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151. Secondary Empty Sella

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

152. Serous Otitis Media, Glue Ear

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

153. Short Rib-Polydactyly Syndrome Type I

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

154. Syndromic Bile Duct Paucity

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

155. SCCD

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

156. Steroid Sensitive Nephrotic Syndrome

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

157. Sacrococcygeal Teratoma

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

158. SOD Defects

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

159. SAP-1 Deficiency

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

160. Slow-Channel Congenital Myasthenic Syndrome

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

161. Subacute (Granulomatous) Thyroiditis

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

162. Sarcoma Family Syndrome of Li and Fraumeni

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

163. Shaggy Aorta Syndrome

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

164. Subtypes Myotonia Fluctuans and Myotonia Permanens

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

165. Steele-Richardson-Olzewski Syndrome

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

166. Sporadic Non-autoimmune Hyperthyroidism

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

167. Scapuloperoneal Syndrome, X-linked

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

168. Severe Combined Immunodeficiency with Jak3 Deficiency

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

169. Steroid 21-Hydroxylase Deficiency

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

170. Secretory Component Deficiency in Human Fetal Pathology

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

171. Stevens-Johnson Syndrome

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

172. Secondary Systemic Carnitine Deficiency

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

173. Subacute Painful Thyroiditis

Author

Alexander K. C. Leung, Cham Pion Kao, Andrew L. Wong, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Bennett Myers, David N. Herrmann, Vikram K. Mahajan, Nand Lal Sharma, Surender Kashyap, C. Ronald Scott, Natalie Gall, Katrin Welt, Karin Scharffetter-Kochanek, Matthew Harries, Tobias Fischer, Ralf Paus, Cornelius F. Boerkoel, Leah I. Elizondo, Thomas Lücke, Markus M. Nöthen, Marcella Rietschel, Undine E. Lang, Sophie Nicole, Bertrand Fontaine, William Lane M. Robson, Thomas Krieg, Julia Weihrauch, Sergio A. Jimenez, Hugo Ten Cate, Itshak Zusman, Pavel Gurevich, Herzl Ben-Hur, Jutta Keller, Jiri Litzman, Yaofeng Zhao, Lennart Hammarstöm, Margherita Bergomi, Carlotta Malagoli, Marco Vinceti, Marie-Estelle Dupont, Olivier Guilbaud, Hermann-Josef Gröne, Zoran V. Popovic, Mario Mancini, Batya B. Davidovici, Batsheva Marcos, Edith Orion, Ronni Wolf, Jean-Louis Vincent, Giora Z. Feuerstein, James C. Keith, Robert R. Ruffolo, Cord Sunderkötter, M. Murat Naki, Cevahir Tekcan, Amy S. Rawls, Daniel C. Link, Carolina Reitzenstein, Jürgen Kopitz, Michael Cantz, Johannes Uhl, John-John B. Schnog, Victor E. A. Gerdes, Bärbel Schütte, Samuel J. Arbes, Darryl C. Zeldin, Alessandra Baumer, Hans-Peter Zenner, Brandy J. Harvey, Jyh-Yeuan Lee, Ina L. Urbatsch, Jan Rémi, Soheyl Noachtar, Sarah H. Elsea, Santhosh Girirajan, Chee-Keong Toh, Rebecca Schüle, Ludger Schöls, Niels Borregaard, Jack B. Cowland, Laura E. Mitchell, Analee J. Etheredge, Denise S. Hill, Richard H. Finnell, Meinhard Schiller, Dorothee Nashan, Stefan Reuter, David Geneviève, Valérie Cormier-Daire, Jozef Gécz, Ravi Savarirayan, Yves Le Loir, Michel Gautier, Jean-Michel Rozet, Josseline Kaplan, Katarzyna Lukasiuk, Asla Pitkänen, Stephan Haas, Sören Siegmund, Manfred V. Singer, Henryk Dancygier, Mark Oette, Vicente Andrés, Rainer Wessely, Deborah P. Merke, Kam-Lun Ellis Hon, Jutta Engel, Hans-Michael Meinck, Amei Ludwig, Hartmut Hengel, Xinkang Wang, Ivor L. Gerber, Eric Sibley, Akihiro Takatsu, Brigitta Bondy, Daniel Markovich, Ting-Ting Huang, Charles J. Epstein, and Hilmar Prange

Published
2009

174. Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib

Author

Manus Ipek, Cheryl L. Nickerson-Nutter, Marina W.H. Shen, Elizabeth A. Murphy, Martin Hegen, Cara Williams, Kun Wu, James C. Keith, Baihua Hu, Steven J. Kirincich, Paresh Thakker, Ronald S Michalak, Katherine L. Lee, John C. McKew, James D. Clark, Leo Albert, Steve Tam, Lihren Chen, Manjunath K. Ramarao, Yonghan Hu, Debra G. Goodwin, Xin Xu, Sum Fuk-Wah, Mark L. Behnke, Frances Donahue, Megan A. Foley, M. Sherry Ku, Jennifer Thomason, William M. Abraham, and Lane Wooder

Subjects
Male, Stereochemistry, Bronchoconstriction, Biological Availability, Calorimetry, In Vitro Techniques, Carrageenan, Chemical synthesis, Benzoates, Cell Line, Rats, Sprague-Dawley, Mice, Structure-Activity Relationship, In vivo, Drug Discovery, Animals, Edema, Humans, Indole test, Sulfonyl, chemistry.chemical_classification, Sulfonamides, Sheep, biology, Cyclooxygenase 2 Inhibitors, Group IV Phospholipases A2, Anti-Inflammatory Agents, Non-Steroidal, Isothermal titration calorimetry, Arthritis, Experimental, Sulfonamide, Rats, Isoenzymes, Enzyme, chemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Protein Binding
Abstract

The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.

Published
2008

175. Dose-dependent effects of recombinant human interleukin-11 on the systemic hemodynamic function and urination

Author

Mark H. Pollack, Kaneatsu Honma, James C. Keith, Nancy L. Koles, and Hasan B. Alam

Subjects
medicine.medical_specialty, Mean arterial pressure, Cardiac output, Swine, medicine.medical_treatment, Urology, Hemodynamics, Urination, Urine, Shock, Hemorrhagic, medicine, Animals, Saline, Dose-Response Relationship, Drug, business.industry, General Medicine, Interleukin-11, Recombinant Proteins, Dose–response relationship, Disease Models, Animal, Effusion, Shock (circulatory), Anesthesia, medicine.symptom, business
Abstract

The purpose of this study was to determine whether recombinant human interleukin-11 (rhIL-11) could dose-dependently improve the hemodynamic function. Using a swine hemorrhagic shock model, rhIL-11 was given at the beginning of resuscitation. The animals were randomized to receive a single dose of rhIL-11 (5, 20, or 50 microg/kg, group I to III for respectively) or saline (group IV). Blood, urine and both pleural and peritoneal effusion were thus obtained and analyzed. The mean arterial pressure (MAP) was higher post-resuscitation (PR) in group III (62.9+/-8.2 mmHg) than in groups I, II and IV (54.9+/-1.7, 53.9+/-4.3, 55.9+/-9.4 mmHg, respectively) (P

