Research Report 2009 Faculty of Medicine

y Research Report 2009 Faculty of Medicine Report 2009 Faculty Research Con nte ts

Table of Contents

Preface ...... 6 Institute of Virology – Clinical and Molecular Virology Chair of Clinical Virology ...... 38 Franz-Penzoldt-Centre of Experimental Biomedicine ...... 40

Preclinical Institutes Institute of Experimental and Clinical Pharmacology Anatomical Institute and Toxicology Chair of Anatomy I ...... 10 Chair of Pharmacology and Toxicology ...... 42 Chair of Anatomy II ...... 12 Chair of Clinical Pharmacology and Clinical Toxicology ...... 44 Institute of Physiology and Pathophysiology Doerenkamp-Chair of Innovations in Animal and Chair of Physiology ...... 14 Consumer Protection ...... 46

Institute of Cellular and Molecular Physiology Institute of Human Genetics Chair of Physiology Chair of Human Genetics ...... 48 (Vegetative Physiology) ...... 16 Institute of Forensic Medicine Institute of Biochemistry – Emil-Fischer-Centre Chair of Forensic Medicine ...... 50 Chair of Biochemistry and Molecular Medicine ...... 18 Chair of Biochemistry and Pathobiochemistry ...... 20 Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine Chair of Occupational and Social Medicine ...... 52

Clinical Theoretical Institutes Institute of Medical Physics Institute of Medical Informatics, Biometry and Chair of Medical Physics ...... 54 Epidemiology Chair of Biometry and Epidemiology ...... 22 Endowed Chair of Medical Informatics ...... 24 Nikolaus-Fiebiger-Centre of Molecular Medicine Chair of Experimental Medicine I (Connective Tissue Research) ...... 56 Institute of the History of Medicine and Chair of Experimental Medicine II Medical Ethics (Molecular Oncology) ...... 58 Chair of the History of Medicine ...... 26 Professorship for Medical Ethics ...... 28

Institute of Pathology Clinical Chairs additionally to Chair of General Pathology and the University Hospital Pathological Anatomy ...... 30 Institute of Biomedicine of Aging Division of Nephropathology ...... 32 Chair of Internal Medicine - Geriatrics ...... 60

Institute of Neuropathology Department of Orthopaedics in the Waldkrankenhaus Chair of Neuropathology ...... 34 Chair of Orthopaedics and Orthopaedic Surgery ...... 62 Division of Orthopaedic Rheumatology ...... 64 Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Chair of Microbiology and Immunology of Infection ...... 36

2 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) UNIVERSITY HOSPITAL Department of Anaesthesiology Chair of Anaesthesiology ...... 98 Department of Medicine 1 – Gastroenterology, Lung Diseases and Endocrinology Chair of Internal Medicine I ...... 66 Department of Obstetrics and Gynaecology Chair of Obstetrics and Gynaecology ...... 100 Department of Medicine 2 – Cardiology and Angiology Department of Radiation Chair of Internal Medicine II ...... 68 Chair of Radiation Therapy ...... 102

Department of Medicine 3 – Department of Pediatrics Rheumatology and Immunology Chair of Pediatrics ...... 104 Chair of Internal Medicine III ...... 70 Division of Pediatric Cardiology ...... 106 Division of Molecular Immunology ...... 72 Department of Dermatology Department of Medicine 4 – Chair of Skin and Venereal Diseases ...... 108 Nephrology and Hypertensiology Chair of Internal Medicine IV ...... 74 Department of Ear, Nose and Throat – Head and Neck Surgery Department of Medicine 5 – Chair of Otorhinolaryngology ...... 110 Haematology and Oncology Division of Phoniatrics and Pediatric Audiology ...... 112 Chair of Haematology and Oncology ...... 76 Department of Ophthalmology Department of Nuclear Medicine Chair of Ophthalmology ...... 114 Chair of Clinical Nuclear Medicine ...... 78 Department of Neurology Institute of Radiology Chair of Neurology ...... 116 Chair of Diagnostic Radiology ...... 80 Division of Molecular Neurology ...... 118 Division of Neuroradiology ...... 82 Department of Neurosurgery Department of Surgery Chair of Neurosurgery ...... 120 Chair of Surgery ...... 84 Division of Pediatric Surgery ...... 86 Department of Psychiatry and Psychotherapy Division of Trauma Surgery ...... 88 Chair of Psychiatry and Psychotherapy ...... 122 Division of Transfusion Medicine and Division of Child and Adolescent Mental Health ...... 124 Haemostaseology ...... 90 Division of Psychosomatics and Psychotherapy ...... 126

Department of Plastic and Hand Surgery ...... 92 Department of Oral and Maxillofacial Surgery Chair of Dental, Oral and Maxillofacial Medicine – Department of Cardiac Surgery especially Oral and Maxillofacial Surgery ...... 128 Chair of Cardiac Surgery ...... 94 Dental Department 1 – Department of Urology Operative Dentistry and Periodontology Chair of Urology ...... 96 Chair of Dental, Oral and Maxillofacial Medicine – especially Operative Dentistry, Periodontology and Pediatric Dentistry ...... 130

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 3 Contents

Dental Department 2 – Prosthetic Dentistry Research Unit (FOR) 832: Chair of Dental, Oral and Maxillofacial Medicine – Regulators of humoral immunity ...... 146 especially Prosthetic Dentistry ...... 132

Research Unit (FOR) 894: Fundamentals on Fluid and Dental Department 3 – Orthodontics and Physical Dynamics in Human Voice Production ...... 147 Orofacial Orthopedics Chair of Dental, Oral and Maxillofacial Medicine – especially Orofacial Orthopedics ...... 134 National Reference Centre for Retroviruses ...... 148

National Genome Research Network – Infection DFG Collaborative Research Centres and and Inflammation – Work package “Viral Infections”, Research Groups Erlangen ...... 149 Collaborative Research Centre (SFB) 423: Kidney injury: pathogenesis and regenerative mechanisms ...... 136 National Genome Research Network – Mental Retardation Network (MRNET), Erlangen ...... 150

Collaborative Research Centre (SFB) 466: Lymphoproliferation and Viral Immunodeficiency ...... 137 Project group of the Academy of Science and Literature, Mainz ...... 151

Collaborative Research Centre (SFB) 473: Switch Processes of Transcription ...... 138 DFG Research Training Groups Collaborative Research Centre (SFB) 539: Research Training Group 516: Cultural Transfer in Glaucomas including Pseudoexfoliation Syndrome ...... 139 the European Middle Ages ...... 152

Collaborative Research Centre (SFB) 603: Research Training Group 592: Lymphocytes – Model-Based Analysis and Visualization of Complex Scenes Differentiation, Activation and Deviation ...... 153 and Sensor Data ...... 140 Research Training Group 1071: Collaborative Research Centre (SFB) 643: Viruses of the Immune System ...... 154 Strategies of Cellular Immune Intervention ...... 141 BioMedTec International Graduate School of Science Clinical Research Unit (KFO) 106: (BIGSS): Lead structures of Cell Function ...... 155 Target Organ Damage in Hypertension ...... 142 Erlangen Graduate School in Advanced Optical Clinical Reserach Unit 130: Technologies (SAOT) ...... 156 Determinants and Modulators of postoperative pain ..... 143

Clinical Research Unit Bavarian Immunotherapy Network (BayImmuNet): Adoptive Immunotherapy ...... 144

Research Unit (FOR) 661: Multimodal Imaging in Pre-clinical Research ...... 145

4 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Interdc is iplinary Centres Appendix Interdisciplinary Centre for Clinical Research Honorary Doctorate ...... 171 (IZKF) ...... 157

A Selection of Awards 2007 – 2008 ...... 172 Interdisciplinary Centre for Public Health (IZPH) ...... 158 Doctorate Theses, Board Qualifications, Additional Qualifications, Habilitations ...... 174 Interdisciplinary Centre for Gerontology (ICG) ...... 159 In Memoriam ...... 191

Interdisciplinary Centre for Functional Genomics (FUGE) ...... 160 Imprint ...... 192

Programmes and Foundations for Research Support ELAN programme for supporting clinical research and teaching ...... 161

Johannes and Frieda Marohn-Foundation ...... 162

Further foundations for research support ...... 163

Academic society Society for Physics and Medicine Erlangen ...... 164

Degree Programmes Degree Program in Medicine ...... 165

Degree Program in Dentistry ...... 167

Degree Program in Molecular Medicine ...... 168

Medical Process Management ...... 170

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 5 Preface

Medical Research in Erlangen

This report for the years 2007-2008 marks the fifth time we have presented an overview of the research areas concentrated on and projects carried out by the various institutes and clinics at the University of Er- langen-Nürnberg Medical School. The aim is to provide an account of the work done in basic research as well as in clinical research projects during the report period. It is meant to be read by a wider audience comprised of interested parties both inside and outside the university sphere. It is intended to serve as a source of information both for internal and interdisciplinary use and to encourage suggestions for future cooperative projects.

Dean of the Medical School The University of Erlangen-Nürnberg Medical School has established Prof. Dr. med. Dr. h. c. Jürgen Schüttler four focal areas of research, all of which were given a high rating by the Science Council in 2006:

1. Immunology and Infection Research, 2. Renal and Vascular Research, In the course of the report period 2007-2008 a wide range of activities 3. Neurosciences (incl. Glaucoma), Pain were carried out aimed at continuing to move forward with the process 4. Tumor Research. of enhancing our reputation as an institution and making our achievements as a leading provider of medical research and training more vi- These research focuses are networked with each other through three sible to an international audience. The research orientation of our Me- interdisciplinary fields: Molecular Medicine, Medical Technology, and dical School is reflected by the existence of the Interdisciplinary Center Clinical Studies. Translational research, i.e. an active effort to transpo- for Clinical Research (IZKF, p. 157), the Franz Penzoldt Center (p. 40), as se findings from basic research into clinical studies involving patients, well as the newly established Center for Clinical Studies (CCS). The lat- is the overarching purpose of all research activity at the University of ter will be responsible, among other things, for coordinating the legal Erlangen-Nürnberg Medical School. Thus, the objective of medical re- aspects of bench-to-bedside research projects. search is seen not solely as being that of discovering new facts and ex- panding medical knowledge for its own sake. It is also seen as being In 2007, inventory was taken of the amount of floor space in Medical that of striving for effectiveness in the pursuit of better therapeutic out- School facilities dedicated to research. This was documented in a Higher comes for our patients. Education Information System (HIS) report on construction planning for teaching and research. The report showed a considerable lack of floor These focal research areas are characterized by interdisciplinary net- space dedicated to research in the clinical sector. This was a reflection works supported by third-party funding provided in the framework of of the large number of excellent research initiatives that have origina- collaborative research centers, graduate research centers, DFG research ted in this sector in recent years. On the basis of this report the Medi- training groups, as well as network projects funded by the Federal Mi- cal School is currently formulating a program aimed at creating space nistry of Education and Research (BMBF) and the EU. A more detailed available for research which is to be allocated for limited periods of time account is given on page 136 ff. of this report. In recent years there has on the basis of applications made to the Research Commission. Consi- been a steady rise in levels of third-party funding. In 2008 the Medical deration is also being given to the development of a system for renting School applied for and obtained more than 32 million euros in third- additional rooms to be used for research purposes. party funding. A further improvement of research conditions resulted from the DFG’s Our Medical School plays an important part in the University of introduction of a lump sum to cover indirect costs incurred by projects, Erlangen’s scientific research focuses: “Molecular LifeS ciences and Me- part of which is passed on by the University or the Medical Center to in- dicine“ as well as “Medical Technology“. There is close cooperation bet- dividual clinics or institutes to use at their own discretion for research- ween the Medical School and the relevant science and engineering de- related purposes. This money has been used, for example, to create a partments in the various research networks. Collaborative Research Cen- position for a research coordinator who advises researchers and assists ter 796, Control Mechanisms of Microbial Effectors in Host Cells, was them in submitting national and international applications for project given a positive assessment by the DFG Senate and approved for fun- funding. The same person initiates and coordinates network projects. ding in late 2008. How do viruses and bacteria cause diseases? Collabo- However, the distribution of funds from the newly introduced lump sum rative Research Center 796 aims to acquire new knowledge on this pi- as well as other research funding and the execution of joint research fun- votal medical problem. Also involved, in addition to the Medical School, ding programs have been made difficult by a separation in the Medical are the various science and engineering departments at the University School administration of Medical Center budgets from those of non-cli- of Erlangen-Nürnberg, as well as the Fraunhofer Institute for Integrated nical institutes. A university working group on medical facility structures Circuits (IIS) in Erlangen. is endeavoring to find a solution to this problem.

