterior to −4° anterior), PTA (range, −10° medial to 14° lateral), and the LUCTR resection (range 2 to 9 mm) and the FJS (median 83), the OKS (median 44), and the KOOS Jr (median 85) (r = 0.000 to 0.079). Conclusions: Surgeons should be cautious about using postoperative FMA, HKAA, TMA, TSA, PTA, and LUCTR values within the present study’s reported ranges to explain success and dissatisfaction after KA TKA.
KW  - total knee arthroplasty
KW  - kinematic alignment
KW  - reoperation
KW  - revision
KW  - phenotype
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288186
SN  - 2075-4426
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Tanoey, Justine
A1  - Baechle, Christina
A1  - Brenner, Hermann
A1  - Deckert, Andreas
A1  - Fricke, Julia
A1  - Günther, Kathrin
A1  - Karch, André
A1  - Keil, Thomas
A1  - Kluttig, Alexander
A1  - Leitzmann, Michael
A1  - Mikolajczyk, Rafael
A1  - Obi, Nadia
A1  - Pischon, Tobias
A1  - Schikowski, Tamara
A1  - Schipf, Sabine M.
A1  - Schulze, Matthias B.
A1  - Sedlmeier, Anja
A1  - Moreno Velásquez, Ilais
A1  - Weber, Katharina S.
A1  - Völzke, Henry
A1  - Ahrens, Wolfgang
A1  - Gastell, Sylvia
A1  - Holleczek, Bernd
A1  - Jöckel, Karl-Heinz
A1  - Katzke, Verena
A1  - Lieb, Wolfgang
A1  - Michels, Karin B.
A1  - Schmidt, Börge
A1  - Teismann, Henning
A1  - Becher, Heiko
T1  - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort
JF  - International Journal of Environmental Research and Public Health
N2  - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.
KW  - perinatal
KW  - adult-onset
KW  - late-onset
KW  - autoimmune
KW  - delivery mode
KW  - sex
KW  - offspring
KW  - NAKO
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216
SN  - 1660-4601
VL  - 19
IS  - 17
ER  - 
TY  - JOUR
A1  - Winter, Anna
A1  - Schulz, Stefan M.
A1  - Schmitter, Marc
A1  - Brands, Roman C.
A1  - Straub, Anton
A1  - Kübler, Alexander
A1  - Borgmann, Anna
A1  - Hartmann, Stefan
T1  - Oral-health-related quality of life in patients with medication-related osteonecrosis of the jaw: a prospective clinical study
JF  - International Journal of Environmental Research and Public Health
N2  - Medication-related osteonecrosis of the jaw (MRONJ) represents an adverse side effect of antiresorptive and antiangiogenic medications. It is associated with impaired quality of life, oral health, and oral function and can be classified into various stages. The purpose of this prospective clinical study is to evaluate the impact of stages I and II MRONJ on oral-health-related quality of life (OHRQoL) and related parameters. Patients’ OHRQoL, satisfaction with life, oral discomfort, and oral health were assessed using the German version of the Oral Health Impact Profile (OHIP-G49), visual analog scales (VAS), and Satisfaction with Life Scale (SWLS) at baseline (T0), 10 days (T1), and 3 months after treatment (T2) in 36 patients. Data were analyzed using Kolmogorov–Smirnov test, two-way mixed ANOVAs, and follow-up Mann–Whitney U tests. The impact of treatment effects on the original seven OHIP domain structures and the recently introduced four-dimensional OHIP structure were evaluated using linear regression analysis. Thirty-six patients received surgical MRONJ treatment. Before treatment, patients’ perceived OHRQoL, oral discomfort, oral health, and satisfaction with life were negatively affected by MRONJ. Surgical treatment significantly improved OHRQoL and related parameters (all p ≤ 0.012). This improvement was greater in patients with higher impairment at T0. OHRQoL and oral restrictions were still impaired after treatment in patients who needed prosthetic treatment. The four-dimensional structure revealed valuable information beyond the standard seven OHIP domains. Increased awareness of MRONJ risks and an interdisciplinary treatment approach for MRONJ patients are needed.