Published
2008

176. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis

Author

Cheryl Nickerson-Nutter, James C. Keith, Martin Hegen, and Mary Collins

Subjects
musculoskeletal diseases, medicine.medical_specialty, Immunology, Drug Evaluation, Preclinical, Arthritis, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Arthritis, Rheumatoid, Mice, Rheumatology, Species Specificity, Internal medicine, Immunopathology, Immunology and Allergy, Medicine, Animals, Humans, Genetically modified animal, Autoimmune disease, Clinical Trials as Topic, business.industry, medicine.disease, Arthritis, Experimental, Rats, Clinical trial, Disease Models, Animal, Treatment Outcome, Rheumatoid arthritis, Antirheumatic Agents, Experimental pathology, business
Abstract

Animal models of rheumatoid arthritis (RA) are widely used for testing potential new therapies for RA. However, the question of which animal model is most predictive of therapeutic efficacy in human RA commonly arises in data evaluation. A retrospective review of the animal models used to evaluate approved, pending RA therapies, and compounds that were discontinued during phase II or III clinical trials found that the three most commonly used models were adjuvant-induced arthritis (AIA) in rats and collagen-induced arthritis (CIA) in rats and mice. Limited data were found for more recently developed genetically modified animal models. Examination of the efficacy of various compounds in these animal models revealed that a compound's therapeutic efficacy, rather than prophylactic efficacy, in AIA and CIA models was more predictive of clinical efficacy in human RA than data from either model alone.

Published
2007

177. Estrogen receptor dependent inhibitors of NF-kappaB transcriptional activation-1 synthesis and biological evaluation of substituted 2-cyanopropanoic acid derivatives: pathway selective inhibitors of NF-kappaB, a potential treatment for rheumatoid arthritis

Author

Christina M. Kraml, Eugene J. Trybulski, Christopher C. Chadwick, Amy Eckert, James C Keith, Douglas M. Ho, Antony A Brazzale, Sue Chippari, Douglas C Harnish, Lisa Borges-Marcucci, Thomas Kenney, and Thomas J. Caggiano

Subjects
Transcriptional Activation, medicine.medical_specialty, Estrogen receptor, Arthritis, Administration, Oral, Crystallography, X-Ray, Proinflammatory cytokine, Cell Line, Animals, Genetically Modified, Rats, Sprague-Dawley, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Internal medicine, Drug Discovery, Nitriles, medicine, Structure–activity relationship, Animals, Estrogen Receptor beta, Humans, Luciferases, Creatine Kinase, Estrogen receptor beta, Chemistry, Anti-Inflammatory Agents, Non-Steroidal, Estrogen Receptor alpha, NF-kappa B, NF-κB, Biological activity, Stereoisomerism, medicine.disease, Inflammatory Bowel Diseases, Arthritis, Experimental, In vitro, Rats, Endocrinology, Rats, Inbred Lew, Antirheumatic Agents, Cancer research, Molecular Medicine, Propionates
Abstract

Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.

Published
2007

178. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection

Author

Kim Milarski, Nicholas A. Parejo, Brian M. Clancy, James C. Keith, Helen Palmer, Xiang-Yang Tan, Emily C Lutterloh, Steven M. Opal, John E. Palardy, Ying Ying Sun, Noubar Kessimian, and Debra D. Pittman

Subjects
Glycation End Products, Advanced, Male, endocrine system diseases, medicine.drug_class, Receptor for Advanced Glycation End Products, Monoclonal antibody, medicine.disease_cause, Critical Care and Intensive Care Medicine, RAGE (receptor), Sepsis, Mice, Listeria monocytogenes, Glycation, medicine, Humans, Animals, Listeriosis, cardiovascular diseases, Receptors, Immunologic, Receptor, Survival rate, Mice, Knockout, Mice, Inbred BALB C, biology, business.industry, Research, nutritional and metabolic diseases, Antibodies, Monoclonal, medicine.disease, Systemic Inflammatory Response Syndrome, Survival Rate, Disease Models, Animal, Immunology, biology.protein, cardiovascular system, Commentary, Antibody, business, human activities
Abstract

Introduction The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily, contributes to acute and chronic disease processes, including sepsis. Methods We studied the possible therapeutic role of RAGE inhibition in the cecal ligation and puncture (CLP) model of polymicrobial sepsis and a model of systemic listeriosis using mice genetically deficient in RAGE expression or mice injected with a rat anti-murine RAGE monoclonal antibody. Results The 7-day survival rates after CLP were 80% for RAGE /- mice (n = 15) (P < 0.01 versus wild-type), 69% for RAGE+/mice (n = 23), and 37% for wild-type mice (n = 27). Survival benefits were evident in BALB/c mice given anti-RAGE antibody (n = 15 per group) over serum-treated control animals (P < 0.05). Moreover, delayed treatment with anti-RAGE antibody up to 24 hours after CLP resulted in a significant survival benefit compared with control mice. There was no significant increase in tissue colony counts from enteric Gram-negative or Grampositive bacteria in animals treated with anti-RAGE antibody. RAGE -/- , RAGE +/- , and anti-RAGE antibody-treated animals were resistant to lethality from Listeria monocytogenes by almost two orders of magnitude compared with wild-type mice. Conclusion Further studies are warranted to determine the clinical utility of anti-RAGE antibody as a novel treatment for sepsis.

Published
2007

179. Dose effects of recombinant human IL-11 on the systemic hemodynamic function in hemorrhagic shock

Author

N Koles, M Pollack, K Honma, James C. Keith, H Alam, and Peter Rhee

Subjects
Resuscitation, business.industry, Hemodynamics, Rodent model, Pharmacology, Critical Care and Intensive Care Medicine, Bioinformatics, law.invention, law, Poster Presentation, Hemorrhagic shock, Recombinant DNA, Medicine, Dose effect, business, Function (biology), Large animal
Abstract

We have previously demonstrated that administration of recombinant human IL-11 (rhIL-11) during resuscitation improves the cardiovascular functions in a rodent model of hemorrhagic shock. The purpose of this study was to elucidate: (1) whether these beneficial effects were dose related, and (2) whether the effects of rhIL-11 could be reproduced in a large animal model.