6 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Translational Research

Moleculare Medicin Medical Technology Clinical Studies

1. Immunology and Infection Research

2. Renal and Vascular Research

3. Neurosciences (incl. Glaucoma), Pain

4. Tumor Research

Research focuses at the University of Erlangen-Nürnberg Medical School.

In 2007 a new organization plan was introduced for the Medical School In June 2007 an agreement was concluded between the administration with a view to promoting its strategic development and to professiona- of the University of Erlangen-Nürnberg and the Medical School on the lizing the Office of the Dean. The plan provides for the introduction of following objectives for the advancement of women in research by the additional assistant deans, including an Assistant Dean for Research as year 2012: to increase the percentage of women who have the formal well as two Assistant Deans of Students. qualifications for professorial positions from 17 % to 25 % and to increase the percentage of women who hold professorial positions from 7 % In 2008, after a report by an international commission of experts on the to 10 %. The ARIADNE mentoring program, already in place in other status of research in Bavaria („Wissenschaftsland Bayern 2020“) attes- divisions of the university, was initiated here in October 2008. The pro- ted to the fact that our Medical School had assumed a leading role in gram brings young academic talent (women who have completed their the establishment of clinical research in Germany over the past twenty doctorates and are working on a professorial qualification) together years, we succeeded in getting the Translational Research Center (TRC) with mentors who have accumulated experience in academic careers. in the framework of a program for the construction of research facilities of national and international importance in accordance with Article Start-up financing and other forms of funding are provided for young 91b of the German constitution. The construction of this facility as part academic talent with a view to helping pave the way to independent re- of the University Medical Center will provide an innovative interdiscip- search for these persons (ELAN Fund, p. 161, Johannes and Frieda Ma- linary infrastructure for clinical research of a kind never before seen at rohn Foundation, p. 162, IZKF Funding for Young Academic Talent, p. a university location in Germany. The TRC will bring together in exem- 157, as well as other foundations, p. 163). plary manner all those areas from which there is a need to translate research results into diagnostic and therapeutic procedures. By this means A new permanent platform for research funding, the Medical Research our Medical School will be able to counteract a much lamented lack of Foundation, was established in Erlangen in December 2007. The foun- development in clinical research and to create new research focuses on ders were the professors and department heads at the Medical School. the basis of a planned strategy. The Medical Research Foundation also conducts fund-raising activities and in some cases connects the awarding of larger amounts of funding With a view to further strengthening our research focuses and to sup- to the temporary dedication of lecture rooms to specific uses. porting the establishment of a Leibniz Institute for Immunology, preparations were made in 2008 for the founding of the Medical Immunolo- gy Campus Erlangen (MICE), an interdisciplinary center at the Universi- New developments in teaching ty of Erlangen-Nürnberg, with the objective of establishing the nucleus of an institute in the course of the next five years. In 2006 the Science Council underscored the transregional activities carried out by our Medical School with a view to promoting further deve- Another unique facility, the Medical Technology Testing and Applica- lopment of teaching. In light of this fact our report contains pertinent tions Center (METEAN), was opened in October 2007. It received a pre- items of information on teaching for each institution. sidential award in 2008 in the framework of the competition „Deutsch- land – Land der Ideen“ (Germany – Land of Ideas). The University of Er- The University of Erlangen-Nürnberg Medical School currently has de- langen-Nürnberg, the Fraunhofer Institute for Integrated Circuits, and gree programs in Medicine (p. 165), Dentistry (S. 167), Molecular Me- the University Medical Center have agreed to work together to transfer dicine (p. 168), and a new master’s degree program in Medical Pro- innovative medical technology as rapidly and effectively as possible to cess Management (p. 170) offered since winter semester 2008/2009. patient care applications.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 7 Preface

Since 2007 the students at the University of Erlangen-Nürnberg Medi- On behalf of the Medical School administration I would like to thank all cal School have regularly ranked among the best three out of 36 medi- those members of our staff who helped produce this report. Particular cal schools in the first phase of degree examinations and have also been thanks go to the Research Director, Dr. Annette Pfeiffer, and the Admi- in the top group in terms of grades received on state examinations re- nistrative Director, Dr. Esther Schnetz, for their active involvement in lating to clinical training. Our Medical School has consistently underta- formulating the text. The report can be downloaded from the website ken efforts to seize on and apply new ideas in teaching with a view to of the Office of the Dean of the Medical School (http://www.dekanat. maintaining these rankings. A changeover to the bachelor’s and master’s med.uni-erlangen.de). degree system is not planned for Medicine and Dentistry in Erlangen, given that this is not expected to produce any time advantages in the We hope our readers enjoy the information we have provided on the training of students and, as such, would not make it possible for them wide range of research carried out at our Medical School. The scientists to get started any earlier in the medical profession. In a memorandum involved will be happy to respond to questions sent in by mail or asked our Medical School stated its opposition to the general implementation in person about their projects. of the “Bologna Process” in medical studies. However, bachelor’s and master’s degree structures have been firmly established in specialized fields such as Molecular Medicine and Medical Process Management. Erlangen, November 2009

In summer semester 2007 a skills lab, PERLE (Practice, Experience and Learning), was created with money taken from tuition fees. Here students are able to improve their skills and prepare for practical examinations with the support of medical specialists and trained student tutors. Funds from this source are also used to finance research projects in teaching. Networked courses continue to be created in interdisciplinary Prof. Dr. med. Dr. h. c. Jürgen Schüttler subjects, all courses are systematically evaluated, and the professionali- Dean of the Medical School zation of student management in the practical year (11th and 12th semesters) continues to be pursued.

In 2008 the Bavarian State Ministry for Science, Research, and the Arts approved the establishment of a Competence Center for the Teaching of Medicine. In this framework the five medical schools in Bavaria have each chosen a focal area in which they want to develop special competence in the coming years and then pass on the knowledge gained to the other medical schools. The University of Erlangen-Nürnberg Medi- cal School has chosen course evaluation as its area of specialization and is working towards the creation of a general system of quality assurance in teaching that can be used by the other medical schools.

8 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008)

Preclinical Institutes

Anatomical Institute Chair of Anatomy I

Address Research towards neuropathological diagnostics of so- Krankenhausstrasse 9 called functional gastrointestinal disorders. 91054 Erlangen Innervation of the gastrointestinal tract Phone: +49 9131 8522265 Project manager: W. Neuhuber, J. Woerl, M. Autonomic innervation of the eye Fax: +49 9131 8522863 Raab, A. Brehmer Project manager: F. Schroedl www.anatomie1.med.uni-erlangen.de Demonstration of enteric co-innervation of stri- Knowledge of choroidal innervation is of key ated muscle in the human esophagus suggests importance for understanding ocular homeo- Head of Institute a possible role of its disturbance in pathogene- stasis. Thus, investigation of intrinsic choroidal Prof. Dr. med. Winfried Neuhuber sis of swallowing disorders. In an in vitro vagus neurons (ICN) and their connections will provide new insights into various aspects of ocu- Contact lar pathogenesis. These intrinsic neurons were Prof. Dr. med. Winfried Neuhuber characterized in both human and birds using Phone: +49 9131 8522265 immunohistochemistry, electron microscopy, Fax: +49 9131 8522863 neuronal tracing and electrophysiology. Based [email protected]. on development of novel techniques for com- uni-erlangen.de plete autonomic denervation of the chicken eye, extensive ongoing studies on the function Research Focus of ICN were performed. Furthermore, putative • Innervation of the gastrointestinal tract lymphatic vessels in the human choroid were • Autonomic innervation of the eye studied in collaboration with the Erlangen De- • Nervous system, inflammation and pain partment of Ophthalmology. • Cell biology of neurofibromatosis type 2 tumor suppressor proteins A motor endplate in striated muscle of human esopah- Nervous system, inflammation and pain gus. Cholinergic vagal (VAChT, blue) and peptidergic Project manager: W. Neuhuber enteric (VIP, green) terminals co-innervate the alpha- In collaboration with the Institute of Experi- Structure of the Institution bungarotoxin labeled motor endplate (red). (from Kall- mental and Clinical Pharmacology and Toxicol- muenzer et al. 2008) ogy, investigations on the influence of the au- Together with Chair II, Chair I composes the In- tonomic nervous system on experimental liver stitute of Anatomy. Altogether, 16 persons are nerve-esophagus preparation of the mouse, we inflammation were continued. We focussed on employed, five of them on an external fund- were able to further demonstrate a function- the role of CGRP, a peptide abundant in senso- ing basis. Research is conducted by 6 scientists al role of enteric co-innervation for inhibitory ry neurons. It partly acts antagonistic to sub- (chairman, senior scientists, postdoctoral fel- modulation of vagally induced striated muscle stance P, the other landmark sensory neuro- lows), 8 doctoral thesis students (both MD and contraction. It appears that TRPV1 expressing peptide, although its effects are more complex. PhD) and 6 technicians. Chair I provides the fa- sensory neurons and neurokinins are also in- These data may have impact on development cilities and logistics for gross anatomy includ- volved in this mechanism. of novel therapeutic strategies in hepatitis and ing body donation. This is essential not only for Afferent vagal terminals around myenteric gan- other immune liver disorders. Likewise, the in- teaching but also for applied clinical research. glia, so-called intraganglionic laminar endings fluence of the autonomic innervation was also Most of the teams investigate various aspects of (IGLEs) are putative mechanosensors probably studied in kidney inflammation. In collabora- autonomic innervation, in particular of the gas- exerting also additional purposes in the enteric tion with the Departments of Nephrology and trointestinal tract and the eye; one group stud- neuronal circuitry. They were further character- Pharmacology, we were able to show allevia- ies cell biology of tumor suppressor genes. A ized with respect to their equipment with ve- tion of experimental glomerulonephritis by broad spectrum of conventional histology, his- sicular glutamate transporters (VGLUT1 and 2) renal denervation. tochemistry and immunohistochemistry, light-, and purinergic P2X2/P2X3 receptors. In addi- In collaboration with the institute of Physiology confocal and electron microscopy, electrophys- tion, glutamate receptors, e.g., GLUR2/3 were and experimental Pathophysiology, we stud- iology (in collaboration with the Institute of demonstrated in myenteric neurons suggest- ied nociceptive innervation of the esophagus Physiology and Experimental Pathophysiology) ing local effects of glutamatergic IGLEs onto through the vagus nerve and the distribution and in vitro preparations of isolated organs as enteric neurons. of CGRP receptors in meninges and trigemi- well as molecular biology are applied. Equip- Morpho-chemical phenotyping of myenteric nal system. Both projects yielded basic data ment and laboratory facilities are available also neurons in the human and porcine intestines for understanding the pathogenesis of gastro- for other groups both within and outside the was continued (collaboration with Depart- esophageal reflux and migraine, respectively. medical faculty. ments of Pathology and Surgery in Erlangen, In collaboration with the Institutes of Pharma- Fuerth and Bamberg). Meanwhile, intrinsic sen- cy, University of Tuebingen, and Pharmacolo- sory neurons and other hitherto poorly discern- gy, University of Frankfurt, we studied the role ible neuron types could be characterized using of CRP2, a molecule of the nitrergic signaling combined morphological and chemical fea- cascade, in an animal model of chronic inflam- tures. Thus, we made an important step ahead matory pain.