KW  - oral-health-related quality of life
KW  - satisfaction with life
KW  - oral health
KW  - medication-related osteonecrosis of the jaw
KW  - treatment benefit
KW  - OHIP-49
KW  - SWLS
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288141
SN  - 1660-4601
VL  - 19
IS  - 18
ER  - 
TY  - JOUR
A1  - Sappey-Marinier, Elliot
A1  - Howell, Stephen M.
A1  - Nedopil, Alexander J.
A1  - Hull, Maury L.
T1  - The trochlear groove of a femoral component designed for kinematic alignment is lateral to the quadriceps line of force and better laterally covers the anterior femoral resection than a mechanical alignment design
JF  - Journal of Personalized Medicine
N2  - Background: A concern about kinematically aligned (KA) total knee arthroplasty (TKA) is that it relies on femoral components designed for mechanical alignment (MAd-FC) that could affect patellar tracking, in part, because of a trochlear groove orientation that is typically 6° from vertical. KA sets the femoral component coincident to the patient’s pre-arthritic distal and posterior femoral joint lines and restores the Q-angle, which varies widely. Relative to KA and the native knee, aligning the femoral component with MA changes most distal joint lines and Q-angles, and rotates the posterior joint line externally laterally covering the anterior femoral resection. Whether switching from a MAd- to a KAd-FC with a wider trochlear groove orientation of 20.5° from vertical results in radiographic measures known to promote patellar tracking is unknown. The primary aim was to determine whether a KAd-FC sets the trochlear groove lateral to the quadriceps line of force (QLF), better laterally covers the anterior femoral resection, and reduces lateral patella tilt relative to a MAd-FC. The secondary objective was to determine at six weeks whether the KAd-FC resulted in a higher complication rate, less knee extension and flexion, and lower clinical outcomes. Methods: Between April 2019 and July 2022, two surgeons performed sequential bilateral unrestricted caliper-verified KA TKA with manual instruments on thirty-six patients with a KAd- and MAd-FC in opposite knees. An observer measured the angle between a line best-fit to the deepest valley of the trochlea and a line representing the QLF that indicated the patient’s Q-angle. When the trochlear groove was lateral or medial relative to the QLF, the angle is denoted + or −, and the femoral component included or excluded the patient’s Q-angle, respectively. Software measured the lateral undercoverage of the anterior femoral resection on a Computed Tomography (CT) scan, and the patella tilt angle (PTA) on a skyline radiograph. Complications, knee extension and flexion measurements, Oxford Knee Score, KOOS Jr, and Forgotten Joint Score were recorded pre- and post-operatively (at 6 weeks). A paired Student’s T-test determined the difference between the KA TKAs with a KAd-FC and MAd-FC with a significance set at p < 0.05. Results: The final analysis included thirty-five patients. The 20.5° trochlear groove of the KAd-FC was lateral to the QLF in 100% (15 ± 3°) of TKAs, which was greater than the 69% (1 ± 3°) lateral to the QLF with the 6° trochlear groove of the MAd-FC (p < 0.001). The KAd-FC’s 2 ± 1.9 mm lateral undercoverage of the anterior femoral resection was less than the 4.4 ± 1.5 mm for the MAd-FC (p < 0.001). The PTA, complication rate, knee extension and flexion, and clinical outcome measures did not differ between component designs. Conclusions: The KA TKA with a KAd-FC resulted in a trochlear groove lateral to the QLF that included the Q-angle in all patients, and negligible lateral undercoverage of the anterior femoral resection. These newly described radiographic parameters could be helpful when investigating femoral components designed for KA with the intent of promoting patellofemoral kinematics.