Published
2007

180. Further modification on phenyl acetic acid based quinolines as liver X receptor modulators

Author

Valerie Clerin, Robert R. Singhaus, Dawn A. Savio, Rayomand J. Unwalla, Elaine Quinet, Liang Chen, Baihua Hu, Annika Goos-Nilsson, Anita R Halpern, Christine Huselton, Irene Feingold, David H. Kaufman, Ronald C. Bernotas, Michael Basso, Qiang-Yuan Liu, Ponnal Nambi, Jay E. Wrobel, James W. Jetter, Farooq Azam, Anna Wilhelmsson, and James C. Keith

Subjects
Agonist, Male, Transcriptional Activation, Spectrometry, Mass, Electrospray Ionization, Magnetic Resonance Spectroscopy, medicine.drug_class, Stereochemistry, Carboxylic acid, Clinical Biochemistry, Carboxylic Acids, Pharmaceutical Science, Receptors, Cytoplasmic and Nuclear, CHO Cells, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Apolipoproteins E, Cricetulus, In vivo, Cricetinae, Drug Discovery, medicine, Animals, Humans, Liver X receptor, Molecular Biology, Chromatography, High Pressure Liquid, Liver X Receptors, Phenylacetates, chemistry.chemical_classification, Mice, Knockout, Chemistry, Organic Chemistry, Quinoline, Aromatic amine, Atherosclerosis, Orphan Nuclear Receptors, Recombinant Proteins, DNA-Binding Proteins, Mice, Inbred C57BL, Nuclear receptor, Quinolines, Solvents, Molecular Medicine, lipids (amino acids, peptides, and proteins), Indicators and Reagents
Abstract

A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRβ and LXRα, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.

Published
2007

181. 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylic acid (PSI-697): identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists

Author

James C. Keith, Valerie Clerin, Desiree H.H. Tsao, Patricia W. Bedard, Silvano DeBernardo, Tam Steve Yik-Kai, Kristin Janz, Alessandro Moretto, Raymond T. Camphausen, Gray D. Shaw, Robert G. Schaub, Qin Wang, Adrian Huang, Natalia Sushkova, and Neelu Kaila

Subjects
Male, Indoles, Endothelium, P-selectin, Carboxylic acid, Administration, Oral, Rats, Sprague-Dawley, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Apolipoproteins E, Dogs, Fibrinolytic Agents, In vivo, Drug Discovery, medicine, Animals, Carotid Stenosis, Leukocyte Rolling, chemistry.chemical_classification, Mice, Knockout, Quinoline, Atherosclerosis, Small molecule, Salicylates, Rats, Endothelial stem cell, P-Selectin, medicine.anatomical_structure, chemistry, Biochemistry, Hydroxyquinolines, Quinolines, Molecular Medicine, Salicylic acid
Abstract

P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.

Published
2007

182. 115-POS

Author

James A. Hamilton, Andrew J. Buckler, and James C. Keith

Subjects
medicine.medical_specialty, Acute coronary syndrome, medicine.diagnostic_test, business.industry, Obstetrics and Gynecology, Magnetic resonance imaging, Disease, medicine.disease, Thrombosis, Preeclampsia, Clinical trial, Internal Medicine, medicine, Radiology, Personalized medicine, business, Stroke
Abstract

Objectives Preeclampsia occurs in 3–5% of pregnancies, remaining the major source of maternal and fetal mortality and morbidity. Imbalances of cytokines, growth factors and soluble receptors in these pathologic pregnancies predispose the vasculature to accelerated atherosclerotic disease, and preeclamptic women and their offspring have a higher life-long risk of cardiovascular disease. Women with cardiovascular disease suffer from under-diagnosis and are more likely to die when acute coronary syndrome or stroke symptoms occur. Validated quantitative imaging biomarkers are needed to assess atherosclerotic plaque stability for prognostic and longitudinal use. Computer-aided prognosis (CAP) applies quantitative image analysis and multi-modal data fusion to provide new tools to physicians. The vascuCAP™ analysis software is proposed as a longitudinal assessment tool for women with a history of preeclampsia. Methods A preclinical rabbit model with various stages of atherosclerotic plaques and luminal thrombosis of vulnerable plaques, closely simulating human disease, was used to assess the feasibility of the experimental vascuCAP™ software to analyze standard magnetic resonance (MR) images and quantitatively measure several crucial plaque parameters: lipid core, fibrosis, neovascularization, intra-plaque hemorrhage, vascular leak, calcification, and arterial wall remodeling (both inward and outward). The vascuCAP™ results were compared to the histological lesions as ground truth. Results Feasibility of vascuCAP™ analysis of arterial plaques including structural measurement and functional feature extraction for discriminating between tissue types consistent with stable and unstable atherosclerotic plaques was demonstrated. A pivotal clinical trial is in progress in carotid and femoral endarterectomy patients, where the vascuCAP™ results will be compared to histological ground truth. Subsequent studies will validate vascuCAP™ in the coronary circulation. Conclusions Through use of MRI and vascuCAP™, longitudinal surveillance of women with a history of preeclampsia could be possible without exposure to ionizing radiation. Assessment of plaque characteristics during therapeutic medical interventions with anti-atherosclerotic agents could provide personalized medicine. Disclosures J.C. Keith: Consultant; Commercial Interest: Elucid Bioimaging, Inc. A.J. Buckler: Commercial Interest: President & CEO, Elucid Bioimaging, Inc, Shareholder, Commercial Interest: Elucid Bioimaging, Inc. J.A. Hamilton: Shareholder, Commercial Interest: Elucid Bioimaging, Inc.

Published
2015

183. WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock

Author

Nicolas A. Parejo, John E. Palardy, Jhung W. Jhung, Patricia Cristofaro, Steven M. Opal, Heather A. Harris, and James C. Keith

Subjects
Agonist, Male, medicine.medical_specialty, Neutropenia, medicine.drug_class, Estrogen receptor, Administration, Oral, Bacteremia, Naphthols, Pharmacology, Critical Care and Intensive Care Medicine, Sepsis, Rats, Sprague-Dawley, Mice, Intestinal mucosa, Intensive care, Internal medicine, medicine, Animals, Ascitic Fluid, Estrogen Receptor beta, Pseudomonas Infections, Intestinal Mucosa, Estrogen receptor beta, Mice, Inbred BALB C, business.industry, Septic shock, Interleukin-6, Tumor Necrosis Factor-alpha, medicine.disease, Listeria monocytogenes, Shock, Septic, Rats, Disease Models, Animal, Endocrinology, Estrogen, Female, business
Abstract

To determine the effect of an estrogen receptor-beta selective agent in experimental models of systemic infection and sepsis.WAY-202196, a nonsteroidal selective estrogen receptor-beta agonist, was tested in the murine listeriosis model, the neutropenic rat Pseudomonas aeruginosa infection, and the mouse cecal ligation and puncture sepsis models.University-affiliated biomedical research laboratory.BALB/c mice and Sprague-Dawley rats.WAY-202196 or control (vehicle) was administered orally in doses ranging from 1.5 to 50 mg/kg at various time points in the three experimental model systems.Susceptibility of mice treated with a single oral dose of up to 50 mg/kg WAY-202196 did not differ from those treated with vehicle alone after systemic challenge by Listeria monocytogenes, suggesting a lack of generalized immunosuppression. In the neutropenic rat model, daily administration of WAY-202196 (50 mg/kg) significantly increased survival against an otherwise lethal challenge of P. aeruginosa 12.4.4 compared with the control group (83% vs. 25% survival; p0.05). Preservation of intestinal mucosal weight and prevention of histopathologic changes were also observed with the administration of WAY-202196. Similar results were obtained in a cecal ligation and puncture model, in which multiple oral doses of WAY-202196 (50 mg/kg) improved survival (83% vs. 0%; p0.05), preserved intestinal epithelial integrity, and significantly reduced systemic bacteremia and peritoneal interleukin-6 and tumor necrosis factor levels. The estrogen receptor-beta agonist provided a comparable level of protection in both male and female animals.These results indicate that oral administration of WAY-202196 preserved gastrointestinal barrier function and improved outcome in experimental models of systemic infection and inflammation. WAY-202196 and similar agents may prove useful clinically as a novel treatment strategy for the treatment or prevention of severe sepsis.