10 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Intraganglionic laminar endings (IGLEs) in a myenteric ganglion of the rat esophagus identified by calretinin immunocytochenmistry (red) contain either the vesicular glutamate transporter 1 (green) or 2 (blue) or both (white in the merge on the right). (from Ewald et al. 2006)

Cell biology of neurofibromatosis type 2 Teaching International Cooperation tumor suppressor proteins Prof. H.-R. Berthoud, Pennington Biomedical Research Project manager: M. Kressel Both anatomical institutes collaborate in teach- Centre Baton Rouge, University of Louisiana, USA Neurofibromatosis type 2 (NF2) gene is a ing anatomy. In particular, Chair I is concerned Prof. C. Chiang, Department of Cell and Developmental tumor suppressor gene whose deletion typical- with courses in gross antomy and parts of Bilogiy, Vanderbilt University Medical Centre, Nashville, USA ly results in schwannomas of the VIIIth cranial interdisciplinary clinical-anatomical seminars Prof. J. B. Furness, Department of Anatomy and Cell Bi- nerve, so-called acoustic neurinomas. Cell bio- and courses of neuroanatomy. The dissection ologiy, Universitsy of Melbourne, Australia logical investigations aimed at elucidating the course with its small group format with cor- Prof. Dr. A. da Silveira, Department of Anatomy, University function of merlin, the protein coded by the related main lecture is of pivotal importance. of Uberlandia, Brazil NF2 gene, were continued. It turned out that Seminars, partly in PBL format and using elec- Prof. T. Takewaki, Department of Basic Veterinary Science, one isoform of this protein functions as a nu- tronic media, provide opportunity for students Gifu University, Japan cleo-cytoplasmic shuttle protein. This extends to train practical application of knowledge they Prof. J.-P. Timmermans, Institute of Histology and Cell Biol- ogy, University of Antwerpen, Belgium the classical view of merlin as a pure linker pro- have acquired in the dissection room (seminars tein between plasma membrane and cytoskel- of imaging methods, surface anatomy, clinical Dr. M.E. De Stefano, Dipt. di Biologia Celluara e di Sviluppo, Università “La Sapienza”, Roma, Italy eton and suggests a nuclear mechanism regu- anatomy). Members of the Institute provide lating cell proliferation. Thus, we focussed on lectures and courses also for other faculties. Prof. Dr. D. Nickla, The New England College of Optometry, Boston, USA

Selected Publications Prof. Dr. M.E. Fitzgerald, Department of Biology, Anatomy and Neurobiology, University of Tennessee, Memphis, USA Kraus T, Neuhuber WL, Raab M (2007) Distribution of Dr. M. Giovannini, Institut Curie, INSERM, Paris, France vesicular glutamate transporter 1 (VGLUT1) in the mouse esophagus. Cell Tissue Res, 329: 205-19 Prof. S. Pulst, Neurogenetics Lab and Division of Neurology, Cedars-Sinai Medical Centre, Los Angeles, USA Weidmann S, Schroedl F, Neuhuber W, Brehmer A (2007) Quantitative estimation of putative primary afferent neurons Meetings and International Training in the myenteric plexus of human small intestine. Histochem Cell Biol, 128: 399-407 Courses Kallmuenzer B, Soerensen B, Neuhuber WL, Woerl J (2008) 25.–28.04.2007: Plastisch-rekonstruktive und aesthetische Enteric co-innervation of striated muscle fibres in human Nasen- und Ohrmuschelchirurgie, Blepharoplastik und oesophagus. Neurogastroenterol Motil, 20: 597-610 Face Lift, Erlangen Lennerz JK, Ruehle V, Ceppa EP, Neuhuber WL, Bunnett 20.10.2007: Anatomie fuer Anaesthesisten, Erlangen NW, Grady EF, Messlinger K (2008) Calcitonin receptor- 18.10.2008: Anatomie fuer Anaesthesisten, Erlangen A NIH3T3 fibroblast transfected with a phospholipid bio- like receptor (CLR), receptor activity-modifying protein sensor (green) and a NF2 fusion construct with mCherry 1 (RAMP1), and calcitonin gene-related peptide (CGRP) (red), which labels vesicles of the late endosomal com- immunoreactivity in the rat trigeminovascular system: partment. (M. Kressel) differences between peripheral and central CGRP receptor distribution. J Comp Neurol, 507: 1277-99 Schroedl F, Brehmer A, Neuhuber WL, Kruse FE, May CA, elucidating transport mechanisms of merlin Cursiefen C (2008) The normal human choroid is endowed with a significant number of lymphatic vessel endothelial to the nucleus. We found binding of merlin to hyaluronate receptor 1 (LYVE-1)-positive macrophages. membrane lipids to be crucial. A repertoire of Invest Ophthalmol Vis Sci, 49: 5222-9 molecular biological and morphological meth- Veelken R, Vogel EM, Hilgers K, Amann K, Hartner A, Sass ods is applied for studying mechanisms that de- G, Neuhuber W, Tiegs G (2008) Autonomic renal denerva- termine its cytoplasmic and nuclear localization ameliorates experimental glomerulonephritis. J Am Soc Nephrol, 19: 1371-8 tions, respectively. In particular, artificial NF2 fusion proteins with green fluorescent protein are used. This resulted already in confining specific protein domains which regulate transport into the nucleus.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 11 Preclinical Institutes

Anatomical Institute Chair of Anatomy II

Address Research β2 observed in POAG. By perfusion of anterior Universitaetsstrasse 19 human eye segments we demonstrated that 91054 Erlangen Morphological changes in glaucomatous TGF-β2 physiologically increases IOP. In an Phone: +49 9131 8522864 eyes ongoing study using porcine eyes, we found Fax: +49 9131 8522862 Project manager: E. Luetjen-Drecoll, O. Tektas that IL1a counteracts this effect and moreover www.anatomie2.med.uni-erlangen.de In the last years we received a number of en- induces expression of ELAM-1, a designated tire globes derived from patients with POAG, marker molecule for the glaucomatous TM. Head of Institute so that for the first time changes in the optic Prof. Dr. med. Elke Luetjen-Drecoll nerve head could be studied qualitatively and Mouse model for glaucomatous changes in quantitatively. We found that in contrast to retina and optic nerve Contact the postlaminar region the capillary density in Project manager: M. Scholz, E. Luetjen-Drecoll Prof. Dr. med. Michael Eichhorn the nerve head was not reduced. There were, The DBA/2J mouse is a commonly used model Phone: +49 9131 8522830 however, significant changes in the vessel walls. for glaucoma. The purpose of our studies fo- Fax: +49 9131 8522862 There was a thickened connective tissue sheath cused on qualitative and quantitative analy- [email protected] containing type IV and type VI collagen, so that ses of morphological investigations of DBA/2J erlangen.de the diffusion distance between vessel lumen eyes in correlation with physiological data. In and Astroglia is increased. This could result in addition, we searched for differences in pro- Research Focus underperfusion. tein composition of the aqueous humor of • Morphological changes in glaucomatous DBA/2J and control mice. Individual data anal- eyes Retrospective 3-D-microscopy ysis showed no general dependency between • Retrospective 3-D-microscopy Project manager: M. Eichhorn, E. Luetjen- elevated IOP and ON in DBA/2J mice. In coop- • Role of aqueous humor factors in glaucoma Drecoll, J. Hornegger eration with the Department of Ophthalmolo- pathogensis Glaucoma research suffers from the lack of an gy (Prof. Kremers), ERG data of DBA/2J and B6 • Mouse model for glaucomatous changes in adequate animal model or an experimental controls were compared with corresponding retina and optic nerve glaucoma model comparable to open angle IOP measurements. In both strains a decrease • Detection of hyaluronan acid by dynamic glaucoma (POAG) in humans. As a conse- in ERG responses with age was observed. In light scattering quence morphological investigations are lim- DBA2/J, however, this decrease was consider- • APC guidance in the anterior eye segment ited to human post mortem eyes. We have ably higher than in B6. A significant correla- • Accommodation and presbyopia started a program to correlate vascular chang- tion with elevated IOP values in DBA2/J was • Influence of Prostaglandin F2α on hair es with axon damage in the optic nerve head not found. growth applying serial sectioning. However, detecting vessels in a tissue requires 3-D reconstruction. Detection of hyaluronan acid by dynamic In collaboration with the Institute of pattern light scattering Structure of the Institution recognition (Prof. Hornegger) we try to devel- Project manager: M. Eichhorn, E. Luetjen-Drec- op algorithms enabling us to visualize the mor- oll, A. Leipertz, A. Froeba The Department of Anatomy consists of Chair I phological structures and their changes in 3-D. The transparency of cornea and lens has to be and Chair II. Chair II has 30 members of staff. 7 maintained all life long, although proteins and positions are financed by grant money. 8 doc- Role of aqueous humor factors in pigment granules set free from the iris and an- toral researchers (from the field of medical, glaucoma pathogensis terior ciliary body permanently circulate in the natural and 1 of computer science) contribute Project manager: M. Birke, E. Luetjen-Drecoll humor aqueous (AqH) and are in contact with to the scientific research.T he curriculum of the TGF-β2 is increased in the AH of app. 50% of the surfaces of the transparent tissues. In col- Anatomical Institute II comprises the functional the POAG patients, being the factor with the laboration with the Institute for Technical Ther- anatomy of the human body including embry- highest incidence thereby. We demonstrated modynamics (Prof. Leipertz, Prof. Froeba) a ology, microscopic anatomy and neuroanato- that TGF-β2 in-vitro strongly activated the de- program was started to detect an inert anti- my. The scientific focus of the Institute lies on novo synthesis of various ECM components adhaesive surface molecule by “dynamic light the investigation of the functional anatomy of frequently found to be accumulated in POAG. scattering”. First results suggest that hyluronan the eye, the pathogenesis of glaucoma, the ba- Concurrently TGF-β2 induced the inhibitory is an interesting candidate. sics of presbyopia, the immunprivilege of the molecule PAI-1, thereby repressing MMP-de- eye and the influence of prostaglandins on hair pendent ECM degradation and additionally APC guidance in the anterior eye segment growth. These investigations are performed by favouring ECM accumulation. These findings Project manager: M. Birke, E. Luetjen-Drecoll the use of immuno-histochemistry, transmis- applied both in TM cells and astrocyts of the Absence of completely endothelial lined lym- sion- and scanning -electron-microscopy, cell optic nerve. In a cooperative study with Prof. phatic capillaries is considered to be one of cultures, molecular biology and physiological Welge-Luessen, we demonstrated that hypox- the basic principles for ocular immunprivilege. methods. There are close collaborations with ia followed by a subsequent reoxygenation However, the anterior eye segment underlies the other projects of the Collaborative Research phase lead to an elevated secretion of TGF-β2 immunological surveillance and moreoever, Centre (SFB) 539 and long-term international by astrocytes, presenting a first mechanisti- the route chosen by APCs to leave this has sig- cooperations. cal explanation for the local increase of TGF- nificant relevance for immune privilege. We

