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Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 … controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Authors: Catherine M. Phelan, Karoline B. Kuchenbaecker, Jonathan P. Tyrer, Siddhartha P. Kar, Kate Lawrenson, Stacey J. Winham, Joe Dennis, Ailith Pirie, Marjorie J. Riggan, Ganna Chornokur, Madalene A. Earp, Paulo C. Lyra, Janet M. Lee, Simon Coetzee, Jonathan Beesley, Lesley McGuffog, Penny Soucy, Ed Dicks, Andrew Lee, Daniel Barrowdale, Julie Lecarpentier, Goska Leslie, Cora M. Aalfs, Katja K. H. Aben, Marcia Adams, Julian Adlard, Irene L. Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Gerasimos Aravantinos, Norbert Arnold, Banu K. Arun, Brita Arver, Jacopo Azzollini, Judith Balmaña, Susana N. Banerjee, Laure Barjhoux, Rosa B. Barkardottir, Yukie Bean, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Marcus Q. Bernardini, Michael J. Birrer, Line Bjorge, Amanda Black, Kenneth Blankstein, Marinus J. Blok, Clara Bodelon, Natalia Bogdanova, Anders Bojesen, Bernardo Bonanni, Åke Borg, Angela R. Bradbury, James D. Brenton, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Fiona Bruinsma, Joan Brunet, Bruno Buecher, Ralf Butzow, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Rikki Cannioto, Michael E. Carney, Terence Cescon, Salina B. Chan, Jenny Chang-Claude, Stephen Chanock, Xiao Qing Chen, Yoke-Eng Chiew, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, Thomas Conner, Linda S. Cook, Jackie Cook, Daniel W. Cramer, Julie M. Cunningham, Aimee A. D’Aloisio, Mary B. Daly, Francesca Damiola, Sakaeva Dina Damirovna, Agnieszka Dansonka-Mieszkowska, Fanny Dao, Rosemarie Davidson, Anna deFazio, Capucine Delnatte, Kimberly F. Doheny, Orland Diez, Yuan Chun Ding, Jennifer Anne Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Laure Dossus, Mercedes Duran, Matthias Dürst, Bernd Dworniczak, Diana Eccles, Todd Edwards, Ros Eeles, Ursula Eilber, Bent Ejlertsen, Arif B. Ekici, Steve Ellis, Mingajeva Elvira, Kevin H. Eng, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Sarah Ferguson, Sandra Fert Ferrer, James M. Flanagan, Zachary C. Fogarty, Renée T. Fortner, Florentia Fostira, William D. Foulkes, George Fountzilas, Brooke L. Fridley, Tara M. Friebel, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, María J. García, Vanesa Garcia-Barberan, Andrea Gehrig, Aleksandra Gentry-Maharaj, Anne-Marie Gerdes, Graham G. Giles, Rosalind Glasspool, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Teodora Goranova, Martin Gore, Mark H. Greene, Jacek Gronwald, Stephen Gruber, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Thomas v. O. Hansen, Patricia A. Harrington, Holly R. Harris, Jan Hauke, Alexander Hein, Alex Henderson, Michelle A. T. Hildebrandt, Peter Hillemanns, Shirley Hodgson, Claus K. Høgdall, Estrid Høgdall, Frans B. L. Hogervorst, Helene Holland, Maartje J. Hooning, Karen Hosking, Ruea-Yea Huang, Peter J. Hulick, Jillian Hung, David J. Hunter, David G. Huntsman, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Edwin S. Iversen, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Mats Jernetz, Allan Jensen, Uffe Birk Jensen, Esther M. John, Sharon Johnatty, Michael E. Jones, Päivi Kannisto, Beth Y. Karlan, Anthony Karnezis, Karin Kast, Catherine J. Kennedy, Elza Khusnutdinova, Lambertus A. Kiemeney, Johanna I. Kiiski, Sung-Won Kim, Susanne K. Kjaer, Martin Köbel, Reidun K. Kopperud, Torben A. Kruse, Jolanta Kupryjanczyk, Ava Kwong, Yael Laitman, Diether Lambrechts, Nerea Larrañaga, Melissa C. Larson, Conxi Lazaro, Nhu D. Le, Loic Le Marchand, Jong Won