Published
2006

184. Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs

Author

Joel Kantrowitz, John A. Butera, James C. Keith, Gwen A. Morgan, Hal S. Feldman, Phil J. Wang, David L. Crandall, Robert E. Swillo, Ketil Haugan, James K. Hennan, Aqel Abu-Qare, Robert P. Smith, Robert G. Schaub, and Bjarne Due Larsen

Subjects
medicine.medical_specialty, Ischemia, Myocardial Infarction, Myocardial Reperfusion Injury, Ventricular tachycardia, chemistry.chemical_compound, Bolus (medicine), Dogs, Microscopy, Electron, Transmission, Internal medicine, Heart rate, Medicine, Animals, Rotigaptide, Pharmacology, business.industry, Myocardium, Gap junction, Hemodynamics, Gap Junctions, medicine.disease, Ventricular Premature Complexes, medicine.anatomical_structure, Treatment Outcome, chemistry, Ventricle, Anesthesia, Cardiology, Molecular Medicine, business, Reperfusion injury, Anti-Arrhythmia Agents, Oligopeptides
Abstract

The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/reperfusion injury has not been studied. The antiarrhythmic peptide rotigaptide (previously ZP123), which maintains gap junction intercellular communication, was tested in dogs subjected to a 60-min coronary artery occlusion and 4 h of reperfusion. Rotigaptide was administered i.v. 10 min before reperfusion as a bolus + i.v. infusion at doses of 1 ng/kg bolus + 10 ng/kg/h infusion (n = 6), 10 ng/kg bolus + 100 ng/kg/h infusion (n = 5), 100 ng/kg bolus + 1000 ng/kg/h infusion (n = 8), 1000 ng/kg bolus + 10 mug/kg/h infusion (n = 6), and vehicle control (n = 5). Premature ventricular complexes (PVCs) were quantified during reperfusion. A series of four or more consecutive PVCs was defined as ventricular tachycardia (VT). The total incidence of VT was reduced significantly with the two highest doses of rotigaptide (20.3 +/- 10.9 and 4.3 +/- 4.1 events; p < 0.05) compared with controls (48.7 +/- 6.0). Total PVCs were reduced significantly from 25.1 +/- 4.2% in control animals to 11.0 +/- 4.4 and 1.7 +/- 1.3% after the two highest doses of rotigaptide. Infarct size, expressed as a percentage of the left ventricle, was reduced significantly from 13.2 +/- 1.9 in controls to 7.1 +/- 1.0 (p < 0.05) at the highest dose of rotigaptide. Ultrastructural evaluation revealed no differences in myocardial injury in the infarct area, area at risk, border zone, or normal zone in vehicle and rotigaptide-treated animals. However, rotigaptide did increase the presence of gap junctions in the area at risk (p = 0.022, Fisher's exact test). Rotigaptide had no effect on heart rate, blood pressure, heart rate-corrected QT interval, or left ventricular end-diastolic pressure. In conclusion, these results demonstrate that rotigaptide is a potent antiarrhythmic compound with cardioprotective effects and desirable safety.

Published
2005

185. The activity of pathway-selective estrogen receptor ligands in experimental septic shock

Author

Steven M. Opal, Robert John Steffan, James C. Keith, John E. Palardy, Jhung W. Jhung, Nicolas A. Parejo, Thomas J. Caggiano, Sue Chippari, Christopher C. Chadwick, Patricia Cristofaro, and Douglas C Harnish

Subjects
medicine.drug_class, Estrogen receptor, Administration, Oral, Inflammation, Polyenes, Pharmacology, Critical Care and Intensive Care Medicine, Sepsis, Rats, Sprague-Dawley, Oral administration, In vivo, Intensive care, Medicine, Animals, Listeriosis, Pseudomonas Infections, Receptor, business.industry, NF-kappa B, medicine.disease, Shock, Septic, Rats, Disease Models, Animal, Receptors, Estrogen, Estrogen, Immunology, Emergency Medicine, Pyrazoles, Female, medicine.symptom, business
Abstract

Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-kappaB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.

Published
2005

186. Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthritis model: responses to disease induction and therapy with the estrogen receptor-beta selective agonist ERB-041

Author

Marc Pinard, Andrew J. Dorner, Eustache Paramithiotis, Lili Wang, Maximillian T. Follettie, Heather A. Harris, Pierre Thibault, Paul Kearney, Clive Hayward, Daniel Chelsky, and James C. Keith

Subjects
Agonist, Male, medicine.medical_specialty, medicine.drug_class, Anti-Inflammatory Agents, Arthritis, Estrogen receptor, Biology, Arthritis, Rheumatoid, chemistry.chemical_compound, Random Allocation, Endocrinology, Internal medicine, medicine, Animals, Estrogen Receptor beta, RNA, Messenger, Receptor, Oxazoles, Fatty acid metabolism, Gene Expression Profiling, Blood Proteins, medicine.disease, Arthritis, Experimental, Rats, Eicosanoid, chemistry, Liver, Estrogen, Organ Specificity, Rats, Inbred Lew, Lymph Nodes, Estrogen receptor alpha, Biomarkers, Spleen
Abstract

Two receptors [estrogen receptor (ER)alpha and ERbeta] mediate the manifold effects of estrogens throughout the body. Although a clear role has been established for ERalpha in the classical effects of estrogen activity, the physiological role of ERbeta is less well understood. A small-molecule ERbeta selective agonist, ERB-041, has potent antiinflammatory activity in the Lewis rat model of adjuvant-induced arthritis. To characterize the response of target organs and pathways responsible for this antiinflammatory effect, mRNA expression profiling of the spleen, lymph node, and liver was performed, in conjunction with a global analysis of the plasma proteome. We find that the expression of a large number of genes and proteins are altered in the disease model and the majority of these are partially or fully reversed by ERB-041 treatment. Regulated pathways include the acute-phase response, eicosanoid synthesis, fatty acid metabolism, and iron metabolism. In addition, many of the regulated genes and proteins are known to be dysregulated in human rheumatoid arthritis, providing further evidence that the manifestations of the Lewis rat adjuvant-induced arthritis model bear similarity to the human disease.