12 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Scanning electronmicrograph of a newly described complex zonular fiber system connecting the zonular plexus with the vitreous membrane (in “Morphology and accommodative function of the vitreous zonule in human and monkey eyes”, Lütjen-Drecoll et al., IOVS, accepted) demonstrated that the entry sites into AH out- Influence of Prostaglandin F2α on hair Selected Publications flow, the trabecular meshwork and the trabec- growth Neumann C, Yu A, Welge-Luessen U, Luetjen-Drecoll E, ulum ciliare, were positive for the lymphatic Project manager: M. Tauchi, E. Luetjen-Drecoll Birke M (2008) The Effect of TGF-{beta}2 on Elastin, Type VI marker podoplanin (Pdpn), as well as the ante- Our research focus is to understand the mech- Collagen, and Components of the Proteolytic Degradation System in Human Optic Nerve Astrocytes. Invest Ophthal- rior iris surface, where APCs enter the anterior anism of trichomegaly induced by a Prosta- mol Vis Sci, 49: 1464-72 eye chamber. Pdpn was shown to bind Ccl21 glandin F2 (PGF2 ). We use mice as a model α α Scholz M, Buder T, Seeber S, Adamek E, Becker CM, Luetjen- in vitro, a ligand for CCR7 expressed on migrat- (eyelashes and dorsal skin hairs) and investi- Drecoll E (2008) Dependency of Intraocular Pressure Eleva- tion and Glaucomatous Changes in DBA/2J and DBA/2J-Rj ing APCs. By immunofluorescens staining we gate the effect of PGF2α on activation of hair detected Ccl21 expression at the iris surface, follicle stem cells and hair growth cycle regu- Mice. Invest Ophthalmol Vis Sci, 49: 613-21 partially colocalizing with Pdpn and CCR7 posi- lation. We characterized mouse eyelashes and Yu AL, Fuchshofer R, Birke M, Kampik A, Bloemendal H, Wel- tive cells exiting the iris there. In vitro cultured found that PGF2 activates hair follicle stem ge-Lussen U (2008) Oxidative stress and TGF-beta2 increase α heat shock protein 27 expression in human optic nerve human TM cells also co-expressed Pdpn and cells to enter anagen phase, extends anagen head astrocytes. Invest Ophthalmol Vis Sci, 49: 5403-11 Ccl21. Taken together, our data suggest the period, and in eye lashes increases bulb thick- Tektas OY, Lütjen-Drecoll E (2009) Structural changes of existence of a migration mechanism based on ness resulting in longer and thicker eyelashes. the trabecular meshwork in different kinds of glaucoma. the constitution of a Ccl21 gradient directed The molecular mechanisms of these events are Exp Eye Res, 88:769-75 out of the iris towards the AH outflow tissues under investigation. via binding to Pdpn. International Cooperation Paul Kaufman, Madison, Wisconsin/USA, USA Accommodation and presbyopia Teaching Majo Klinik Rochester, USA Project manager: E. Luetjen-Drecoll Prof. D. Kerjaschki, Wien, Austria Flexible intraocular lenses can only be sufficient Chair II of the Anatomical Institute organizes to reestablish accommodation if the remain- the lectures “functional anatomy” and “func- ing accommodative apparatus is still working. tional histology”, the accompanying courses In the present studies we have investigated 1) “anatomical demonstration” and “microscopic whether the opened and ageing lens capsule anatomy” as well as the “neuroanatomical sem- still has enough elasticity; 2) morphology and inar”. The lectures and courses are attended ageing of the vitreous zonule; 2) afferent inner- by the students of human medicine, dentistry vation of the ciliary muscle. The studies were and molecular medicine. Prof. Eichhorn is part performed in collaboration with P. Kaufman, of the teaching stuff in the MAOT and SAOT Madison, Wisconsin. He performed the exper- graduate schools. iments and investigated shape changes of the accommodation apparatus in presbyopic Rhe- sus monkeys. Their UBM data were compared with our morphological ones. We found that 1) the opened lens capsule still has enough elasticity to allow accommodation; 2) that there is a complex vitreous zonule which in ageing animals restricts muscle movement. Lysis of this zonule restored muscle contraction; 3) that there is a complex afferent innervation at all muscle tendon regions and overlying the circular muscle portion. Intrinsic ganglion cells seem to allow an intrinsic circuit to fine modulate ciliary muscle contraction.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 13 Preclinical Institutes

Institute of Physiology and Pathophysiology Chair of Physiology

Address phy, functional imaging, and psychophysics tion, frequency and propagation of action po- Universitaetsstrasse 17 in healthy humans and chronic pain patients. tentials to the central nervous system. 91054 Erlangen Phone: +49 9131 8522295 Trigeminal nociception and headaches Fax: +49 9131 8522497 Research Project manager: K. Messlinger www.physiologie1.uni-erlangen.de The group is working on nociceptive processes Neurophysiologic principles of higher in the cranial dura mater, trigeminal ganglion Head of Institute brain functions and spinal trigeminal nucleus as basis of head- Prof. Dr. med. Christian Alzheimer Project manager: C. Alzheimer aches. Single-fibres are recorded from dura Our research focuses on the electric behavior nerves in vitro to study sensitivity and respons- Contact of CNS neurons under normal and pathological es to CGRP, prostaglandins or histamine, prob- Prof. Dr. med. Peter Reeh conditions. Using high resolution neurophysi- ably involved in generation of headaches. Re- Phone: +49 9131 8522228 ologic techniques, we investigate function and lease of these mediators and actions on dural Fax: +49 9131 8522497 regulation of ion channels and synapses. Our blood vessels are analyzed as well. Intracellular [email protected] aim is to understand basic neural processes signal transduction is studied using immuno- which are essential for cognitive functions and histochemical and molecular biological meth- Research Focus affective behavior and the impairment of which ods. Central nervous mechanisms of headache • Neurophysiologic principles of higher brain might cause neuropsychiatric disorders. In par- are examined by recording from secondary functions ticular, we are studying the following topics: neurons in the spinal trigeminal nucleus and • Transduction, integration, plasticity in pri- 1) Role of muscarinic acetylcholine receptor testing potential headache drugs. mary nociceptive neurons subtypes in synaptic plasticity, learning and • Trigeminal nociception and headaches memory. • Microneurography of nociceptive axons in 2) Role of activin, a member of the Transform- human ing Growth Factor β superfamily, as a “mas- • Functional imaging of brain activity by fMRI ter molecule” tuning glutamatergic and GABAergic neurotransmission, and its impact on cognition, emotions and neuropro- Structure of the Institution tection. 3) Interaction between BACE1, a crucial en- The institute comprises one reoccupied chair zyme in the amyloid cascade of Alzheimer´s and two professorships for physiology with disease, and properties and expression of their work groups, two further groups are as- Na+ channels. sociated to an Academic Directorate and a professor emeritus. In addition, the institute Transduction, integration, plasticity in houses collaborating work groups of the Ne- primary nociceptive neurons phrological, Anesthesiological, and Neurologi- Project manager: P. Reeh cal Hospitals, guest researchers of the Medical Research on primary nociceptive neurons, their and Gynaecological Hospitals as well as from electrophysiological and neurochemical re- CGRP meets its receptor in the rat dura mater Japan and Spain. sponses to noxious stimuli and chemical medi- CGRP (red) is expressed in perivascular nerve fibers. The Altogether 55 persons work in the institute, 14 ators. Isolated preparations and cultured dor- CGRP receptor protein CLR (green) appears in smooth of them funded by grants. The research is done sal root ganglion cells as well as transfected muscle cells (blue) of arteries (left) but not veins (right upper half). by 22 PhD/MD scientists, 21 doctoral students cell lines are used to study action potential dis- and 12 technical assistants. charge, ionic currents and release of substance The institute is just integrating new work P and calcitonin gene-related peptide. Aim is to groups that study synapses and ion channels elucidate nociceptive transduction and integra- of central nervous neurons using electrophysi- tion of stimuli as well as possible pharmacologi- ological and histochemical means and bring- cal interventions. Specific topic is sensitization ing new biophysical and molecular biological by tissue acidosis and inflammatory mediators expertise. Many common interests and tech- as well as their intracellular signal transduc- nical-methodical synergies are arising with the tion. Transgenic mouse strains lacking differ- established groups that are focusing on pain ent metabotropic and ionotropic receptors or physiology and predominantly work on pri- thermally activated ion channels (TRPV1) are mary and secondary sensory neurons. Their studied. Voltage-controlled ion channels (NaV, research spectrum covers cellular and molecu- HCN) recently came in focus, because only few lar biological questions and extends over be- subtypes decide on excitability, i.e. on genera- havioral physiology towards microneurogra-

14 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Microneurography of nociceptive axons in Teaching Selected Publications human Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Project manager: H.O. Handwerker, B. Namer In the context of preclinical training of students Kobayashi J, Nau C, Wood JN, Reeh PW (2007) Sensory Microneurography, recording of single unit ac- of medicine, dentistry and molecular medicine neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature, 447: 855-8 tion potentials, is applied to awake human sub- the institute mainly teaches neurophysiology. jects or patients. Three major projects: Besides the classical teaching methods, which Leffler A, Fischer MJ, Rehner D, KienelS , Kistner K, Sauer SK, Gavva NR, Reeh PW, Nau C (2008) The vanilloid receptor 1) Mechano-insensitive “sleeping” unmyelinat- are lectures, practical courses and seminars, TRPV1 is activated and sensitized by local anesthetics in ed nociceptors had been found particularly also internet-based seminars are provided. Half rodent sensory neurons. J Clin Invest, 118: 763-76 sensitive to histamine which plays a major of the practical courses are given as a block Lennerz JK, Ruehle V, Ceppa EP, Neuhuber WL, Bunnett role in mediating itch sensations. Another which is positively evaluated by the students. NW, Grady EF, Messlinger K (2008) Calcitonin receptor- very similar itch sensation is evoked by a pro- This appreciation is further supported by up- like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) tease isolated from mucuna pruriens, which grading of the experimental setups that were immunoreactivity in the rat trigeminovascular system: surprisingly excites a different subpopula- funded by the students’ fees. Colleagues from differences between peripheral and central CGRP receptor tion of unmyelinated nociceptors. The prop- the hospitals are regularly invited to comple- distribution. J Comp Neurol, 507: 1277-99 erties of these separate peripheral pathways ment actual topics from a clinical point of view Schoedel AL, Zimmermann K, Handwerker HO, Forster C of pruritus are studied with psychophysio- which they often do with presenting a patient. (2008) The influence of simultaneous ratings on cortical BOLD effects during painful and non-painful stimulation. logical and electrophysiological methods. Furthermore, interdisciplinary lectures are Pain, 135: 131-41 2) Aging of nociceptors occurs throughout the given to students of natural and technical sci- Namer B, Carr R, Johanek LM, Schmelz M, Handwerker long life span of humans which is not com- ences and of psychology who selected medi- HO, Ringkamp M (2008) Separate peripheral pathways for parable to that of laboratory animals. It is cine as subsidiary subject or main focus. To pruritus in man. J Neurophysiol, 100: 2062-9 shown that characteristic functional chang- them not only neurophysiology but all topics Zheng F, Adelsberger H, Mueller MR, Fritschy JM, Werner S, es such as spontaneous activity and lower- of physiology are presented. Alzheimer C (2009) Activin tunes GABAergic neurotransmis- ing of stimulation thresholds, but also loss of sion and modulates anxiety-like behavior. Mol Psychiatry, 14: 332-46 excitability in a subgroup of C-fibers, reflect a normal aging process, though previously International Cooperation regarded as pathologic. S. Werner, Inst. Cell Biology, ETH Zuerich, Switzerland 3) Recording of nerve fibers in patients with L. Negri, Univ. La Sapienza, Roma, Italy chronic polyneuropathies allows character- A. Babes, Univ. Bucharest, Romania izing pathologic discharge patterns and altered conductile properties in particular in G. Kobal, Altria Client Services, Richmond, USA diabetic polyneuropathy. K. Mizumura, RIEM, Nagoya Univ., Japan C. Belmonte, Dept. Neuroscience, Univ. Miguel Hernandez, Functional imaging of brain activity by Alicante, Spain fMRI A. Ikoma, Dept. of Dermatology, Univ. Hospital Kyoto, Japan Project manager: C. Forster P. McNaughton, Univ. Cambridge, U.K. Functional magnetic resonance imaging (fMRI) G. Pethoe, Univ. of Pecs, Hungary is a well established method to image the local R.H. LaMotte, Dept. of Anaesthesiology, Yale Univ., New activity of the human brain during process- Haven, USA ing of various stimuli and tasks. The method is E. Jørum, K. Ørstavik, Dept. Clin. Neurophysiology, Univ. used to identify brain regions involved in proof Oslo, Norway cessing of pain and itch. Areas of the brainstem are particularly in focus. By variation of the experimental paradigms the function of various brain regions and their contribution to perception of the corresponding stimulus are determined. Common projects with the Psychiatry and Psychotherapy Hospitals analyze the central changes induced by psychogenic or emotional stress and by addiction.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 15 Preclinical Institutes