Lee, Shashikant B. Lele, Arto Leminen, Dominique Leroux, Jenny Lester, Fabienne Lesueur, Douglas A. Levine, Dong Liang, Clemens Liebrich, Jenna Lilyquist, Loren Lipworth, Jolanta Lissowska, Karen H. Lu, Jan Lubinński, Craig Luccarini, Lene Lundvall, Phuong L. Mai, Gustavo Mendoza-Fandiño, Siranoush Manoukian, Leon F. A. G. Massuger, Taymaa May, Sylvie Mazoyer, Jessica N. McAlpine, Valerie McGuire, John R. McLaughlin, Iain McNeish, Hanne Meijers-Heijboer, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Melissa A. Merritt, Roger L. Milne, Gillian Mitchell, Francesmary Modugno, Joanna Moes-Sosnowska, Melissa Moffitt, Marco Montagna, Kirsten B. Moysich, Anna Marie Mulligan, Jacob Musinsky, Katherine L. Nathanson, Lotte Nedergaard, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Robert L. Nussbaum, Kunle Odunsi, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Curtis Olswold, David M. O’Malley, Kai-Ren Ong, N. Charlotte Onland-Moret, Nicholas Orr, Sandra Orsulic, Ana Osorio, Domenico Palli, Laura Papi, Tjoung-Won Park-Simon, James Paul, Celeste L. Pearce, Inge Søkilde Pedersen, Petra H. M. Peeters, Bernard Peissel, Ana Peixoto, Tanja Pejovic, Liisa M. Pelttari, Jennifer B. Permuth, Paolo Peterlongo, Lidia Pezzani, Georg Pfeiler, Kelly-Anne Phillips, Marion Piedmonte, Malcolm C. Pike, Anna M. Piskorz, Samantha R. Poblete, Timea Pocza, Elizabeth M. Poole, Bruce Poppe, Mary E. Porteous, Fabienne Prieur, Darya Prokofyeva, Elizabeth Pugh, Miquel Angel Pujana, Pascal Pujol, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Kerstin Rhiem, Patricia Rice, Andrea Richardson, Mark Robson, Gustavo C. Rodriguez, Cristina Rodríguez-Antona, Jane Romm, Matti A. Rookus, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Helga B. Salvesen, Dale P. Sandler, Minouk J. Schoemaker, Leigha Senter, V. Wendy Setiawan, Gianluca Severi, Priyanka Sharma, Tameka Shelford, Nadeem Siddiqui, Lucy E. Side, Weiva Sieh, Christian F. Singer, Hagay Sobol, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Zsofia Stadler, Doris Steinemann, Dominique Stoppa-Lyonnet, Lara E. Sucheston-Campbell, Grzegorz Sukiennicki, Rebecca Sutphen, Christian Sutter, Anthony J. Swerdlow, Csilla I. Szabo, Lukasz Szafron, Yen Y. Tan, Jack A. Taylor, Muy-Kheng Tea, Manuel R. Teixeira, Soo-Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Liv Cecilie Vestrheim Thomsen, Darcy L. Thull, Laima Tihomirova, Anna V. Tinker, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Alicia Tone, Britton Trabert, Ruth C. Travis, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Anne M. van Altena, David van den Berg, Annemarie H. van der Hout, Rob B. van der Luijt, Mattias van Heetvelde, Els van Nieuwenhuysen, Elizabeth J. van Rensburg, Adriaan Vanderstichele, Raymonda Varon-Mateeva, Ana Vega, Digna Velez Edwards, Ignace Vergote, Robert A. Vierkant, Joseph Vijai, Athanassios Vratimos, Lisa Walker, Christine Walsh, Dorothea Wand, Shan Wang-Gohrke, Barbara Wappenschmidt, Penelope M. Webb, Clarice R. Weinberg, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Juul T. Wijnen, Lynne R. Wilkens, Alicja Wolk, Michelle Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Kristin K. Zorn, Steven A. Narod, Douglas F. Easton, Christopher I. Amos, Joellen M. Schildkraut, Susan J. Ramus, Laura Ottini, Marc T. Goodman, Sue K. Park, Linda E. Kelemen, Harvey A. Risch, Mads Thomassen, Kenneth Offit, Jacques Simard, Rita Katharina Schmutzler, Dennis Hazelett, Alvaro N. Monteiro, Fergus J. Couch, Andrew Berchuck, Georgia Chenevix-Trench, Ellen L. Goode, Thomas A. Sellers, Simon A. Gayther, Antonis C. Antoniou, Paul D. P. Pharoah