Published
2005

187. Administration of recombinant interleukin-11 improves the hemodynamic functions and decreases third space fluid loss in a porcine model of hemorrhagic shock and resuscitation

Author

Kaneatsu, Honma, Nancy L, Koles, Hasan B, Alam, Peter, Rhee, Florence M, Rollwagen, Cara, Olsen, James C, Keith, and Matthew, Pollack

Subjects
Carbon Monoxide, Time Factors, Swine, Resuscitation, Hemodynamics, Blood Pressure, Shock, Hemorrhagic, Sodium Chloride, Interleukin-11, Recombinant Proteins, Disease Models, Animal, Random Allocation, Lactates, Pressure, Animals, Cardiac Output
Abstract

We have previously demonstrated that the administration of recombinant human interleukin-11 (rhIL-11) during resuscitation improves the blood pressure in a rodent model of hemorrhagic shock. The purpose of this study was to determine whether the effects of rhIL-11 could be reproduced in a large animal model and to elucidate the impact of rhIL-11 administration on the intravascular volume status and the degree of third space fluid loss after resuscitation. A 40% blood volume hemorrhage was induced in swine (n = 45, weight of 25-35 kg) followed by a 1-h shock period and resuscitation with 0.9% sodium chloride (three times the shed blood volume). The animals were randomized to receive sham hemorrhage (group I, sham); sham hemorrhage and 50 microg/kg rhIL-11 (group II, sham + IL-11); no drug (group III, saline); or 50 microg/kg rhIL-11 (group IV, IL-11). Blood and urine samples were obtained and analyzed at baseline, at the end of hemorrhaging, and thereafter once every hour. The pleural and peritoneal effusions were precisely quantified by using clinically accepted criteria. The mean arterial pressure (MAP) was higher postresuscitation (PR) in groups I, II, and IV (71.4 +/- 7.5 mmHg, 71.0 +/- 8.9 mmHg, and 72.9 +/- 12.3 mmHg, respectively) than in group III (59.9 +/- 10.9 mmHg), and the cardiac output of PR was higher in group IV (3.46 +/- 0.56 L/min) than in group III (2.99 +/- 0.62 L/min; P0.01). The difference in MAP between groups I and II became statistically significant at 40 min after rhIL-11 injection and such a difference persisted for 90 min. After resuscitation, the urine output was higher, and the urine specific gravity and third space fluid loss were lower in group IV (1434 +/- 325 mL and 1.0035, 82 +/- 21 mL) than in group III (958 +/- 390 mL and 1.0053, 125 +/- 32 mL; P0.05). In a porcine model of hemorrhagic shock, the administration of rhIL-11 at the start of resuscitation significantly improved the cardiac output and blood pressure. This strategy also significantly reduced the extent of third space fluid losses while also having a favorable impact on the intravascular volume status as evidenced by the improved urine output.

Published
2005

188. Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity

Author

Yelena Leathurby, Lisa Borges-Marcucci, Leo M. Albert, Eugene John Trybulski, Douglas C. Harnish, Susan Chippari, Amy Eckert, Richard C. Winneker, Edward Martin Matelan, Robert John Steffan, James C. Keith, Ramesh A. Bhat, Christopher C. Chadwick, Mark A. Ashwell, Steven J. Adelman, and Heather A. Harris

Subjects
Male, medicine.medical_specialty, Transcription, Genetic, Transgene, Estrogen receptor, Inflammation, Stimulation, Biology, Ligands, Inflammatory bowel disease, Cell Line, Animals, Genetically Modified, chemistry.chemical_compound, Mice, Internal medicine, medicine, Animals, Estrogen Receptor beta, Humans, Receptor, Transcription factor, HLA-B27 Antigen, Multidisciplinary, Uterus, Estrogen Receptor alpha, NF-kappa B, NF-κB, Biological Sciences, medicine.disease, Inflammatory Bowel Diseases, Rats, Mice, Inbred C57BL, Endocrinology, chemistry, Receptors, Estrogen, Cancer research, Pyrazoles, Female, medicine.symptom
Abstract

Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-κB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-κB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.

Published
2005

189. Treatment with interleukin-11 affects plasma leptin levels in inflamed and non-inflamed rabbits

Author

Inge Depoortere, James C. Keith, Theo Thijs, and Theo L. Peeters

Subjects
Leptin, medicine.medical_specialty, Physiology, medicine.medical_treatment, Clinical Biochemistry, Inflammation, Biology, Biochemistry, Motilin, Cell Line, Cellular and Molecular Neuroscience, Endocrinology, Weight loss, Internal medicine, Weight Loss, medicine, Animals, RNA, Messenger, digestive, oral, and skin physiology, Colitis, Interleukin-11, Interleukin 11, Cytokine, Gastrointestinal hormone, Gene Expression Regulation, Anorectic, Rabbits, medicine.symptom, hormones, hormone substitutes, and hormone antagonists
Abstract

Treatment with the anti-inflammatory cytokine, interleukin-11 (IL-11), in rabbits with TNBS-colitis reduces tissue damage but does not normalize body weight loss despite an increase in plasma levels of motilin, known to stimulate food intake. We investigated whether IL-11 could increase plasma levels of the anorectic peptide, leptin in non-inflamed and inflamed rabbits. In addition, the effect of IL-11 and leptin on motilin mRNA expression in the T84 cell line was tested. Five days post-inflammation, weight loss amounted 10.7+/-1.2%, but plasma leptin and motilin levels were unaffected. During IL-11 treatment, weight loss remained and plasma leptin levels dose-dependently increased with 27+/-5% (4 microg/kg day) and 108+/-7% (720 microg/kg day). Motilin levels increased in parallel with 23+/-12% or 256+/-97%. In non-inflamed animals, a prompt decrease in weight (-11.9+/-1%) was observed after treatment with the highest dose of IL-11 and this was associated with an increase in plasma leptin (70+/-18%) and motilin levels (113+/-7%). Both IL-11 and leptin stimulated motilin mRNA expression in T84 cells with a different time profile. In conclusion, the increase in plasma leptin levels during IL-11 treatment induces wasting in normal rabbits and may be one of the major factors involved in the maintenance of body weight loss in rabbits with colitis. Increase of motilin expression by leptin may be part of a feedback mechanism.

Published
2004

190. Evaluation of an estrogen receptor-beta agonist in animal models of human disease

Author

Yelena Leathurby, Ruth A. Henderson, Yogendra P. Kharode, Michael S. Malamas, James Marzolf, Richard C. Winneker, Yuan Zhu, Barry S. Komm, Richard Eric Mewshaw, Chris P. Miller, Heather A. Harris, Donald E. Frail, Leo M. Albert, and James C. Keith

Subjects
Agonist, medicine.medical_specialty, medicine.drug_class, Ovariectomy, Estrogen receptor, Arthritis, Weight Gain, Inflammatory bowel disease, Cell Line, Animals, Genetically Modified, Rats, Sprague-Dawley, Mice, Endocrinology, Mammary Glands, Animal, Bone Density, Internal medicine, medicine, Animals, Estrogen Receptor beta, Humans, Receptor, Oxazoles, Estrogen receptor beta, HLA-B27 Antigen, business.industry, Uterus, medicine.disease, Inflammatory Bowel Diseases, Arthritis, Experimental, Rats, Bone Diseases, Metabolic, Disease Models, Animal, Receptors, Estrogen, Estrogen, Rats, Inbred Lew, Female, business, beta 2-Microglobulin, Estrogen receptor alpha
Abstract

The discovery of a second estrogen receptor (ER), called ERβ, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERβ and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERβ does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50–75%). These data suggest that one function of ERβ may be to modulate the immune response, and that ERβ-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.