KW  - total knee arthroplasty
KW  - lateral trochlear undercoverage
KW  - prosthetic design
KW  - kinematic alignment
KW  - patellofemoral relationship
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290482
SN  - 2075-4426
VL  - 12
IS  - 10
ER  - 
TY  - JOUR
A1  - Haarmann, Axel
A1  - Vollmuth, Christoph
A1  - Kollikowski, Alexander M.
A1  - Heuschmann, Peter U.
A1  - Pham, Mirko
A1  - Stoll, Guido
A1  - Neugebauer, Hermann
A1  - Schuhmann, Michael K.
T1  - Vasoactive soluble endoglin: a novel biomarker indicative of reperfusion after cerebral large-vessel occlusion
JF  - Cells
N2  - Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-β co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.
KW  - endoglin
KW  - brain endothelium
KW  - stroke
KW  - shedding
KW  - mechanical thrombectomy
KW  - hypoxia
KW  - reperfusion injury
KW  - biomarker
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304995
SN  - 2073-4409
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Haake, Markus
A1  - Haack, Beatrice
A1  - Schäfer, Tina
A1  - Harter, Patrick N.
A1  - Mattavelli, Greta
A1  - Eiring, Patrick
A1  - Vashist, Neha
A1  - Wedekink, Florian
A1  - Genssler, Sabrina
A1  - Fischer, Birgitt
A1  - Dahlhoff, Julia
A1  - Mokhtari, Fatemeh
A1  - Kuzkina, Anastasia
A1  - Welters, Marij J. P.
A1  - Benz, Tamara M.
A1  - Sorger, Lena
A1  - Thiemann, Vincent
A1  - Almanzar, Giovanni
A1  - Selle, Martina
A1  - Thein, Klara
A1  - Späth, Jacob
A1  - Gonzalez, Maria Cecilia
A1  - Reitinger, Carmen
A1  - Ipsen-Escobedo, Andrea
A1  - Wistuba-Hamprecht, Kilian
A1  - Eichler, Kristin
A1  - Filipski, Katharina
A1  - Zeiner, Pia S.
A1  - Beschorner, Rudi
A1  - Goedemans, Renske
A1  - Gogolla, Falk Hagen
A1  - Hackl, Hubert
A1  - Rooswinkel, Rogier W.
A1  - Thiem, Alexander
A1  - Romer Roche, Paula
A1  - Joshi, Hemant
A1  - Pühringer, Dirk
A1  - Wöckel, Achim
A1  - Diessner, Joachim E.
A1  - Rüdiger, Manfred
A1  - Leo, Eugen
A1  - Cheng, Phil F.
A1  - Levesque, Mitchell P.
A1  - Goebeler, Matthias
A1  - Sauer, Markus
A1  - Nimmerjahn, Falk
A1  - Schuberth-Wagner, Christine
A1  - Felten, Stefanie von
A1  - Mittelbronn, Michel
A1  - Mehling, Matthias
A1  - Beilhack, Andreas
A1  - van der Burg, Sjoerd H.
A1  - Riedel, Angela
A1  - Weide, Benjamin
A1  - Dummer, Reinhard
A1  - Wischhusen, Jörg
T1  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
JF  - Nature Communications
N2  - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
KW  - cancer microenvironment
KW  - immunotherapy
KW  - T cells
KW  - tumour immunology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333
VL  - 14
ER  - 
TY  - JOUR
A1  - Adam, Alexander
A1  - Deimel, Stephan
A1  - Pardo-Medina, Javier
A1  - García-Martínez, Jorge
A1  - Konte, Tilen
A1  - Limón, M. Carmen
A1  - Avalos, Javier
A1  - Terpitz, Ulrich
T1  - Protein activity of the \(Fusarium\) \(fujikuroi\) rhodopsins CarO and OpsA and their relation to fungus−plant interaction
JF  - International Journal of Molecular Sciences
N2  - Fungi possess diverse photosensory proteins that allow them to perceive different light wavelengths and to adapt to changing light conditions in their environment. The biological and physiological roles of the green light-sensing rhodopsins in fungi are not yet resolved. The rice plant pathogen Fusarium fujikuroi exhibits two different rhodopsins, CarO and OpsA. CarO was previously characterized as a light-driven proton pump. We further analyzed the pumping behavior of CarO by patch-clamp experiments. Our data show that CarO pumping activity is strongly augmented in the presence of the plant hormone indole-3-acetic acid and in sodium acetate, in a dose-dependent manner under slightly acidic conditions. By contrast, under these and other tested conditions, the Neurospora rhodopsin (NR)-like rhodopsin OpsA did not exhibit any pump activity. Basic local alignment search tool (BLAST) searches in the genomes of ascomycetes revealed the occurrence of rhodopsin-encoding genes mainly in phyto-associated or phytopathogenic fungi, suggesting a possible correlation of the presence of rhodopsins with fungal ecology. In accordance, rice plants infected with a CarO-deficient F. fujikuroi strain showed more severe bakanae symptoms than the reference strain, indicating a potential role of the CarO rhodopsin in the regulation of plant infection by this fungus.