Date Published: 1st May 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. … Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C\textgreaterT, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A\textgreaterC, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5’-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.

Authors: Sandrine Tchatchou, Angela Riedel, Stefan Lyer, Julia Schmutzhard, Olga Strobel-Freidekind, Sabine Gronert-Sum, Carola Mietag, Mauro D’Amato, Bettina Schlehe, Kari Hemminki, Christian Sutter, Nina Ditsch, Anneke Blackburn, Linda Zhai Hill, D. Joseph Jerry, Peter Bugert, Bernhard H. F. Weber, Dieter Niederacher, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Rita K. Schmutzler, Christoph Engel, Alfons Meindl, Claus R. Bartram, Jan Mollenhauer, Barbara Burwinkel

Date Published: 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Identification of six new susceptibility loci for invasive epithelial ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation … carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P \textless 5 \times 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Authors: Karoline B. Kuchenbaecker, Susan J. Ramus, Jonathan Tyrer, Andrew Lee, Howard C. Shen, Jonathan Beesley, Kate Lawrenson, Lesley McGuffog, Sue Healey, Janet M. Lee, Tassja J. Spindler, Yvonne G. Lin, Tanja Pejovic, Yukie Bean, Qiyuan Li, Simon Coetzee, Dennis Hazelett, Alexander Miron, Melissa Southey, Mary Beth Terry, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Susan L. Neuhausen, Yuan Chun Ding, Thomas v. O. Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Daniel Barrowdale, Joe Dennis, Javier Benitez, Ana Osorio, Maria Jose Garcia, Ian Komenaka, Jeffrey N. Weitzel, Pamela Ganschow, Paolo Peterlongo, Loris Bernard, Alessandra Viel, Bernardo Bonanni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Laura Papi, Laura Ottini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Debra Frost, Jo Perkins, Radka Platte, Steve Ellis, Andrew K. Godwin, Rita Katharina Schmutzler, Alfons Meindl, Christoph Engel, Christian Sutter, Olga M. Sinilnikova, Francesca Damiola, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Kathleen Claes, Kim de Leeneer, Judy Kirk, Gustavo C. Rodriguez, Marion Piedmonte, David M. O’Malley, Miguel de La Hoya, Trinidad Caldes, Kristiina Aittomäki, Heli Nevanlinna, J. Margriet Collée, Matti A. Rookus, Jan C. Oosterwijk, Laima Tihomirova, Nadine Tung, Ute Hamann, Claudine Isaccs, Marc Tischkowitz, Evgeny N. Imyanitov, Maria A. Caligo, Ian G. Campbell, Frans B. L. Hogervorst, Edith Olah, Orland Diez, Ignacio Blanco, Joan Brunet, Conxi Lazaro, Miquel Angel Pujana, Anna Jakubowska, Jacek Gronwald, Jan Lubinski, Grzegorz Sukiennicki, Rosa B. Barkardottir, Marie Plante, Jacques Simard, Penny Soucy, Marco Montagna, Silvia Tognazzo, Manuel R. Teixeira, Vernon S. Pankratz, Xianshu Wang, Noralane Lindor, Csilla I. Szabo, Noah Kauff, Joseph Vijai, Carol A. Aghajanian, Georg Pfeiler, Andreas Berger, Christian F. Singer, Muy-Kheng Tea, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Gad Rennert, Anna Marie Mulligan, Sandrine Tchatchou, Irene L. Andrulis, Gord Glendon, Amanda Ewart Toland, Uffe Birk Jensen, Torben A. Kruse, Mads Thomassen, Anders Bojesen, Jamal Zidan, Eitan Friedman, Yael Laitman, Maria Soller, Annelie Liljegren, Brita Arver, Zakaria Einbeigi, Marie Stenmark-Askmalm, Olufunmilayo I. Olopade, Robert L. Nussbaum, Timothy R. Rebbeck, Katherine L. Nathanson, Susan M. Domchek, Karen H. Lu, Beth Y. Karlan, Christine Walsh, Jenny Lester, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Diether Lambrechts, Els van Nieuwenhuysen, Ignace Vergote, Sandrina Lambrechts, Ed Dicks, Jennifer A. Doherty, Kristine G. Wicklund, Mary Anne Rossing, Anja Rudolph, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Kirsten B. Moysich, Kunle Odunsi, Lara Sucheston, Shashi Lele, Lynne R. Wilkens, Marc T. Goodman, Pamela J. Thompson, Yurii B. Shvetsov, Ingo B. Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Liisa M. Pelttari, Ralf Butzow, Francesmary Modugno, Joseph L. Kelley, Robert P. Edwards, Roberta B. Ness, Andreas Du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Keitaro Matsuo, Satoyo Hosono, Sandra Orsulic, Allan Jensen, Susanne Kruger Kjaer, Estrid Hogdall, Hanis Nazihah Hasmad, Mat Adenan Noor Azmi, Soo-Hwang Teo, Yin-Ling Woo, Brooke L. Fridley, Ellen L. Goode, Julie M. Cunningham, Robert A. Vierkant, Fiona Bruinsma, Graham G. Giles, Dong Liang, Michelle A. T. Hildebrandt, Xifeng Wu, Douglas A. Levine, Maria Bisogna, Andrew Berchuck, Edwin S. Iversen, Joellen M. Schildkraut, Patrick Concannon, Rachel Palmieri Weber, Daniel W. Cramer, Kathryn L. Terry, Elizabeth M. Poole, Shelley S. Tworoger, Elisa V. Bandera, Irene Orlow, Sara H. Olson, Camilla Krakstad, Helga B. Salvesen, Ingvild L. Tangen, Line Bjorge, Anne M. van Altena, Katja K. H. Aben, Lambertus A. Kiemeney, Leon F. A. G. Massuger, Melissa Kellar, Angela Brooks-Wilson, Linda E. Kelemen, Linda S. Cook, Nhu D. Le, Cezary Cybulski, Hannah Yang, Jolanta Lissowska, Louise A. Brinton, Nicolas Wentzensen, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Helen Baker, Honglin Song, Diana Eccles, Ian McNeish, James Paul, Karen Carty, Nadeem Siddiqui, Rosalind Glasspool, Alice S. Whittemore, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Bu-Tian Ji, Wei Zheng, Xiao-Ou Shu, Yu-Tang Gao, Barry Rosen, Harvey A. Risch, John R. McLaughlin, Steven A. Narod, Alvaro N. Monteiro, Ann Chen, Hui-Yi Lin, Jenny Permuth-Wey, Thomas A. Sellers, Ya-Yu Tsai, Zhihua Chen, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha Menon, Patricia Harrington, Alice W. Lee, Anna H. Wu, Celeste L. Pearce, Gerry Coetzee, Malcolm C. Pike, Agnieszka Dansonka-Mieszkowska, Agnieszka Timorek, Iwona K. Rzepecka, Jolanta Kupryjanczyk, Matt Freedman, Houtan Noushmehr, Douglas F. Easton, Kenneth Offit, Fergus J. Couch, Simon Gayther, Paul P. Pharoah, Antonis C. Antoniou, Georgia Chenevix-Trench