Published
2003

191. Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease

Author

Douglas C. Harnish, Leo M. Albert, James C. Keith, Agnes Ciarletta, Amy Eckert, Marion Kasaian, and Yelena Leathurby

Subjects
Physiology, medicine.drug_class, Colon, Transgene, Estrogen receptor, Inflammation, Bone Marrow Cells, Enzyme-Linked Immunosorbent Assay, Biology, Inflammatory bowel disease, Cell Degranulation, Animals, Genetically Modified, Physiology (medical), Endopeptidases, medicine, Animals, Mast Cells, Fulvestrant, HLA-B27 Antigen, Peroxidase, HLA-B27, Hepatology, Estradiol, Gastroenterology, NF-kappa B, medicine.disease, NFKB1, Mast cell, Inflammatory Bowel Diseases, beta-N-Acetylhexosaminidases, Rats, medicine.anatomical_structure, Receptors, Estrogen, Estrogen, Immunology, Cytokines, medicine.symptom
Abstract

A well-established model of bowel inflammation is the HLA-B27 transgenic rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens have previously been shown to modulate the immune system, and both estrogen receptors (ERα and ERβ) are present in the intestine and cells of the immune system. Therefore, the ability of estrogen to ameliorate disease progression in the HLA-B27 transgenic rat was determined. HLA-B27 transgenic rats with chronic diarrhea were treated with 17α-ethynyl-17β-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores of the degree of ulceration, inflammatory cell infiltration, fibrosis, and lesion depth of the colon were also improved by EE treatment. Because neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase (MPO) activity was measured. MPO levels were reduced by 80% by EE treatment. Cotreatment with the pure ER antagonist ICI-182780 (ICI) blocked the effects of EE on stool character, MPO activity, and histology scores, strongly suggesting that the activity of EE is mediated through ER. Mast cell proteases can promote neutrophil infiltration, and gene expression analysis demonstrated that mast cell protease 1, 3, and 4 mRNA were all decreased in colons from estrogen-treated rats. In addition, a direct effect of estrogen on bone marrow-derived mast cell activity was demonstrated, suggesting that ER-mediated inactivation of mast cells may contribute to the improvement in the clinical sign and histological scores in this model.

Published
2003

192. Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

Author

Marjorie S. Read, James C. Keith, Timothy C. Nichols, Elizabeth P. Merricks, Dwight A. Bellinger, Bonita J. Rup, Karen E. Russell, Kyle P. McCarthy, Eva H. N. Olsen, Robin A. Raymer, and Robert G Schaub

Subjects
Male, Injections, Subcutaneous, Immunology, Antibodies, Heterophile, Hemorrhage, Pilot Projects, Biochemistry, Hemophilia B, Immune tolerance, Factor IX, Immune system, Dogs, Antigen, Coagulopathy, medicine, Immune Tolerance, Animals, Humans, Whole blood, biology, business.industry, Antibody titer, Reproducibility of Results, Cell Biology, Hematology, medicine.disease, Recombinant Proteins, Disease Models, Animal, Animals, Newborn, biology.protein, Antibody, business, medicine.drug, Animals, Inbred Strains
Abstract

Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P < .001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P = .0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B. (Blood. 2003;102:4393-4398)

Published
2003

193. IL-11-induced reduction of C/EBP transcription factor binding may contribute to the IL-12 downregulation in tumor-bearing mice

Author

Milena Ivanova, James C. Keith, Diana M. Lopez, and Marta Torroella-Kouri

Subjects
Cancer Research, medicine.medical_specialty, Mammary tumor, Oncogene, medicine.medical_treatment, Cell cycle, Biology, Endocrinology, Cytokine, Immune system, Oncology, Apoptosis, Internal medicine, medicine, Interleukin 12, Macrophage
Abstract

Using a mammary tumor model syngeneic to BALB/c mice, we have characterized several tumor-derived factors. We now report that the DA-3 cell line derived from this tumor, as well as the in vivo tumor itself, express IL-11. The expression of IL-11 in the tumor is detectable at the transcriptional and translational levels, as evidenced by RT-PCR and Western blots. Using a murine IL-11 ELISA, we observed no differences in IL-11 production between normal and tumor-bearer's macrophages or T cells, with or without activation. Interestingly, elevated levels of IL-11 were found in the sera of tumor-bearers, when compared to normal animals and even higher levels of IL-11 were detected in the tumor cystic fluid. Macrophages from mice bearing large mammary tumors show an impaired production of IL-12 and NO, whereas T cells from the same animals display a deficient production of IFN-gamma. Pretreatment of normal macrophages with IL-11 resulted in no decrease in NO production, nor an impaired production of IFN-gamma was observed in normal T cells upon pretreatment with IL-11. However, pretreatment of normal macrophages with IL-11 resulted in a decreased production of IL-12, as revealed by ELISA and RT-PCR. Electromobility shift assays showed decreased binding of the transcription factor C/EBP to the IL-12p40 promoter of LPS-activated macrophages from normal animals, upon pretreatment with IL-11. In contrast, no differences were observed in the levels of NFkappaB binding under the same experimental conditions. Our results suggest that tumor-derived IL-11 may play a role in the depressed IL-12 production by macrophages, leading to the impaired immune functions observed during mammary tumorigenesis.

Published
2003

194. IL-11-induced reduction of C/EBP transcription factor binding may contribute to the IL-12 downregulation in tumor-bearing mice

Author

Marta, Torroella-Kouri, James C, Keith, Milena, Ivanova, and Diana M, Lopez

Subjects
Lipopolysaccharides, Male, Transcription, Genetic, T-Lymphocytes, Electrophoretic Mobility Shift Assay, Enzyme-Linked Immunosorbent Assay, Adenocarcinoma, Lymphocyte Activation, Nitric Oxide, Interferon-gamma, Mice, Tumor Cells, Cultured, Animals, Promoter Regions, Genetic, Mice, Inbred BALB C, Interleukin-12 Subunit p40, Reverse Transcriptase Polymerase Chain Reaction, NF-kappa B, Mammary Neoplasms, Experimental, DNA, Neoplasm, Macrophage Activation, Interleukin-11, Interleukin-12, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Protein Subunits, Depression, Chemical, Protein Biosynthesis, CCAAT-Enhancer-Binding Proteins, Macrophages, Peritoneal, Female, Neoplasm Transplantation, Protein Binding
Abstract