Institute of Cellular and Molecular Physiology Chair of Physiology (Vegetative Physiology)

Address trafficking, sorting, endocytosis/exocytosis, In this context, the group of Prof. Korbmach- Waldstrasse 6 protein-protein interaction between transport er investigates the molecular mechanisms in- 91054 Erlangen proteins and regulatory proteins as well as involved in the regulation of the epithelial sodi- Phone: +49 9131 8522301 teractions with elements of the cytoskeleton. um channel (ENaC). Ion flux through ENaC is Fax: +49 9131 8522770 The experimental investigation of these com- the rate limiting step for sodium absorption in www.physiologie2.uni-erlangen.de plex topics requires a range of sophisticated the aldosterone sensitive distal nephron. The Head of Institute electrophysiological, cell physiological and mo- appropriate regulation of ENaC activity is crit- lecular biological methods. In addition to cel- ical for the maintenance of body sodium bal- Prof. Dr. med. Christoph Korbmacher lular model systems (cell culture, heterologous ance and hence for the long term control of ar- Contact expression systems), transgenic and knock-out terial blood pressure. This is evidenced by ‚gain Prof. Dr. med. Christoph Korbmacher mice are used to study the function and regu- of function‘ mutations of ENaC which cause a Phone: +49 9131 8522301 lation of ion transport processes in native tis- hereditary form of severe salt-sensitive arterial Fax: +49 9131 8522770 sues and in the whole animal. This integrated hypertension (Liddle‘s syndrome). [email protected] approach provides fascinating opportunities The molecular mechanisms involved in ENaC to gain novel insights into physiological and regulation are still incompletely understood Research Focus pathophysiological mechanisms and may lead and involve a complex network of regulato- • Renal epithelial ion channels to a better understanding of disease processes. ry proteins, kinases, and proteases. Proteo- • Cardiac ion channels lytic activation of ENaC may be pathophysi- ologically relevant in the context of inflamma- Research tory kidney disease and may contribute to so- Structure of the Institution dium retention in nephrotic syndrome. The Renal epithelial ion channels group of Prof. Korbmacher uses a combination The Department of Cellular and Molecular Project manager: C. Korbmacher of electrophysiological and molecular biologi- Physiology (Chair of Systems Physiology) is In the kidney and in other epithelial organs ion cal techniques to characterize the functional housed in a teaching and research building channels are involved in the highly selective interaction of ENaC with regulatory proteins in central location. In addition to modern re- and regulated control of ion fluxes across api- and to identify channel regions that are rele- search laboratories the building offers a lecture cal and basolateral membranes of renal epithe- vant for ENaC regulation by kinases and pro- hall with a capacity of 200 seats and seminar lial cells. These ion channels are important for teases. Moreover, they investigate the role of rooms for small group teaching and practi- intracellular ion homeostasis and transepitheli- lipid microdomains (‘lipid rafts’) in the plasma cal classes. The Department makes a substan- al electrolyte transport. The delicate regulation membrane for ENaC function and its associa- tial contribution to the physiology teaching of of these ion channels is pivotal for the main- tion with regulatory proteins. preclinical medical and dental students and is tenance of a healthy ‘milieu interieur‘ as evi- A better understanding of the molecular mech- also involved in the molecular medicine course. denced by severe disease states that can result anisms involved in ENaC regulation will hope- The renal physiology research group at the from abnormal ion channel function. Indeed, fully provide novel insights into the physiology Department is headed by the Chair of the De- the study of molecular mechanisms involved and pathophysiology of arterial hypertension. partment, Prof. Dr. med. Christoph Korbmach- in epithelial ion channel regulation is likely to This ultimately may lead to new diagnostic and er, the additional cardiac physiology research be relevant to understand a range of diseases therapeutic concepts. group is headed by an Associate Professor, Prof. (e.g. cystic fibrosis, kidney stones, high arteri- The research projects are funded by grants Dr. med. Tilmann Volk. al blood pressure, and salt loosing syndromes). from the Deutsche Forschungsgemeinschaft in The research focus of the Department is the Acute and chronic diseases of the kidney are the context of the centre research grant Collab- study of renal and cardiac ion channels. This often associated with high blood pressure. orative Research Centre (SFB) 423 (‘Kidney pa- research area is of pathophysiological rele- Moreover, the kidney is thought to play a crit- thology: Pathogenesis and regenerative mech- vance, since an inappropriate regulation of ical role in the pathogenesis of essential hy- anisms’) and from the IZKF (interdisciplinary renal and cardiac ion channels may cause ar- pertension, a condition affecting about 50% centre of clinical research). terial hypertension or cardiac arrhythmias, of the population above the age of 50. There respectively. This research focus fits very well is emerging evidence that subtle damage to Cardiac ion channels into the broader context of research activities the kidney may compromise renal salt excre- Project manager: T. Volk at Erlangen known to have a strong renal and tion causing salt retention which may lead to The key interest of Prof. Volk`s group is to iden- cardiovascular research focus as evidenced e.g. arterial hypertension. In particular, the sodium tify cellular and molecular mechanisms that by the DFG funded centre research grant Col- transport processes in the distal nephron and regulate the function and expression of cardi- laborative Research Centre (SFB) 423 entitled collecting duct appear to be important for the ac ion channels and thereby lead to differenc- ‘Kidney pathology: Pathogenesis and regen- long term control of blood pressure. There- es in action potential duration (APD) and con- erative mechanisms’. fore, it is important to understand the molec- tractility in the heart. The analysis of ion channels involves studies at ular mechanisms involved in the regulation of It is well established that regional differences in the level of the cell membrane but also includes these transport processes. APD in different areas of the heart are of great aspects of cellular physiology such as protein importance for a normal course of repolarisa-

16 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) tion. Within the left ventricular free wall, for example, APD is much longer in endocardial than in epicardial myocytes with the consequence, that endocardial myocytes repolarise last although they become depolarised first. Hence, the wave of excitation travels from endocardial to epicardial regions, while the wave of re- Analysis in the research laboratory polarisation travels in the opposite direction. Source: University Hospital Erlangen Under pathological conditions such as cardiac hypertrophy or failure, this well organised sequence of events is altered, which is thought to contribute to the increased risk of cardiac arrhythmia and sudden cardiac death of patients with cardiac hypertrophy or failure. An increas- Teaching Selected Publications ing body of evidence supports the observation Goltz D, Schultz JH, Stucke C, Wagner M, Bassalaý P, that cardiac hypertrophy or failure lead to an The Chair of Physiology (Department of Phys- Schwoerer AP, Ehmke H, Volk T (2007) Diminished Kv4.2/3 increase in APD primarily in epicardial regions, iology and Pathophysiology) and the Chair but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats. Cardiovasc whereas midmyocardial or endocardial regions of Systems Physiology (Department of Cellu- Res, 74: 85-95 are less affected. lar and Molecular Physiology) jointly organise Wielpuetz MO, Lee IH, Dinudom A, Boulkroun S, Farman N, In order to understand the mechanisms under- all curricular teaching of physiology (lectures, Cook DI, Korbmacher C, Rauh R (2007) (NDRG2) stimulates lying this region-specific effect of cardiac hy- seminars and practical classes) for medical and amiloride-sensitive Na+ currents in Xenopus laevis oocytes pertrophy, Prof. Volk‘s group investigates the dental students and for students following the and fisher rat thyroid cells. J Biol Chem, 282: 28264-73 consequences of cardiac hypertrophy in ani- course of molecular medicine. The Depart- Bertog M, Cuffe JE, Pradervand S, Hummler E, Hartner mal models. Using the patch-clamp technique ment of Cellular and Molecular Physiology con- A, Porst M, Hilgers KF, Rossier BC, Korbmacher C (2008) Aldosterone responsiveness of the epithelial sodium channel on isolated myocytes from different regions of tributes to the teaching of cellular physiology (ENaC) in colon is increased in a mouse model for Liddle‘s the left ventricular free wall of rats with ascend- and is responsible for teaching the physiology syndrome. J Physiol, 586: 459-75 ing aortic stenosis, a decrease in the transient of organ systems (e.g. heart, circulation, kid- Diakov A, Bera K, Mokrushina M, Krueger B, Korbmacher C outward potassium current (Ito ) was identified ney, salt and water homeostasis, respiration, (2008) Cleavage in the {gamma}-subunit of the epithelial as the primary cause underlying the increase in acid base homeostasis, gastrointestinal physi- sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels. J Physiol, APD in epicardial regions. The specific impor- ology, hormones). In addition the Department 586: 4587-608 tance of Ito for an altered organisation of repo- contributes to a course entitled Molecular Nesterov V, Dahlmann A, Bertog M, Korbmacher C (2008) larisation in cardiac hypertrophy is underlined Pathomechanisms for molecular medicine stu- Trypsin can activate the epithelial sodium channel (ENaC) by the observation that other ionic currents, dents and also offers advanced practicals and in microdissected mouse distal nephron. Am J Physiol Renal such as the L-type Ca2+ current, are largely un- thesis projects for these students. An overview Physiol, 295: F1052-62 affected by hypertrophy. of the subject and its theoretical foundation is Wagner M, Rudakova E, Volk T (2008) Aldosterone-induced Apart from affecting the regional organisation presented in traditional plenary lectures which changes in the cardiac L-type Ca(2+) current can be prevented by antioxidants in vitro and are absent in rats on of repolarisation, alterations in the magnitude are supplemented by interactive small group low salt diet. Pflugers Arch, 457: 339-49 of Ito indirectly influence the intracellular Ca2+ seminars. These seminars reinforce the topics homeostasis of ventricular myocytes. A reduc- of the plenary lecture and emphasize relevant tion of Ito leads to an increase in transmem- clinical aspects. In practical classes theoretical branous Ca2+ influx, a phenomenon which concepts are illustrated by experiments and can also be observed as a result of a reduction the students have the opportunity to acquire of Ito in cardiac hypertrophy thereby suggest- practical skills. The practical course covers ing a mechanism by which cellular contractil- topics such as cardiac and circulatory physi- ity is increased. ology, ECG, blood, kidney, metabolism, res- It is hoped that a more detailed characteriza- piration and spiroergometry. The progress of tion of cardiac ion channels will lead to a better the students is monitored by multiple choice understanding of the mechanisms underlying exams. These exams are routinely evaluated cardiac repolarisation and will help to develop and conform to quality criteria recommended therapeutic strategies to influence the organ- for medical exams, e.g. by the ‘Kompetenzzen- isation of repolarisation and hence to prevent trum fuer Pruefungen in der Medizin – Baden- the development of malignant arrhythmia. Wuerttemberg’.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 17 Preclinical Institutes

Institute of Biochemistry – Emil-Fischer-Centre Chair of Biochemistry and Molecular Medicine