KW  - fungal rhodopsins
KW  - CarO
KW  - OpsA
KW  - Fusarium fujikuroi
KW  - Oryza sativa
KW  - rice–plant infection
KW  - green light perception
KW  - indole-3-acetic acid (IAA)
KW  - bakanae
KW  - patch-clamp
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285125
SN  - 1422-0067
VL  - 19
IS  - 1
ER  - 
TY  - JOUR
A1  - Grotemeyer, Alexander
A1  - Fischer, Judith F.
A1  - Koprich, James B.
A1  - Brotchie, Jonathan M.
A1  - Blum, Robert
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
T1  - Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease
JF  - Journal of Neuroinflammation
N2  - Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.
KW  - neurodegeneration
KW  - movement disorder
KW  - neuroinflammation
KW  - Parkinson’s disease
KW  - inflammasome
KW  - dopaminergic cells
KW  - NLRP3
KW  - MCC950
KW  - microglia
KW  - T cells
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357652
VL  - 20
ER  - 
TY  - JOUR
A1  - China, Swarup
A1  - Burrows, Susannah M.
A1  - Wang, Bingbing
A1  - Harder, Tristan H.
A1  - Weis, Johannes
A1  - Tanarhte, Meryem
A1  - Rizzo, Luciana V.
A1  - Brito, Joel
A1  - Cirino, Glauber G.
A1  - Ma, Po-Lun
A1  - Cliff, John
A1  - Artaxo, Paulo
A1  - Gilles, Mary K.
A1  - Laskin, Alexander
T1  - Fungal spores as a source of sodium salt particles in the Amazon basin
JF  - Nature Communications
N2  - In the Amazon basin, particles containing mixed sodium salts are routinely observed and are attributed to marine aerosols transported from the Atlantic Ocean. Using chemical imaging analysis, we show that, during the wet season, fungal spores emitted by the forest biosphere contribute at least 30% (by number) to sodium salt particles in the central Amazon basin. Hydration experiments indicate that sodium content in fungal spores governs their growth factors. Modeling results suggest that fungal spores account for ~69% (31–95%) of the total sodium mass during the wet season and that their fractional contribution increases during nighttime. Contrary to common assumptions that sodium-containing aerosols originate primarily from marine sources, our results suggest that locally-emitted fungal spores contribute substantially to the number and mass of coarse particles containing sodium. Hence, their role in cloud formation and contribution to salt cycles and the terrestrial ecosystem in the Amazon basin warrant further consideration.
KW  - atmospheric chemistry
KW  - biogeochemistry
KW  - environmental sciences
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222492
VL  - 9
ER  - 
TY  - JOUR
A1  - Winter, Anna
A1  - Schulz, Stefan M.
A1  - Schmitter, Marc
A1  - Müller-Richter, Urs
A1  - Kübler, Alexander
A1  - Kasper, Sylvia
A1  - Hartmann, Stefan
T1  - Comprehensive geriatric assessment and quality of life aspects in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)
JF  - Journal of Clinical Medicine
N2  - To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov–Smirnov test, Spearman’s rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be “frail”. Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.