Date Published: 1st Feb 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using … 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P \textless 5 \times 10-8 with ten variants at nine new loci. At P \textless 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Authors: Roger L. Milne, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K. Bolla, Lesley McGuffog, Qin Wang, Cora M. Aalfs, Marcia Adams, Julian Adlard, Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B. Ambrosone, Christopher I. Amos, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Bernd Auber, Paul L. Auer, Margreet G. E. M. Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Monica Barile, Laure Barjhoux, Rosa B. Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Yves-Jean Bignon, Kathleen R. Blazer, Marinus J. Blok, Carl Blomqvist, William Blot, Kristie Bobolis, Bram Boeckx, Natalia V. Bogdanova, Anders Bojesen, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Aniko Bozsik, Angela R. Bradbury, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Brigitte Bressac-de Paillerets, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Joan Brunet, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Jinyoung Byun, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Federico Canzian, Olivier Caron, Angel Carracedo, Brian D. Carter, J. Esteban Castelao, Laurent Castera, Virginie Caux-Moncoutier, Salina B. Chan, Jenny Chang-Claude, Stephen J. Chanock, Xiaoqing Chen, Ting-Yuan David Cheng, Jocelyne Chiquette, Hans Christiansen, Kathleen B. M. Claes, Christine L. Clarke, Thomas Conner, Don M. Conroy, Jackie Cook, Emilie Cordina-Duverger, Sten Cornelissen, Isabelle Coupier, Angela Cox, David G. Cox, Simon S. Cross, Katarina Cuk, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Rosemarie Davidson, Kim de Leeneer, Peter Devilee, Ed Dicks, Orland Diez, Yuan Chun Ding, Nina Ditsch, Kimberly F. Doheny, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Isabel Dos-Santos-Silva, Stéphane Dubois, Pierre-Antoine Dugué, Martine Dumont, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Bernd Dworniczak, Diana Eccles, Ros Eeles, Hans Ehrencrona, Ursula Eilber, Bent Ejlertsen, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Laurence Faivre, Peter A. Fasching, Ulrike Faust, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Pragna Gaddam, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, José A. García-Sáenz, Mia M. Gaudet, Marion Gauthier-Villars, Andrea Gehrig, Vassilios Georgoulias, Anne-Marie Gerdes, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Paul Goodfellow, Mark H. Greene, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Daphne Gschwantler-Kaulich, Pascal Guénel, Qi Guo, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Emily Hallberg, Ute Hamann, Nathalie Hamel, Susan Hankinson, Thomas v. O. Hansen, Patricia Harrington, Steven N. Hart, Jaana M. Hartikainen, Catherine S. Healey, Alexander Hein, Sonja Helbig, Alex Henderson, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Shirley Hodgson, Frans B. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Bob Hoover, John L. Hopper, Chunling Hu, Guanmengqian Huang, Peter J. Hulick, Keith Humphreys, David J. Hunter, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Uffe Birk Jensen, Esther M. John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Karin Kast, Renske Keeman, Michael J. Kerin, Carolien M. Kets, Machteld Keupers, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Sung-Won Kim, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela N. Kristensen, Torben A. Kruse, Ava Kwong, Anne-Vibeke Lænkholm, Yael Laitman, Fiona Lalloo, Diether Lambrechts, Keren Landsman, Christine Lasset, Conxi Lazaro, Loic Le Marchand, Julie Lecarpentier, Andrew Lee, Eunjung Lee, Jong Won Lee, Min Hyuk Lee, Flavio Lejbkowicz, Fabienne Lesueur, Jingmei Li, Jenna Lilyquist, Anne Lincoln, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jennifer T. Loud, Jan Lubinski, Craig Luccarini, Michael Lush, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Kathleen E. Malone, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, Sylvie Mazoyer, Catriona McLean, Hanne Meijers-Heijboer, Primitiva Menéndez, Jeffery Meyer, Hui Miao, Austin Miller, Nicola Miller, Gillian Mitchell, Marco Montagna, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Sue Nadesan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Dieter Niederacher, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Robert L. Nussbaum, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, Kai-Ren Ong, Jan C. Oosterwijk, Nick Orr, Ana Osorio, V. Shane Pankratz, Laura Papi, Tjoung-Won Park-Simon, Ylva Paulsson-Karlsson, Rachel Lloyd, Inge Søkilde Pedersen, Bernard Peissel, Ana Peixoto, Jose I. A. Perez, Paolo Peterlongo, Julian Peto, Georg Pfeiler, Catherine M. Phelan, Mila Pinchev, Dijana Plaseska-Karanfilska, Bruce Poppe, Mary E. Porteous, Ross Prentice, Nadege Presneau, Darya Prokofieva, Elizabeth Pugh, Miquel Angel Pujana, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Kerstin Rhiem, Andrea Richardson, Gustavo C. Rodriguez, Atocha Romero, Jane Romm, Matti A. Rookus, Anja Rudolph, Thomas Ruediger, Emmanouil Saloustros, Joyce Sanders, Dale P. Sandler, Suleeporn Sangrajrang, Elinor J. Sawyer, Daniel F. Schmidt, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Sheila Seal, Leigha Senter, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xin Sheng, Hermela Shimelis, Martha J. Shrubsole, Xiao-Ou Shu, Lucy E. Side, Christian F. Singer, Christof Sohn, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Christa Stegmaier, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Harald Surowy, Christian Sutter, Anthony Swerdlow, Csilla I. Szabo, Rulla M. Tamimi, Yen Y. Tan, Jack A. Taylor, Maria-Isabel Tejada, Maria Tengström, Soo H. Teo, Mary B. Terry, Daniel C. Tessier, Alex Teulé, Kathrin Thöne, Darcy L. Thull, Maria Grazia Tibiletti, Laima Tihomirova, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Martine Tranchant, Thérèse Truong, Kathy Tucker, Nadine Tung, Jonathan Tyrer, Hans-Ulrich Ulmer, Celine Vachon, Christi J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Alessandra Viel, Joseph Vijai, Daniel Vincent, Jason Vollenweider, Lisa Walker, Zhaoming Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Jelle Wesseling, Alice S. Whittemore, Juul T. Wijnen, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H. Wu, Lucy Xia, Xiaohong R. Yang, Drakoulis Yannoukakos, Daniela Zaffaroni, Wei Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Kristin K. Zorn, Manuela Gago-Dominguez, Arto Mannermaa, Håkan Olsson, Manuel R. Teixeira, Jennifer Stone, Kenneth Offit, Laura Ottini, Sue K. Park, Mads Thomassen, Per Hall, Alfons Meindl, Rita K. Schmutzler, Arnaud Droit, Gary D. Bader, Paul D. P. Pharoah, Fergus J. Couch, Douglas F. Easton, Peter Kraft, Georgia Chenevix-Trench, Montserrat García-Closas, Marjanka K. Schmidt, Antonis C. Antoniou, Jacques Simard