Address following a sublethal strychnine poisoning are type varies considerably between strains de- Fahrstrasse 17 similar to those observed in the glycine re- spite an identical mutant allele probably due 91054 Erlangen ceptor-associated neurological motor disorder, to splice differences. Phone: +49 9131 8524191 hyperekplexia (startle disease, stiff-baby syn- The molecular pathomechanism of an addition- Fax: +49 9131 8522485 drome) that is characterized by increased star- al mouse mutant entla characterized by a hy- www.biochem.uni-erlangen.de tle reaction and episodic muscle stiffness. In- perexcitatory syndrome was elucidated. This Head of Institute deed, defects within the glycine receptor gene syndrome is caused by an exon duplication in are found in hereditary hyperekplexia. the Cacna2d2 gene which modulates the elec- Prof. Dr. med. Cord-Michael Becker The glycine receptor is a ligand-gated ion chan- trophysiological properties of voltage-gated Contact nel, composed of 2 α- and 3 β-subunits, each calcium channels. Prof. Dr. phil. nat. Ralf Enz comprising four transmembrane domains con- Phone: +49 9131 8526205 nected by intra- and extracellular loops of vary- Synaptic signal complexes in the retina Fax: +49 9131 8522485 ing length. Project manager: R. Enz [email protected] The main focus of the group is the character- The central nervous system (CNS) is regulated ization of structure-function relationships of by neurotransmitter receptors and ion chan- Research Focus the glycine receptor and its disease associated nels that coassemble with enzymes and scaf- • Receptors and receptor associated diseases mutations. Upon recombinant expression, the fold proteins into synaptic signaling complex- of the nervous system secondary structure of the N-terminal domain es. Malfunction of these protein complexes • Synaptic signal complexes in the retina of the glycine receptor resembles the immu- can lead to impaired signal transduction and • Mass spectrometry: Analysis of molecular noglobulin-like structure of the acetylcholine may ultimately cause diseases such as epi- heterogeneities binding protein of the mollusc Lymnaea stag- lepsy, schizophrenia and autism. The retina • Bioinformatics of biomolecular interactions nalis. This isolated N-terminal domain binds as part of the CNS is ideally suited to study the antagonist strychnine with high affinity. basic principles of synaptic signaling mech- Besides different subunits, allelic and splice anisms. Therefore, structure and function of Structure of the Institution variants contribute to the heterogeneity of the synaptic signaling complexes of glutamate and receptor. A splice variant of the GlyRβ-subunit γ-aminobutyric acid (GABA) receptors are in- The Institute of Biochemistry comprises the lacking exon 7 (βΔ7) is highly expressed in glial vestigated in the healthy and diseased retina. Chair of Biochemistry and Molecular Medicine cells, and was also found in extra-neuronal tis- Metabotropic glutamate receptors interact and the Chair of Biochemistry and Pathobio- sues (heart, liver). The expression of this βΔ7- with protein phosphatase-1, RanBPM, Filamin- chemistry, in addition to the professorship of subunit in tissues lacking the ligand-binding A and band 4.1-proteins. GABAC receptors bind Bioinformatics. The Institute of Biochemistry α1-subunit indicates alternative glycinergic sig- PNUTS and Tax1BP1. Furthermore, ZIP proteins constitutes the interdisciplinary Emil-Fischer- nal transmission pathways. interact with GABAC receptors, voltage-gat- Centre together with the Institute of Experi- The localization of a mutation in the glycine ed potassium channels and protein kinase C. mental and Clinical Pharmacology and Toxi- receptor gene influences the biogenesis and These protein complexes regulate intracellu- cology of the Medical Faculty and the Institute function of the receptor channel. A full in- lar signal cascades and control the sub-cellular of Pharmaceutical Chemistry of the Science activation of the glycine receptor gene was targeting of neurotransmitter receptors. Map- Faculty. found in patients with recessive hyperekplex- ping of interacting protein regions and model- The Chair has a total of 40 employees (half of ia where homozygosity for a large deletion ing of their 3D-structure led to the definition of them funded by grants), including 12 scientists, leads to the complete loss of the α1‑subunit. a new consensus sequence for proteins binding 13 postgraduate students and 8 technicians. Besides these genetic forms, an autoimmune to protein phosphatase-1. variant of a glycine receptor disease was char- To analyze retinal gene expression in glaucoma, acterized with autoantibodies directed against we used the DBA/2J mouse model. These ani- Research the α1‑subunit. Even in several tumor cell lines mals suffer from an elevated intraocular pres- transcripts of the glycine receptor genes were sure leading to degeneration of the optic nerve Receptors and receptor associated diseases detectable. and deregulation of epithelial sodium channel of the nervous system Glycine receptor defects of the mouse mu- expression. Project manager: C.-M. Becker, K. Becker, C. tants spastic, spasmodic and oscillator serve A detailed knowledge of the structure, expres- Kluck, C. Villmann as genetic models for hypertonic motor dis- sion and function of synaptically localized sig- The strychnine sensitive glycine receptor is an orders and serve as therapeutic test systems nal complexes is fundamental to understand inhibitory neurotransmitter receptor of the for neuron-specific gene transfer. The spastic the function of the retina and the CNS. The postsynaptic membrane predominantly ex- mouse has an insertion mutation in the Glrb description of new players contributing to this pressed in spinal cord and brain stem partic- gene by an intronic LINE-1 element resulting mechanism has the potential to identify key ipating in neuronal regulation of the muscle in missplicing and a dramatic numerical loss proteins that can be targeted, e.g. by specif- tone. The toxic alkaloid strychnine inhibits gly- of functional receptors. Studies with different ic drugs. cine binding and leads to death. Symptoms mouse strains revealed that the spastic pheno-

18 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Mass spectrometry: Analysis of molecular heterogeneities Project manager: K. Schiebel, N. Vogel, W. Xiang, E. Schachmann Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-

MS) is a method to determine the molecular High-tech molecular basic research mass of biomolecules such as DNA, proteins Source: University Hospital Erlangen and lipids. Genetic polymorphisms may alter the predis- position for diseases and are therefore used as molecular markers. Our group has developed methods for the MALDI-TOF-MS based diagnosis of molecular heterogeneities in hyperekplex- tions by a variety of computational tools (e.g. Selected Publications ia, thrombosis, cancer and other diseases. An sequence data analysis, molecular modeling, Dinkel H, Sticht H (2007) A computational strategy for the association of polymorphisms of the prion pro- and molecular dynamics). prediction of functional linear peptide motifs in proteins. tein gene promoter to a prolonged incubation Molecular dynamics simulations are used to Bioinformatics, 23: 3297-303 time in BSE infected cattle was demonstrated. study the dynamics of viral proteins (e.g. HIV Kashkevich K, Humeny A, Ziegler U, Groschup MH, Nicken P, On protein level, our group focuses on the protease), the conformational transitions of Leeb T, Fischer C, Becker CM, Schiebel K (2007) Functional relevance of DNA polymorphisms within the promoter identification and characterization of proteins human proteins (e.g. Alzheimer Aβ-Amyloid), region of the prion protein gene and their association to by MALDI-TOF-MS. After separation of com- or the effect of covalent modifications on mo- BSE infection. FASEB J, 21: 1547-55 plex protein mixtures, the proteins of inter- lecular recognition processes. Molecular mod- Oertel J, Villmann C, Kettenmann H, Kirchhoff F, Becker est are analyzed by comparison of mass fin- eling is used to generate the structure of isolat- CM (2007) A novel glycine receptor beta subunit splice gerprints of specific proteins to fingerprints ed proteins or biomolecular complexes, which variant predicts an unorthodox transmembrane topology. Assembly into heteromeric receptor complexes. J Biol Chem, stored in data bases. In addition, posttransla- provides the basis for a molecular understand- 282: 2798-807 tional modifications (PTM, like phosphoryla- ing of the effects of mutations on protein sta- Hutchinson M, Waters P, McHugh J, Gorman G, O‘Riordan tion, glycosylation, glycation) of specific pro- bility and binding properties. In addition, se- S, Connolly S, Hager H, Yu P, Becker CM, Vincent A (2008) teins are characterized and quantified. During quence based methods are developed that Progressive encephalomyelitis, rigidity, and myoclonus: a neurodegeneration, free radical attack leads to allow an improved detection of functional lin- novel glycine receptor antibody. Neurology, 71: 1291-2 oxidation of methionine and cysteine residues, ear interaction motifs. Such motifs play an im- Rose M, Duetting E, Schroeder N, Sticht H, Brandstaetter nitrosative stress-induced modifications of ty- portant role for the interactions of numerous JH, Enz R (2008) PNUTS forms a trimeric protein complex with GABA(C) receptors and protein phosphatase 1. Mol rosine and cysteine residues as well as oxida- pathogens with the target molecules of their Cell Neurosci, 37: 808-19 tive deimination of arginine residues. All these host. PTMs are detectable by MALDI-TOF-MS. International Cooperation The neuronal cell death is investigated in glau- Dr. A. Pickford, University of Portsmouth, UK coma of DBA/2J mice and β-bungarotoxin- Teaching A. Vincent, St Vincent‘s University Hospital, Dublin, Irland induced neuronal cell death in cell culture. A. Triller, INSERM, Paris, France In neurodegeneration, lipid composition of Both Chairs of the institute jointly carry out the membranes changes as shown by MALDI-TOF- curricular education (lectures, seminars, practi- MS. Currently, an HPLC coupled electrospray cal courses) in biochemistry and molecular bi- iontrap MS (ESI-IT-MS) is being established ology for students of medicine, dentistry, and that allows even further characterization of molecular medicine as well as the biochemical biomolecules. practicals of students of pharmacy. For students of molecular medicine the Chair orga- Bioinformatics of biomolecular interactions nizes the modules of neuroscience and molec- Project manager: H. Sticht ular pathomechanisms. The professorship of Protein-protein interactions play a crucial role bioinformatics teaches in the course program for the transduction of information in biolog- of molecular medicine and computer sciences. ical signaling pathways. The identification of the underlying principles of molecular recognition is important for the understanding of regulatory mechanisms and for the prediction of novel, physiologically relevant protein interactions. The bioinformatics group is primarily interested in investigating molecular interac-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 19 Preclinical Institutes

Institute of Biochemistry – Emil-Fischer-Centre Chair of Biochemistry and Pathobiochemistry