Using a mammary tumor model syngeneic to BALB/c mice, we have characterized several tumor-derived factors. We now report that the DA-3 cell line derived from this tumor, as well as the in vivo tumor itself, express IL-11. The expression of IL-11 in the tumor is detectable at the transcriptional and translational levels, as evidenced by RT-PCR and Western blots. Using a murine IL-11 ELISA, we observed no differences in IL-11 production between normal and tumor-bearer's macrophages or T cells, with or without activation. Interestingly, elevated levels of IL-11 were found in the sera of tumor-bearers, when compared to normal animals and even higher levels of IL-11 were detected in the tumor cystic fluid. Macrophages from mice bearing large mammary tumors show an impaired production of IL-12 and NO, whereas T cells from the same animals display a deficient production of IFN-gamma. Pretreatment of normal macrophages with IL-11 resulted in no decrease in NO production, nor an impaired production of IFN-gamma was observed in normal T cells upon pretreatment with IL-11. However, pretreatment of normal macrophages with IL-11 resulted in a decreased production of IL-12, as revealed by ELISA and RT-PCR. Electromobility shift assays showed decreased binding of the transcription factor C/EBP to the IL-12p40 promoter of LPS-activated macrophages from normal animals, upon pretreatment with IL-11. In contrast, no differences were observed in the levels of NFkappaB binding under the same experimental conditions. Our results suggest that tumor-derived IL-11 may play a role in the depressed IL-12 production by macrophages, leading to the impaired immune functions observed during mammary tumorigenesis.

Published
2003

195. Interleukin-11

Author

James C. Keith

Subjects
chemistry.chemical_classification, Methionine, Interleukin, Placentation, Biology, Cell biology, Amino acid, Interleukin 11, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Biochemistry, In vivo, medicine, Bone marrow, Receptor
Abstract

This chapter focuses on interleukin -11 (IL-11), which is a bone marrow stroma-derived hematopoietic cytokine. It is highly conserved, 178 amino acid cationic protein. The human and the nonhuman primate genes for IL-11 have been localized to the long arm of chromosome 19 at band 19q13.3-q13.4. IL-11 is a member of the IL-6 ligand family, as it utilizes gpl30 as the signaling component of its receptor, and amino acid residues 59 (methionine), 42 (lysine), and 99 (lysine) that are critical for function of the IL-11 protein, being completely conserved in the mouse, nonhuman primate, and human proteins. interleukin -11 has multiple activities that continue to be characterized. Initial in vitro and in vivo studies demonstrated a hematopoietic activity for interleukin-11, largely manifested as thrombopoiesis in humans, and rhIL-11 has been developed, and approved by the United States Food and Drug Administration for use in the prevention of severe thrombocytopenia occurring after cancer chemotherapy. Studies of cells and tissues from other organ systems indicate that IL-11 is produced by a variety of other cell types, and has activity in protection and restoration of the gastrointestinal mucosa, major effects as an immunomodulating agent, and activity in bone metabolism. Developmental investigations in mice indicate a widespread distribution of IL-11 expression in the embryo as IL-11 signaling is an absolute requirement for the normal development of placentation, and survival to birth.

Published
2003

196. Age-dependent atrial remodeling induced by recombinant human interleukin-11: implications for atrial flutter/fibrillation

Author

James C. Keith, Amir Pelleg, Jian-Fang Ren, Luiz Belardinelli, Jiang Xu, and Alessandro Mugelli

Subjects
Male, medicine.medical_specialty, Heart disease, Normal diet, Refractory period, Heart Ventricles, Blood Pressure, Electrocardiography, Internal medicine, Atrial Fibrillation, Medicine, Animals, cardiovascular diseases, Heart Atria, Pharmacology, Fibrillation, medicine.diagnostic_test, business.industry, P wave, Age Factors, Cardiac Pacing, Artificial, Atrial fibrillation, Organ Size, Diet, Sodium-Restricted, medicine.disease, Atrial Function, Interleukin-11, Rats, Inbred F344, Recombinant Proteins, Rats, Electrophysiology, Endocrinology, Atrial Flutter, cardiovascular system, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Atrial flutter
Abstract

Recombinant human interleukin-11 (rhIL-11) has been used to alleviate side effects caused by chemotherapy in patients with neoplastic diseases and as an experimental anti-inflammatory agent. Its use in elderly patients has been associated with increased frequency of atrial flutter/fibrillation (AF). The mechanism of the latter phenomenon was studied in a rat model in vivo. Adult and old Fischer 344 rats fed with either normal diet or sodium-restricted diets were treated with rhIL-11 or vehicle (control) (1 mg/kg/day, i.p., 7 days); cardiac electrophysiologic parameters and atrial dimensions were determined. In adult rats, rhIL-11 was without effect, and atrial pacing did not induce AF. In contrast, in old rats, rhIL-11 shortened atrial refractoriness and increased atrial dimensions. Also, atrial pacing induced AF in old rats treated with rhIL-11 more than in controls. These effects of rhIL-11 in old rats were reversed by sodium-restricted diet. It was concluded that rhIL-11 induces age-dependent atrial remodeling manifested by atrial stretch and reduced atrial refractoriness, which favor AF. Na retention is the most likely mechanism underlying this effect of rhIL-11.

Published
2002

197. Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis

Author

John E. Palardy, James C. Keith, Nicolas A. Parejo, Steven M. Opal, Jhung W. Jhung, Vasu Maganti, and Erik Marchese

Subjects
Neutropenia, medicine.medical_treatment, Administration, Oral, Bacteremia, Biology, Sepsis, Rats, Sprague-Dawley, Interferon-gamma, medicine, Immunology and Allergy, Animals, RNA, Messenger, Leukopenia, Tumor Necrosis Factor-alpha, Mucous membrane, Interleukin, medicine.disease, Interleukin-11, Recombinant Proteins, Rats, Interleukin 11, Infectious Diseases, medicine.anatomical_structure, Cytokine, Immunology, Tumor necrosis factor alpha, Female, medicine.symptom
Abstract

Recombinant human interleukin (IL)-11 is a multifunctional cytokine with hematopoietic, immunomodulatory, and epithelial cell protective activities. IL-11alpha receptors are expressed on the luminal surface of intestinal epithelial cells. It was hypothesized that orally administered IL-11 would prevent mucosal damage and protect against microbial invasion in a neutropenic rat model of gram-negative sepsis. IL-11 was administered daily by enteric, coated multiparticle pellets over the course of chemotherapy-induced neutropenia. Compared with the placebo group, IL-11-treated rats retained mucosal mass and had prolonged survival time, reduced pathologic changes, and reduced systemic levels of bacterial endotoxin and concentrations of Pseudomonas aeruginosa in target tissues. Enterocyte messenger RNA levels for tumor necrosis factor-alpha and interferon-gamma revealed that oral IL-11 reduced but did not prevent increased expression of these cytokine genes. These results indicate that orally administered IL-11 may preserve epithelial cell integrity in the presence of cytoreductive chemotherapy. This may represent a new treatment strategy for the prevention of infection in neutropenic hosts.