Date Published: 1st Dec 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Identifying neural correlates of memory and language disturbances in herpes simplex encephalitis: a voxel-based morphometry (VBM) study.
LIFE Adult

Abstract (Expand)

Herpes simplex encephalitis (HSE) is a severe neurological disease that often leads to persistent cognitive deficits in survivors. Memory and naming impairments have been reported most, although direct … association between memory and naming performance and disease-related atrophy has not yet been demonstrated in vivo for a larger sample of patients. In the present work, a voxel-based morphometry (VBM) analysis was conducted on 3T magnetic resonance imaging (MRI) of 13 HSE survivors. The gray matter density values were correlated with scores indicating verbal memory decline, as well as errors/omissions in picture naming; both were obtained through neuropsychological assessment. Analysis of individual lesion patterns revealed a considerable inter-individual variability, mainly with atrophy in the basal forebrain, adjacent frontal cortex, medial and lateral temporal cortex, insula and thalamus. The neuropsychological data analysis revealed correlation between verbal memory decline and atrophy especially in the left hippocampal region, whereas naming problems were associated with gray matter loss especially in the lateral temporal lobe, the thalamus and the left insula. These results confirm, for the first time, the assumptions of earlier studies about the considerable variability of individual lesion patterns in HSE in a whole-brain approach in vivo, and thus the anatomical validity of VBM.

Authors: S. Frisch, F. Thiel, A. Marschhauser, A. Villringer, A. Horstmann, M. L. Schroeter

Date Published: 10th Dec 2014

Publication Type: Not specified

Human Diseases: viral encephalitis

Identifying neural correlates of visual consciousness with ALE meta-analyses.
LIFE Adult

Abstract (Expand)

Neural correlates of consciousness (NCC) have been a topic of study for nearly two decades. In functional imaging studies, several regions have been proposed to constitute possible candidates for NCC, … but as of yet, no quantitative summary of the literature on NCC has been done. The question whether single (striate or extrastriate) regions or a network consisting of extrastriate areas that project directly to fronto-parietal regions are necessary and sufficient neural correlates for visual consciousness is still highly debated [e.g., Rees et al., 2002, Nat Rev. Neurosci 3, 261-270; Tong, 2003, Nat Rev. Neurosci 4, 219-229]. The aim of this work was to elucidate this issue and give a synopsis of the present state of the art by conducting systematic and quantitative meta-analyses across functional magnetic resonance imaging (fMRI) studies using several standard paradigms for conscious visual perception. In these paradigms, consciousness is operationalized via perceptual changes, while the visual stimulus remains invariant. An activation likelihood estimation (ALE) meta-analysis was performed, representing the best approach for voxel-wise meta-analyses to date. In addition to computing a meta-analysis across all paradigms, separate meta-analyses on bistable perception and masking paradigms were conducted to assess whether these paradigms show common or different NCC. For the overall meta-analysis, we found significant clusters of activation in inferior and middle occipital gyrus; fusiform gyrus; inferior temporal gyrus; caudate nucleus; insula; inferior, middle, and superior frontal gyri; precuneus; as well as in inferior and superior parietal lobules. These results suggest a subcortical-extrastriate-fronto-parietal network rather than a single region that constitutes the necessary NCC. The results of our exploratory paradigm-specific meta-analyses suggest that this subcortical-extrastriate-fronto-parietal network might be differentially activated as a function of the paradigms used to probe for NCC.

Authors: S. Bisenius, S. Trapp, J. Neumann, M. L. Schroeter

Date Published: 15th Nov 2015

Publication Type: Not specified

Impact of chronic smoking on P3 components in a three-stimulus oddball paradigm
LIFE Adult

Abstract (Expand)

Background: The P3 is related to cognitive functions, psychopathology and effects of cognition-improving and -impairing drugs. Studies assessing the chronic effects of smoking on P3 mostly reported a … reduction of P3 amplitude for chronic and former smokers. To date, only a few studies have analyzed this impact by using a three-stimulus oddball paradigm. This study tries to replicate previous smoking associations applying an eyes-closed active three-stimulus oddball paradigm in a well-diagnosed population based sample of healthy elderly subjects who were allowed to smoke ad libitum. The study also tries to estimate whether smoking is a relevant confounder in P3 assessment within the analyzed sample. Methods: From the Leipzig Health Care Study (LIFE) current, former and non-smokers without mental or neurological disorders were matched by age, sex and qualification. Risky alcohol consumption was further exclusion criterion given the strong association between alcoholism and P3 amplitude reduction. Results: Smoking status was not associated with any P3 parameter, with exception of prolonged P3a latency at Fz in former smokers compared to never smokers. Also, there were no significant effects of smoking status on any of the behavioral measures or a correlation with smoking-related data. Discussion: This study indicates that smoking does not seem to relevantly impact the P3 components in non-abstaining healthy elderly subjects when confounders are controlled for.