Address Research SoxD Proteins Fahrstrasse 17 Project manager: C. Stolt 91054 Erlangen Transcription factors as regulators of The three closely related SoxD proteins Sox5, Phone: +49 9131 8524621 neural development Sox6 and Sox13 participate as regulatory pro- Fax: +49 9131 8522484 Several groups are interested in the character- teins in the development of several neuronal www.biochem.uni-erlangen.de ization of transcriptional regulators that partic- subpopulations and glial cells of the nervous Head of Institute ipate during development of the mammalian system. Own studies indicate that SoxD pro- Prof. Dr. rer. nat. Michael Wegner nervous system in determination and differen- teins function as modulators of SoxE function tiation of neural stem cells to glia and neurons. in glia. Both Sox5 and Sox6 antagonize Sox9 Contact Work is mainly focused on transcription factors and Sox10 during embryonic development in Prof. Dr. rer. nat. Michael Wegner of the Sox protein family and their interacting oligodendrocytes and thereby prevent preco- Phone: +49 9131 8524620 partners. Analysis of these transcription factors cious specification and terminal differentiation Fax: +49 9131 8522484 will lead to a better understanding of develop- within this cell lineage. A similar mode of action [email protected] mental defects, tumor formation and regener- has also been determined for SoxD proteins in ative processes in the nervous system. neural crest derivatives such as melanocytes. Research Focus Here, SoxD proteins recruit transcriptional co- • Transcription factors as regulators of neural SoxE Proteins repressors to the regulatory regions of those development Project manager: M. Wegner genes that would otherwise be activated by • SoxE Proteins Transgenic mouse models have shown that the SoxE proteins in a cell-specific manner. • SoxD Proteins three closely related group E Sox proteins Sox8, • SoxC Proteins Sox9 and Sox10 have numerous functions dur- SoxC Proteins • GCM proteins as switches in organ ing nervous system development. Sox9 and Project manager: E. Sock development Sox10 are essential for survival and pluripoten- All SoxC proteins occur according to own data • Signal transduction processes at the forming cy of neural crest stem cells, the source for most in many tissues and organs during embryogen- neuromuscular synapse cells of the peripheral nervous system. Sox9 esis. Whereas loss of Sox4 or Sox11 leads to se- • -Thymosins, substrates of transglutaminas- β and Sox10 furthermore determine which de- vere developmental defects (such as heart and es during blood coagulation, angiogenesis, rivatives develop from neural crest stem cells. outflow tract malformations, B-cell maturation wound healing, and apoptosis In Sox10-deficient mice, glial cells are missing defects, asplenia, skeletal malformations and from the peripheral nervous system. The enter- hypoplasias of several organs), Sox12 deletion ic nervous system is completely absent. remains without obvious phenotypic conse- Structure of the Institution In the central nervous system, Sox9 and Sox10 quences in the mouse. Despite strong expres- regulate several steps in gliogenesis. Sox9 is re- sion of all three SoxC proteins in the developing The Chair of Biochemistry and Pathobiochem- sponsible for the specification of neural stem nervous system, neural defects become visible istry and the Chair of Biochemistry and Molec- cells into oligodendrocytes, whereas Sox10 only upon combined deletion of more than one ular Medicine constitute the Institute of Bio- guides terminal differentiation and myelina- SoxC protein. Nervous system defects are pre- chemistry. They are furthermore part of the tion in oligodendrocytes as a direct activator dominantly caused by changes in proliferation Emil-Fischer-Centre which in addition harbours of myelin genes. During the period between and apoptosis. Overexpression studies in the the Institute of Experimental and Clinical Phar- specification and terminal differentiation, oli- mouse have, however, also pointed to an in- macology and Toxicology (Faculty of Medi- godendrocyte development is jointly regulated fluence ofS oxC proteins on neural maturation. cine), the Chair of Medicinal Chemistry and the by Sox9 and Sox10. Functional support comes Chair of Food Chemistry (both Faculty of Nat- from the related Sox8 which is co-expressed at GCM proteins as switches in organ ural Sciences). The Chair of Biochemistry and lower levels. development Pathobiochemistry employs 36 scientists and Functions of group E Sox proteins were not Project manager: S. Hashemolhosseini technicians of whom 22 are on grant money. only obvious in transgenic mouse models, but Mammals contain GCMa and GCMb as mem- Several groups study transcription and post- are equally reflected in human disease. Hetero- bers of the GCM family of transcription factors. transcriptional processes as well as β-thymosins zygous haploinsufficientS ox10 mutations lead GCMa is selectively expressed in placenta, kid- with regard to molecular mechanisms and to Waardenburg-Hirschsprung disease, where- ney and thymus, whereas GCMb occurs exclu- physiological roles in development, disease and as dominant-negative heterozygous mutations sively in the parathyroid gland. All GCM pro- regeneration of the nervous system and other present as a combination of Waardenburg- teins regulate differentiation as transcriptional organ systems. The technological spectrum is Hirschsprung disease, peripheral neuropathy switches. Altered GCMa expression has been broad and ranges from biochemical and mo- and central leukodystrophy. associated with pre-eclampsia and intra-uter- lecular methods to the generation and charac- ine growth retardation, GCMb malfunctions terization of transgenic mice. with hypoparathyroidism and tumors of thyroid and parathyroid glands. Current work focuses on the role of GCMa in kidney and thymus of the adult organism, particularly under pathological conditions.

20 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Signal transduction processes at the form- cent peptides are novel tools to study the in- Selected Publications ing neuromuscular synapse teraction of β-thymosins with other proteins Stolt CC, Schlierf A, Lommes P, Hillgaertner S, Werner T, Project manager: S. Hashemolhosseini as well as their intracellular distribution in liv- Kosian T, Sock E, Kessaris N, Richardson WD, Lefebvre V, Muscle-specific MuSK is the main switch for ing cells. Surprisingly, thymosin 4 is actively Wegner M (2006) SoxD proteins influence multiple stages of β oligodendrocyte development and modulate SoxE protein synaptogenesis at the postsynaptic appara- transported and enriched in the nucleus. The function. Dev Cell, 11: 697-709 tus of the neuromuscular junction. Own work signal sequence responsible for the transloca- Hoser M, Baader SL, Boesl MR, Ihmer A, Wegner M, Sock E identified Erbin and CK2 as binding partners of tion into the nucleus resides in the N-terminal (2007) Prolonged glial expression of Sox4 in the CNS leads MuSK. Protein kinase CK2 furthermore bound part of the peptide. Because of the size (5000 to architectural cerebellar defects and ataxia. J Neurosci, 27: 5495-505 MuSK via its β subunit, phosphorylates MuSK da) thymosin β4 was expected to freely dif- and thereby regulates the stability of acetyl- fuse through the nuclear pore complex into Zoubek RE, Hannappel E (2007) Influence of the N termi- choline (AChR) clusters. Muscle-specific CK2 - the nucleus. However, when thymosin 4 is nus and the actin-binding motif of thymosin beta4 on its β β interaction with G-actin. Ann N Y Acad Sci, 1112: 435-41 deficient mice are myasthenic. To identify the added to permeabilized cells, it is evenly dis- Finzsch M, Stolt CC, Lommes P, Wegner M (2008) Sox9 and cause for the destabilization of AChR aggre- tributed within cytoplasm but excluded from Sox10 influence survival and migration of oligodendrocyte gates in CK2β-deficient muscles, their pheno- the nucleus. Present studies aim at the mech- precursors in the spinal cord by regulating PDGF receptor alpha expression. Development, 135: 637-46 type is compared with the one of CK2α/CK2α’- anisms for the asymmetric distribution of thy- deficient muscles. Behavioural tests and elec- mosin β4 in cells and its impact on apoptosis Schubert SW, Lamoureux N, Kilian K, Klein-Hitpass L, trophysiological studies are performed and and cancerogenesis. Hashemolhosseini S (2008) Identification of integrin-alpha4, changes of transcriptome and phosphopro- Rb1, and syncytin a as murine placental target genes of the transcription factor GCMa/Gcm1. J Biol Chem, 283: 5460-5 teome are determined in muscle cells deficient Stolt CC, Lommes P, Hillgaertner S, Wegner M (2008) The for CK2 subunits. For the first time, the molec- Teaching transcription factor Sox5 modulates Sox10 function during ular function of CK2 subunits at the postsyn- melanocyte development. Nucleic Acids Res, 36: 5427-40 apse will be determined and the contribution of The Chair of Biochemistry and Molecular Medi- CK2-dependent signal transduction to human cine and the Chair of Biochemistry and Patho- International Cooperation myasthenia and myopathy be understood. biochemistry jointly organize and carry out all Prof. Jean-Paul Borg, Inserm-Institut, Paoli-Calmettes- curricular activities (lectures, seminars, practi- Université de la Méditerranée, Marseille, France Prof. Hans-Rudolph Brenner, Pharmazentrum/Biozentrum, β-Thymosins, substrates of transglutamin- cal courses) in biochemistry and molecular bi- Basel, Switzerland ases during blood coagulation, angiogen- ology for students of medicine and dentistry esis, wound healing, and apoptosis during the preclinical phase of their studies. Prof. Patrik Ernfors, Karolinska Institutet, Stockholm, Schweden Project manager: E. Hannappel Similarly, all teaching in biochemistry and mo- Thymosins were originally isolated from thy- lecular biology for students of molecular medi- Prof. Allen Goldstein, George-Washington-University, Wash- ington, USA mus, but do not represent thymic hormones. cine is jointly performed by the two Chairs. The Prof. Veronique Lefebvre, Lerner Institute, Cleveland, USA Thymosin β4 is now regarded as the main Chair of Biochemistry and Pathobiochemistry intracellular G-actin sequestering peptide in furthermore contributes significantly to teach- Prof. James Lupski, Baylor College, Houston,Texas, USA most mammalian cells. Domains of thymosin ing activities in neurobiology, cell biology and Prof. Lin Mei, Medical College of Georgia, Augusta, USA β4 were identified which are important for the developmental biology for students of molec- Prof. Mengsheng Qiu, University of Louisville, Louisville, USA interaction with G- and F-actin. Apart from ular medicine. Together with the Chair of Bio- Prof. Clarke Slater, University NewCastle, NewCastle, this intracellular function of thymosin β4, this chemistry and Molecular Medicine it ensures England peptide seems to be a player in wound heal- the biochemical training of students from the Prof. Xin Yuan, Harvard Medical School, Boston, USA ing and inflammation. β-thymosins are sub- department of medicinal chemistry. strates of transglutaminases. Glutaminyl res- Meetings and International Training Courses idues of β-thymosins can be cross-linked to amino groups of other molecules. Surprisingly, 10.–11.10.2008: Third International Symposium of the Col- laborative Research Centre (SFB) 473: “Transcriptional Con- these derivatives are still able to sequester G- trol of Development and Disease”, Erlangen, Deutschland actin. Blood platelets contain a high concen- Research Equipment tration of thymosin β4. During aggregation of blood platelets, thymosin β4 is cross-linked by Molecular Devices, Zeiss Fluoreszenz-Mikroskop factor XIIIa to the fibrin clot.T his research thus also provides insight on how small, soluble peptides can be fixed to extracellular structures by transglutaminases to promote further physiological effects. β-Thymosins can be labelled by fluorescent derivatives of cadaverine. The fluorescent β-thymosins are comparable to the natural β-thymosins with respect to their G-actin sequestering ability. Therefore, these fluores-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 21 Clinical Theoretical Institutes

Institute of Medical Informatics, Biometry and Epidemiology Chair of Biometry and Epidemiology

Address detection of trends in contact allergy (increase, and improved classification rules. In a multi- Waldstrasse 6 possibly in particular subgroups) and for quali- disciplinary project with the Department of 91054 Erlangen ty control purposes. Additionally, research proj- Ophthalmology and the Instiute of Informat- Phone: +49 9131 8522750 ects prompt special analyses, for instance in a ics a computer based system for the diagnosis Fax: +49 9131 8522721 pharmaco-epidemiological project for assess- “suspected glaucoma”, based on image analy- www.imbe.med.uni-erlangen.de ment of contact allergy risk following applica- sis and other data, is being developed. Head of Institute tion of topical therapeutics, or the impact of meteorological conditions on patch test reac- Prognosis modeling for censored and high- Prof. Dr. rer. nat. Olaf Gefeller tivity. Moreover, the network “ESSCA” (www. dimensional data Contact essca-dc.org) is collecting and analysing such Project manager: T. Hothorn, O. Gefeller Prof. Dr. rer. nat. Olaf Gefeller data on a European level since 2002, with the The modeling of a censored outcome based on Phone: +49 9131 8522750 data centre at the Chair of Medical Biometry several, possibly many explanatory variables is Fax: +49 9131 8522721 and Epidemiology. of fundamental importance for the analysis of [email protected] The epidemiology of malignant melanoma and clinical and experimental studies with time-to- acquired melanocytic nevi is a further research event primary outcomes. The application of Research Focus interest: acquired melanocytic nevi, surrogate new methods (for instance, ensemble methods • Dermatoepidemiology or potential precursor of malignant melanoma, for regression problems with continuous and • Epidemiological Concepts of Population Risk are addressed as outcome in a bi-centric cross censored outcomes) and optimisation meth- • Participation in Collaborative Research sectional study NAEVAC (impact of vaccina- ods can solve difficult problems.T he aim of this Centre 539 tion and infections on nevus density in school- project is the evaluation of tree-based meth- • Prognosis modeling for censored and high- children) in Salzgitter and Erlangen including ods, such as survival trees or so-called Random dimensional data 2086 children. With a similar aim the current Forests, and boosting algorithms for the fitting • Co-operative epidemiological and clinical MONA-study includes an standardised assess- of various models for censored outcomes. The studies ment of student cohorts. In cooperation with estimation of models with empirical risk min- Lower Saxonian health authorities the cmonde- imisation employing gradient boosting makes study attempts to monitor childhood UV expo- it possible to formulate in a uniform theory, Structure of the Institution sure via nevus density. adapt and compare both classical linear models as well as additive and flexible nonparamet- The institute comprises the Endowed Chair of Epidemiological Concepts of ric variants. The possibility in particular to es- Medical Informatics (Prof. H.-U. Prokosch) and Population Risk timate classical models in a high dimensional the Chair of Biometry and Epidemiology. Staff Project manager: O. Gefeller setting exploiting the variable selection prop- of the Chair of Biometry and Epidemiology in- The methodological project addresses statisti- erties of these algorithms renders these meth- cludes 16 scientists (9 post-docs, 7 doctoral cal methods for multifactorial risk attribution ods very interesting for application in biostatis- students) and 3 further employees. 50% of staff in epidemiology. Partitioning methods such as tics and motivates their evaluation. is financed by external funds. the partial attributable risk and its hierarchi- Different working groups address biostatistical cal and grouped variants divide the combined Co-operative epidemiological and methods and epidemiological research. More- attributable risk of all risk factors into compo- clinical studies over, the Chair cooperates with various clinical nents that can be attributed to single risk fac- Project manager: various researchers. A MPI-PC-Cluster with 15 nodes is tors. The specification of rules for the partition- This area of activity comprises diverse research available as infrastructure for computer-inten- ing process is inspired by methods of mathe- topics addressed in cooperation with different sive biostatistical simulation studies. matical game theory. In addition to conceptual departments. Usually, biometrical aspects of aspects of defining the methods, the construc- study design and statistical analysis have been tion of point and interval estimators for their provided by the Chair of Medical Biometry and Research practical application is of central interest. Soft- Epidemiology in these cooperative projects. ware tools for epidemiologic researchers are The most important projects in the reporting Dermatoepidemiology also developed. period include: Project manager: A. Pfahlberg, W. Uter • a cross-sectional study in the field of environ- In clinical contact allergy research a close co- Participation in Collaborative Research mental medicine addressing the internal bur- operation with the German contact dermatitis Centre 539 den with acrylamide and monoarylamines group (DKG) e.V. and the multi-centric project Project manager: B. Lausen, O. Gefeller • implementation of a remote database for information network of Department of Derma- With the aim of improving early diagnosis of electronic data capturing in a number of tology (IVDK, www.ivdk.org), maintained by glaucoma new approaches of machine-based phase II studies on vaccination therapy in an institute at the University of Göttingen has learning are evaluated and further developed. patients with progressive malignant mela- been established. Pooled data collected in the Data from cross-sectional and longitudinal noma along with development of statisti- participating allergy departments is analysed in studies (in particular FDT, HRT, GDx, colour cal methods terms of contact allergy surveillance, i.e. early image (Kowa), OCT data) contribute to new