KW  - frailty
KW  - geriatric cancer patient
KW  - recurrent/metastatic head and neck squamous cell carcinoma
KW  - oral health-related quality of life
KW  - prosthetic rehabilitation
KW  - oral functional capacity
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363096
SN  - 2077-0383
VL  - 12
IS  - 17
ER  - 
TY  - JOUR
A1  - Dubail, Johanne
A1  - Huber, Céline
A1  - Chantepie, Sandrine
A1  - Sonntag, Stephan
A1  - Tüysüz, Beyhan
A1  - Mihci, Ercan
A1  - Gordon, Christopher T.
A1  - Steichen-Gersdorf, Elisabeth
A1  - Amiel, Jeanne
A1  - Nur, Banu
A1  - Stolte-Dijkstra, Irene
A1  - van Eerde, Albertien M.
A1  - van Gassen, Koen L.
A1  - Breugem, Corstiaan C.
A1  - Stegmann, Alexander
A1  - Lekszas, Caroline
A1  - Maroofian, Reza
A1  - Karimiani, Ehsan Ghayoor
A1  - Bruneel, Arnaud
A1  - Seta, Nathalie
A1  - Munnich, Arnold
A1  - Papy-Garcia, Dulce
A1  - De La Dure-Molla, Muriel
A1  - Cormier-Daire, Valérie
T1  - SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects
JF  - Nature Communications
N2  - Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7−/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7−/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.
KW  - bone development
KW  - disease genetics
KW  - medical genetics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226377
VL  - 9
ER  - 
TY  - JOUR
A1  - Bittner, Stefan
A1  - Bobak, Nicole
A1  - Feuchtenberger, Martin
A1  - Herrmann, Alexander M
A1  - Göbel, Kerstin
A1  - Kinne, Raimund W
A1  - Hansen, Anker J
A1  - Budde, Thomas
A1  - Kleinschnitz, Christoph
A1  - Frey, Oliver
A1  - Tony, Hans-Peter
A1  - Wiendl, Heinz
A1  - Meuth, Sven G
T1  - Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients
JF  - Arthritis Research & Therapy
N2  - Introduction

CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients.

Methods

Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1.

Results

K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months.

Conclusions

Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis.
KW  - neurology
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139334
VL  - 13
IS  - R21
ER  - 
TY  - JOUR
A1  - Jahnke, Frank
A1  - Gies, Christopher
A1  - Aßmann, Marc
A1  - Bayer, Manfred
A1  - Leymann, H.A.M.
A1  - Foerster, Alexander
A1  - Wiersig, Jan
A1  - Schneider, Christian
A1  - Kamp, Martin
A1  - Höfling, Sven
T1  - Giant photon bunching, superradiant pulse emission and excitation trapping in quantum-dot nanolasers
JF  - Nature Communications
N2  - Light is often characterized only by its classical properties, like intensity or coherence. When looking at its quantum properties, described by photon correlations, new information about the state of the matter generating the radiation can be revealed. In particular the difference between independent and entangled emitters, which is at the heart of quantum mechanics, can be made visible in the photon statistics of the emitted light. The well-studied phenomenon of superradiance occurs when quantum–mechanical correlations between the emitters are present. Notwithstanding, superradiance was previously demonstrated only in terms of classical light properties. Here, we provide the missing link between quantum correlations of the active material and photon correlations in the emitted radiation. We use the superradiance of quantum dots in a cavity-quantum electrodynamics laser to show a direct connection between superradiant pulse emission and distinctive changes in the photon correlation function. This directly demonstrates the importance of quantum–mechanical correlations and their transfer between carriers and photons in novel optoelectronic devices.
KW  - photon bunching
KW  - quantum mechanics
KW  - superradiant pulse emission
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166144
VL  - 7
IS  - 11540
ER  -