Authors: N. Mauche, C. Sander, P. Jawinski, C. Enzenbach, S. Olbrich, P. Schonknecht, U. Hegerl, T. Hensch

Date Published: 1st Sep 2015

Publication Type: Not specified

Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study.
SepNet - German Competence Network Sepsis

Abstract (Expand)

INTRODUCTION: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The … objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. METHODS: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. RESULTS: Median time to AT was 2.1 (IQR 0.8 - 6.0) hours and 3 hours (-0.1 - 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). CONCLUSIONS: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

Authors: F. Bloos, D. Thomas-Ruddel, H. Ruddel, C. Engel, D. Schwarzkopf, J. C. Marshall, S. Harbarth, P. Simon, R. Riessen, D. Keh, K. Dey, M. Weiss, S. Toussaint, D. Schadler, A. Weyland, M. Ragaller, K. Schwarzkopf, J. Eiche, G. Kuhnle, H. Hoyer, C. Hartog, U. Kaisers, K. Reinhart

Date Published: 3rd Mar 2014

Publication Type: Not specified

Human Diseases: bacterial infectious disease

Impact of genetic similarity on imputation accuracy.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Genotype imputation is a common technique in genetic research. Genetic similarity between target population and reference dataset is crucial for high-quality results. Although several … reference panels are available, it is often not clear which is the most optimal for a particular target dataset to be imputed. Maximizing genetic similarity between study sample and intended reference panels may be the straight forward method for selecting the genetically best-matched reference. However, the impact of genetic similarity on imputation accuracy has not yet been studied in detail. RESULTS: We performed a simulation study in 20 ethnic groups obtained from POPRES. High-quality SNPs were masked and re-imputed with MaCH, MaCH-minimac and IMPUTE2 using four different HapMap reference panels (CEU, CHB-JPT, MEX and YRI). Imputation accuracy was assessed by different statistics. Genetic similarity between ethnic groups and reference populations were measured by F -statistics (F(ST)) originally proposed by Wright and G -statistics (G(ST)) introduced by Nei and others. To assess the predictive power of these measures regarding imputation accuracy, we analysed relations between them and corresponding imputation accuracy scores. We found that population genetic distances between homogeneous reference and target populations were strongly linearly correlated with resulting imputation accuracies irrespective of considered distance measure, imputation accuracy measure, missingness and imputation software used. Possible exception was African population. CONCLUSION: Usage of G(ST) or F(ST)-related measures for predicting the optimal reference panel for imputation frameworks relying on a specific reference is highly recommended. A cut-off of G(ST) < 0.01 is recommended to achieve good imputation results for high-frequency variants and small data sets. The linear relationship is less pronounced for low-frequency variants for which we also observed a dependence of imputation accuracy on the number of polymorphic sites in the reference. We also show that the software specific measures MaCH-Rsq and IMPUTE-info must be interpreted with caution if the genetic distance of target and reference population is high.

Authors: N. R. Roshyara, M. Scholz

Date Published: 22nd Jul 2015

Publication Type: Not specified

Impact of image acquisition on voxel-based-morphometry investigations of age-related structural brain changes.
LIFE Adult

Abstract (Expand)

A growing number of magnetic resonance imaging studies employ voxel-based morphometry (VBM) to assess structural brain changes. Recent reports have shown that image acquisition parameters may influence … VBM results. For systematic evaluation, gray-matter-density (GMD) changes associated with aging were investigated by VBM employing acquisitions with different radiofrequency head coils (12-channel matrix coil vs. 32-channel array), different pulse sequences (MP-RAGE vs. MP2RAGE), and different voxel dimensions (1mm vs. 0.8mm). Thirty-six healthy subjects, classified as young, middle-aged, or elderly, participated in the study. Two-sample and paired t-tests revealed significant effects of acquisition parameters (coil, pulse sequence, and resolution) on the estimated age-related GMD changes in cortical and subcortical regions. Potential advantages in tissue classification and segmentation were obtained for MP2RAGE. The 32-channel coil generally outperformed the 12-channel coil, with more benefit for MP2RAGE. Further improvement can be expected from higher resolution if the loss in SNR is accounted for. Use of inconsistent acquisition parameters in VBM analyses is likely to introduce systematic bias. Overall, acquisition and protocol changes require careful adaptations of the VBM analysis strategy before generalized conclusion can be drawn.