Published
2001

198. Recombinant human interleukin-11 decreases severity of acute necrotizing pancreatitis in mice

Author

James C. Keith, Makio Kobayashi, Tatsuo Sawada, Naoaki Hayashi, Hideo Saotome, Kyoko Shimizu, and Keiko Shiratori

Subjects
Lipopolysaccharides, Male, medicine.medical_specialty, Necrosis, Pancreatic disease, Endocrinology, Diabetes and Metabolism, Binding, Competitive, Mice, Endocrinology, Internal medicine, Edema, Internal Medicine, medicine, Animals, RNA, Messenger, Pancreas, Mice, Inbred BALB C, Hepatology, business.industry, Pancreatitis, Acute Necrotizing, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Interleukin, Lipase, medicine.disease, Interleukin-11, Recombinant Proteins, Interleukin 11, Kinetics, Amylases, Acute pancreatitis, Pancreatitis, medicine.symptom, Pancreatic injury, business, Ceruletide
Abstract

Interleukin (IL)-11 has anti-inflammatory activity in animal models of gut inflammation, endotoxemia, and radiation-induced thoracic injury. The aim of the present study was to investigate the protective role of IL-11 in a model of acute necrotizing pancreatitis in mice. Acute pancreatitis was induced by administration of seven intraperitoneal injections of cerulein (50 microg/kg) at hourly intervals. Lipopolysaccharide (LPS) was injected 5 hours after the first cerulein injection. Treatment with recombinant human IL-11 (rhIL-11) was started 30 minutes before the first cerulein injection and repeated 4 hours later. Serum levels of amylase, lipase, and tumor necrosis factor (TNF)-alpha were measured at the end of the experiments. The severity of pancreatitis was evaluated by histological scoring using a semiquantitative analysis of hematoxylin and eosin-stained sections of the pancreas. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to quantify the intrapancreatic TNF-alpha mRNA levels. Serum amylase and lipase levels progressively increased with a maximum reached between 8 and 11 hours. Treatment with rhIL-11 significantly decreased amylase and lipase levels at 6 and 8 hours. Serum TNF-alpha peaked at 6 hours and rapidly decreased thereafter. The elevation of serum TNF-alpha was markedly inhibited by treatment with rhIL-11. Histologically, treatment of rhIL-11 reduced the severity of pancreatic injury including edema, inflammatory cell infiltration, and hemorrhage at 6 hours. Intrapancreatic TNF-alpha mRNA levels were reduced by >50% in the rhIL-11-treated group at 6 hours. In conclusion, rhIL-11 decreased the severity of experimental pancreatitis early on but not later and inhibited the intrapancreatic TNF mRNA expression in vivo, suggesting that the protective effect of IL-11 during the early stage of acute pancreatitis may be mediated, at least in part, through modulation of TNF production.

Published
2000

199. Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects

Author

Ullrich S. Schwertschlag, Kevin Dykstra, Anne Stone, James C. Keith, Holly Rogge, and John Loewy

Subjects
Adult, Male, medicine.medical_specialty, Anemia, medicine.medical_treatment, Hematocrit, Placebo, Hydrochlorothiazide, Internal medicine, Medicine, Humans, Pharmacology (medical), Plasma Volume, Aldosterone, Pharmacology, Triamterene, medicine.diagnostic_test, business.industry, Osmolar Concentration, Sodium, Middle Aged, medicine.disease, Interleukin-11, Crossover study, Recombinant Proteins, Endocrinology, Toxicity, Female, Diuretic, business, Atrial Natriuretic Factor, medicine.drug
Abstract

Recombinant human interleukin-11 (rhIL-11), or Neumega rhIL-11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti-inflammatory and immune-modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL-11-induced volume retention and devise a possible therapeutic intervention to ameliorate this effect. Eighteen healthy volunteers (9 male and 9 female) on a controlled sodium (180 mEq/day) and potassium (120 mEq/day) diet were randomized to one of six treatment sequences in a three-period crossover design. Each subject received 25 micrograms/kg IL-11 s.c. once daily, 25 micrograms/kg IL-11 s.c. once daily + Maxzide-25 twice daily, or placebo for 7 days in a crossover design. There was a 14-day washout period between treatment periods. Renal clearance parameters indicated that mean sodium excretion was decreased compared to placebo within 8 hours after dosing with rhIL-11, with these results reaching statistical significance 8 to 16 hours postdose (p < 0.01). The cumulative sodium excretion (mEq +/- SD) over the 7-day treatment period for each respective treatment group was the following: rhIL-11 = 833 +/- 154, rhIL-11 + Maxzide-25 twice daily = 1114 +/- 178, and placebo = 982 +/- 193 (p < 0.01). Hemoglobin concentration and hematocrit values, used as indicators of hemodilution, decreased in the rhIL-11-treated group as compared to the baseline and placebo groups (p < 0.01). Concurrent dosing with Maxzide-25 twice daily reduced the rhIL-11-associated hemodilution by about 50%.

Published
2000

200. Cytotoxic effects of tumour necrosis factor (TNF)-alpha and interferon-gamma on cultured human trophoblast are modulated by fibronectin

Author

James C. Keith, Lisbeth Vercruysse, F.A. Van Assche, Robert Pijnenborg, and C Luyten

Subjects
Embryology, medicine.medical_specialty, Interferon type II, Cell Survival, medicine.medical_treatment, Biology, Interferon-gamma, Epidermal growth factor, Pregnancy, Internal medicine, Genetics, medicine, Humans, Interferon gamma, Molecular Biology, reproductive and urinary physiology, Cells, Cultured, Tumor Necrosis Factor-alpha, Growth factor, Obstetrics and Gynecology, Trophoblast, Cell Biology, Molecular biology, Fibronectins, Trophoblasts, Fibronectin, Cytokine, medicine.anatomical_structure, Endocrinology, Reproductive Medicine, embryonic structures, biology.protein, Tumor necrosis factor alpha, Female, Developmental Biology, medicine.drug
Abstract

Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, produced by maternal inflammatory cells, may compromise trophoblast survival at the trophoblast-maternal interface and notably in the placental bed which is invaded by trophoblast. Extracellular matrix components, e.g. fibronectin, may enhance trophoblast survival. A possible protective effect of fibronectin against toxic effects of TNF-alpha and IFN-gamma was investigated in cultured trophoblasts isolated from six human term placentas, grown on uncoated and fibronectin-coated plastics. IFN-gamma and increasing doses of TNF-alpha resulted in decreasing viability of trophoblast on uncoated as well as fibronectin-coated dishes, as shown by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays, but for each TNF/IFN treatment condition viability on fibronectin was higher (P < 0.001). Epidermal growth factor (EGF), a growth factor reported to protect against TNF-alpha/IFN-gamma induced toxicity, resulted in further increased viability, but not if IFN-gamma was included in the treatment. EGF caused increased fibronectin secretion into the medium (P < 0.001), and double cytokeratin/fibronectin immunostaining confirmed the trophoblastic nature of fibronectin secreting cells. We conclude that fibronectin increases viability, but does not completely abolish the cytotoxic action of TNF-alpha and IFN-gamma on trophoblast. The protective effect of EGF may be related to stimulation of fibronectin secretion by trophoblast.

Published
2000

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