Authors: D. P. Streitburger, A. Pampel, G. Krueger, J. Lepsien, M. L. Schroeter, K. Mueller, H. E. Moller

Date Published: 15th Feb 2014

Publication Type: Not specified

Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study.
SepNet - German Competence Network Sepsis

Abstract (Expand)

PURPOSE: To estimate the incidence density, point prevalence and outcome of severe sepsis and septic shock in German intensive care units (ICUs). METHODS: In a prospective, multicentre, longitudinal … observational study, all patients already on the ICU at 0:00 on 4 November 2013 and all patients admitted to a participating ICU between 0:00 on 4 November 2013 and 2359 hours on 1 December 2013 were included. The patients were followed up for the occurrence of severe sepsis or septic shock (SEPSIS-1 definitions) during their ICU stay. RESULTS: A total of 11,883 patients from 133 ICUs at 95 German hospitals were included in the study, of whom 1503 (12.6 %) were diagnosed with severe sepsis or septic shock. In 860 cases (57.2 %) the infections were of nosocomial origin. The point prevalence was 17.9 % (95 % CI 16.3-19.7).The calculated incidence rate of severe sepsis or septic shock was 11.64 (95 % CI 10.51-12.86) per 1000 ICU days. ICU mortality in patients with severe sepsis/septic shock was 34.3 %, compared with 6 % in those without sepsis. Total hospital mortality of patients with severe sepsis or septic shock was 40.4 %. Classification of the septic shock patients using the new SEPSIS-3 definitions showed higher ICU and hospital mortality (44.3 and 50.9 %). CONCLUSIONS: Severe sepsis and septic shock continue to be a frequent syndrome associated with high hospital mortality. Nosocomial infections play a major role in the development of sepsis. This study presents a pragmatic, affordable and feasible method for the surveillance of sepsis epidemiology. Implementation of the new SEPSIS-3 definitions may have a major effect on future epidemiological data.

Editor:

Date Published: 1st Oct 2016

Publication Type: Journal article

Human Diseases: disease by infectious agent

Incident Subjective Cognitive Decline Does Not Predict Mortality in the Elderly--Results from the Longitudinal German Study on Ageing, Cognition, and Dementia (AgeCoDe).
LIFE Adult

Abstract (Expand)

OBJECTIVE: Subjective cognitive decline (SCD) might represent the first symptomatic representation of Alzheimer's disease (AD), which is associated with increased mortality. Only few studies, … however, have analyzed the association of SCD and mortality, and if so, based on prevalent cases. Thus, we investigated incident SCD in memory and mortality. METHODS: Data were derived from the German AgeCoDe study, a prospective longitudinal study on the epidemiology of mild cognitive impairment (MCI) and dementia in primary care patients over 75 years covering an observation period of 7.5 years. We used univariate and multivariate Cox regression analyses to examine the relationship of SCD and mortality. Further, we estimated survival times by the Kaplan Meier method and case-fatality rates with regard to SCD. RESULTS: Among 971 individuals without objective cognitive impairment, 233 (24.0%) incidentally expressed SCD at follow-up I. Incident SCD was not significantly associated with increased mortality in the univariate (HR = 1.0, 95% confidence interval = 0.8-1.3, p = .90) as well as in the multivariate analysis (HR = 0.9, 95% confidence interval = 0.7-1.2, p = .40). The same applied for SCD in relation to concerns. Mean survival time with SCD was 8.0 years (SD = 0.1) after onset. CONCLUSION: Incident SCD in memory in individuals with unimpaired cognitive performance does not predict mortality. The main reason might be that SCD does not ultimately lead into future cognitive decline in any case. However, as prevalence studies suggest, subjectively perceived decline in non-memory cognitive domains might be associated with increased mortality. Future studies may address mortality in such other cognitive domains of SCD in incident cases.

Authors: S. Roehr, T. Luck, K. Heser, A. Fuchs, A. Ernst, B. Wiese, J. Werle, H. Bickel, C. Brettschneider, A. Koppara, M. Pentzek, C. Lange, J. Prokein, S. Weyerer, E. Mosch, H. H. Konig, W. Maier, M. Scherer, F. Jessen, S. G. Riedel-Heller

Date Published: 15th Jan 2016

Publication Type: Not specified

Human Diseases: dementia

Incident subjective memory complaints and the risk of subsequent dementia.
LIFE Adult

Abstract (Expand)

OBJECTIVE: In this study, we aimed to analyze the association between new-incident-subjective memory complaints (SMC) and risk of subsequent dementia in a general population sample aged 75+ years. … METHOD: Data were derived from follow-up (FUP) waves I-V of the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate dementia-free survival times of individuals with and without incident SMC and multivariable Cox proportional hazards regression to assess the association between incident SMC and risk of subsequent dementia, controlled for covariates. RESULTS: Of 443 non-demented individuals, 58 (13.1%) developed dementia during a subsequent 5.4-year follow-up period. Participants with incident SMC showed a significantly higher progression to dementia (18.5% vs. 10.0%; P=0.010) and a significantly shorter mean dementia-free survival time than those without (6.2 vs. 6.8 years; P=0.008). The association between incident SMC and risk of subsequent dementia remained significant in the multivariable Cox analysis (adjusted hazard ratio=1.8; P=0.028). CONCLUSION: Our findings suggest higher progression to dementia and shorter dementia-free survival in older individuals with incident SMC. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia.

Authors: T. Luck, M. Luppa, H. Matschinger, F. Jessen, M. C. Angermeyer, S. G. Riedel-Heller

Date Published: 10th Sep 2014

Publication Type: Not specified

Human Diseases: dementia

Incremental value of Veterans Specific Activity Questionnaire and the YMCA-step test for the assessment of cardiorespiratory fitness in population-based studies.
LIFE Heart

Abstract (Expand)

BACKGROUND: Cardiorespiratory fitness is a well-established independent predictor of cardiovascular health. However, the relevance of alternative exercise and non-exercise tests for cardiorespiratory … fitness assessment in large cohorts has not been studied in detail. We aimed to evaluate the YMCA-step test and the Veterans Specific Activity Questionnaire (VSAQ) for the estimation of cardiorespiratory fitness in the general population. METHODS: One hundred and five subjects answered the VSAQ, performed the YMCA-step test and a maximal cardiopulmonary exercise test (CPX) and gave BORG ratings for both exercise tests (BORGSTEP, BORGCPX). Correlations of peak oxygen uptake on a treadmill (VO2_PEAK) with VSAQ, BORGSTEP, one-minute, post-exercise heartbeat count, and peak oxygen uptake during the step test (VO2_STEP) were determined. Moreover, the incremental values of the questionnaire and the step test in addition to other fitness-related parameters were evaluated using block-wise hierarchical regression analysis. RESULTS: Eighty-six subjects completed the step test according to the protocol. For completers, correlations of VO2_PEAK with the age- and gender-adjusted VSAQ, heartbeat count and VO2_STEP were 0.67, 0.63 and 0.49, respectively. However, using hierarchical regression analysis, age, gender and body mass index already explained 68.8% of the variance of VO2_PEAK, while the additional benefit of VSAQ was rather low (3.4%). The inclusion of BORGSTEP, heartbeat count and VO2_STEP increased R(2) by a further 2.2%, 3.3% and 5.6%, respectively, yielding a total R(2) of 83.3%. CONCLUSIONS: Neither VSAQ nor the YMCA-step test contributes sufficiently to the assessment of cardiorespiratory fitness in population-based studies.

Authors: A. Teren, S. Zachariae, F. Beutner, R. Ubrich, M. Sandri, C. Engel, M. Loffler, S. Gielen

Date Published: 15th Dec 2015

Publication Type: Not specified

[Indication and Evidence of Internationally Developed Online Coaches as Intervention for Mental Illness - a Meta-Review].
LIFE Adult

Abstract (Expand)

OBJECTIVE: The aim of the study was to investigate the current state of research concerning internationally developed Online Coaches for treatment support and prevention of mental disorders. Evidence … and effectiveness of the Online Coaches ought to be explored. METHODS: A systematic literature search was performed in international databases in order to provide a meta-review of existing Online Coaches for mental disorders. The assessment of the methodological quality and evidence of the studies was based on the established guidelines of the Scottish Intercollegiate Guideline Network. RESULTS: 52 studies (24 meta-analyses, 16 systematic reviews, 2 health-technology assessment reports, and 10 RCT studies) were identified. The efficacy was demonstrated for a variety of Online Coaches for mental disorders, especially for anxiety and depressive disorders, insomnia, and post-traumatic stress disorders, with predominantly acceptable and high quality. CONCLUSION: The present work provides an overview of internationally developed Online Coaches in the field of mental health care. Online Coaches can serve as a useful supplement to the treatment and prevention of mental disorders.

Authors: J. Stein, S. Rohr, T. Luck, M. Lobner, S. G. Riedel-Heller

Date Published: 30th Aug 2017

Publication Type: Journal article

Human Diseases: disease of mental health

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support … the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Authors: F. M. Brunkhorst, C. Engel, F. Bloos, A. Meier-Hellmann, M. Ragaller, N. Weiler, O. Moerer, M. Gruendling, M. Oppert, S. Grond, D. Olthoff, U. Jaschinski, S. John, R. Rossaint, T. Welte, M. Schaefer, P. Kern, E. Kuhnt, M. Kiehntopf, C. Hartog, C. Natanson, M. Loeffler, K. Reinhart

Date Published: 10th Jan 2008

Publication Type: Not specified

Human Diseases: bacterial infectious disease

In-vivo Dynamics of the Human Hippocampus across the Menstrual Cycle.
LIFE Adult

Abstract (Expand)

Sex hormones fluctuate during the menstrual cycle. Evidence from animal studies suggests similar subtle fluctuations in hippocampal structure, predominantly linked to estrogen. Hippocampal abnormalities … have been observed in several neuropsychiatric pathologies with prominent sexual dimorphism. Yet, the potential impact of subtle sex-hormonal fluctuations on human hippocampal structure in health is unclear. We tested the feasibility of longitudinal neuroimaging in conjunction with rigorous menstrual cycle monitoring to evaluate potential changes in hippocampal microstructure associated with physiological sex-hormonal changes. Thirty longitudinal diffusion weighted imaging scans of a single healthy female subject were acquired across two full menstrual cycles. We calculated hippocampal fractional anisotropy (FA), a measure sensitive to changes in microstructural integrity, and investigated potential correlations with estrogen. We observed a significant positive correlation between FA values and estrogen in the hippocampus bilaterally, revealing a peak in FA closely paralleling ovulation. This exploratory, single-subject study demonstrates the feasibility of a longitudinal DWI scanning protocol across the menstrual cycle and is the first to link subtle endogenous hormonal fluctuations to changes in FA in vivo. In light of recent attempts to neurally phenotype single humans, our findings highlight menstrual cycle monitoring in parallel with highly sampled individual neuroimaging data to address fundamental questions about the dynamics of plasticity in the adult brain.

Authors: C. Barth, C. J. Steele, K. Mueller, V. P. Rekkas, K. Arelin, A. Pampel, I. Burmann, J. Kratzsch, A. Villringer, J. Sacher

Date Published: 7th Oct 2016

Publication Type: Not specified

[IT infrastructures in patient-oriented research. Current status and need for action 2015]
LIFE - Leipzig Research Center for Civilization Diseases

Abstract

Not specified

Authors: U.Sax, C. Bauer, T. Ganslandt, T. Kirsten

Date Published: 2016

Publication Type: Not specified

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