22 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) • identification of prognostically relevant factors in a cohort of patients with moderate to severe atopic eczema • an intervention study with the “Department of Medicine 2” on acupuncture treatment of hypertension • multi-centric European studying on “Accel- erated Partial Breast Irradiation” (www.apbi. uni-erlangen.de) Chaired by the Department of Radiation Therapy and a controlled clinical trial on the multimodal therapy of rectal cancer (CAO/ARO/AIO-04) • biostatistical support of the ENT department in studies on the therapy of nasal polyps, diagnostic value of perfusion imaging in tumours of the parotis and of contrast enhanced ultrasound measurement of perfusion dynamics in cervical lymph nodes • the multi-centric “German Chronic Kidney Disease Study (GCKD)” funded by the BMBF and the “Kuratorium fuer Heimdialyse”.

Teaching

In the context of curricular teaching the Chair contributes to the “multidisciplinary field I” (Medical Informatics, Biometry and Epidemiol- Visualisation of the Model Fit of a “Random Forest” Model based on Epidemiological Data on the ogy) for medical students (lecture and seminars Prognosis of Malignant Melanoma in small groups). Moreover, this introduction to biometry and epidemiology (lecture and seminars in small groups) is part of the bachelor phase of the course on “molecular medicine” together with a seminar on the practice Selected Publications International Cooperation of data analysis which teaches basic program- Hothorn T, Buehlmann P, Dudoit S, Molinaro A, van der Prof. J. D. Johansen, National Allergy Research Centre, ming skills in the statistical programme “R”. Laan MJ (2006) Survival ensembles. Biostatistics, 7: 355-73 Gentofte Hospital, Univ. Kopenhagen, Denmark Regarding the new master course “medical Gefeller O, Tarantino J, Lederer P, Uter W, Pfahlberg AB Prof. Geir E. Eide, Haukeland Hospital, Universitaet Bergen, process management” the Chair is responsible (2007) The relation between patterns of vacation sun Norwegen exposure and the development of acquired melanocytic for the part of “health care management II / Prof. Sandrine Dudoit, School of Public Health, UCLA nevi in German children 6-7 years of age. Am J Epidemiol, Berkeley, USA public health and evidence-based medicine” 165: 1162-9 (seminar). For students of medicine and den- Rabe C, Lehnert-Batar A, Gefeller O (2007) Generalized ap- tal medicine a seminar on “design and data proaches to partitioning the attributable risk of interacting Meetings and International Training analysis in clinical and experimental studies” is risk factors can remedy existing pitfalls. J Clin Epidemiol, Courses 60: 461-8 offered twice each term. This seminar can be 12.12.2008: Workshop “Parallel Computing”, IMBE, Er- used by the students to discuss any statistical Uter W, Hegewald J, Kraenke B, Schnuch A, Gefeller O, langen, Deutschland, AG Statistical Computing (GMDS/ Pfahlberg A (2008) The impact of meteorological condi- issues they encounter when working at their IBS-DR), der AG Klassifikation und Datenanalyse in den tions on patch test results with 12 standard series allergens Biowissenschaften (GfKl), Collaborative Research Centre medical thesis. (fragrances, biocides, topical ingredients). Br J Dermatol, (SFB) 539 158: 734-9 de Pádua CA, Schnuch A, Nink K, Pfahlberg A, Uter W (2008) Allergic contact dermatitis to topical drugs-- epidemiological risk assessment. Pharmacoepidemiol Drug Saf, 17: 813-21 Brenning A, Lausen B (2008) Estimating error rates in the classification of paired organs. Stat Med, 27: 4515-31

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 23 Clinical Theoretical Institutes

Institute of Medical Informatics, Biometry and Epidemiology Endowed Chair of Medical Informatics

Address The head of the Chair for Medical Informatics, Evaluation of health information systems Krankenhausstrasse 12 Professor Hans-Ulrich Prokosch, is at the same Project manager: T. Buerkle 91054 Erlangen time responsible, as Chief Information Officer Cost-benefit-analyses aiming at the assessment Phone: +49 9131 8526720 (CIO), for operative design and strategic devel- of profitability often precede the introduction Fax: +49 9131 8526754 opment of information processing in the Erlan- of new medical information systems. After sys- www.imi.med.uni-erlangen.de gen University Hospital. tem implementation, however, evaluation of Head of Institute the effects of new information technologies on user satisfaction, work processes, process costs Prof. Dr. biol. hum. Hans-Ulrich Prokosch Research or even on medical care, are rarely performed. Contact Other preconditions for an efficient use of new Prof. Dr. biol. hum. Hans-Ulrich Prokosch Architecture of health information systems technologies in the health system are the eval- Phone: +49 9131 8526721 Project manager: H.-U. Prokosch uation of user attitudes towards such new tech- Fax: +49 9131 8526754 Research around the design, implementation nologies/systems, the user-friendliness of the [email protected] and management of Hospital Information Sys- interface and of the acceptance of new tech- tems (HIS) is currently in a transition phase. nologies. Within all these health technology Research Focus For many years optimization of communica- assessment analyses, issues of health econom- • Architecture of health information systems tion processes as well as the integration of het- ics as well as socio-technological issues have to • Evaluation of health information systems erogeneous departmental systems into a con- be taken into account. In this context, the Chair • Inference, assessment and visualization of sistent and comprehensive HIS was the major for Medical Informatics investigates new eval- medical facts out of medical databases task in this context. Today however, we are uation methods and applies them in practical • Process analysis, process modelling and faced with new challenges. The integration evaluation studies. The European research proj- process optimization efforts need to be extended across the bor- ect “eHealth Consumer Trends Survey”, was an • Medical ontologies and medical knowledge ders of the hospital, to establish telematic net- analysis citizens‘/patients‘ attitudes, wishes and processing works across institutional borders. Parallel to real usage of Internet technologies for ques- • IT-infrastructure applications for medical this, requirements within a hospital also have tions of health. research changed. The main focus is no longer only on functions for order entry/results review or med- Inference, assessment and visualization of ical documentation. The questions of how to medical facts out of medical databases Structure of the Institution optimize process support, to integrate clinical Project manager: T. Ganslandt pathways and to establish integrated electronic Both in-patient and out-patient treatment rou- Together with the Chair for Biometry and Epi- decision support functions have gained major tinely involve digital recording and documen- demiology, the Chair for Medical Informatics importance. Integration of clinical guidelines tation of numerous data elements. In view of makes up the Institute for Medical Informat- or clinical pathways and electronic communi- this ever-increasing flood of information, a pur- ics, Biometry and Epidemiology. The Chair for cation between hospitals and doctors are part poseful editing and visualization of these data Medical Informatics is, at the same time, mem- of the topics adressed in this context, as well is of the utmost importance for clinical users. ber of the Technical Faculty, in the latter case in as transferring functionalities to modern elec- By the means hitherto available, metaphors form of the research group M. tronic input media and mobile appliances. Hos- and tools for evaluation or presentation, dem- The Chair for Medical Informatics has 14 scien- pital-wide image data management has to be onstration of clinical treatment procedures is tific employees, 7 of them are paid by projects. supported by processes that nowadays include only insufficiently possible. The “Pathifier”- Research work is done by 6 scientics with doc- the radiological background and its connection project of the Chair for Medical Informatics is toral degrees, 10 doctoral candidates and one to the IT-infrastructure as well as the peculiari- aimed at the design, implementation and cus- medical documentalist. ties of image generating, image processing and tomization of a software tool for the visualiza- The design and introduction of electronic image distribution in the departments of car- tion of patient data by means of the timeline- health files, the integration of knowledge- diology, radiology, nuclear medicine, derma- paradigm. This paradigm allows for a multi- processing fuctions into hospital information tology, pathology and other image-generat- tude of data elements to be presented both in- systems, the modelling and optimization of ing departments. The Chair of Medical Infor- tuitively and graphically. Pathifier is currently clincial workflows, data-warehouse- and data- matics of Erlangen-Nürnberg University is con- being used in its pilot phase and evaluated at mining-applications, the design of image man- cerned with the abovementioned questions in the University Hospital. The systems permits a agement systems, the development of meth- the contexts of piloting the clinical workplace flexible adaptation to the existing data sourc- ods and procedures for multi-sector-networks system SOARIAN, of the OPAL-health-project es and can therefore be transferred to other as well as electronic health files for citizens, (supported by the German Federal Research IT-contexts easily. This could be demonstrated the evaluation of the effects of IT-measures Ministry) directed at the analysis of the poten- within the frame of international cooperations and electronic information systems on all partial for RFID-technologies in hospitals, and of by further pilot phase installations at the hos- ticipants in the health system, usage of mobile various health telematics projects. pital Innsbruck, Austria, and the Hôpital Euro- technologies in medicine and the design of IT- péen George Pompidou, Paris, France. infrastructures in research and development are evaluated by various scientific teams.

24 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Process analysis, process modelling and process optimization Project manager: T. Buerkle We are currently facing an explosion of health care costs due to longer average life spans, an increasingly over-aging population, multi- morbidity in old age and increased diagnosti- cal and therapeutical possibilities. Potential for cost saving in medical treatment results from an optimized process management of treatment workflows, together with a better run- to-capacity of expensive diagnostic and therapeutical apparatuses. Clinical pathways, which have hitherto been used for that purpose, can be augmented by modern software tools. In this context, analysis of clinical workflows and modelling of clinical processes are indispensable prerequisites for an IT-based optimization of clinical workflows.

Medical ontologies and medical knowledge processing Project manager: R. Sojer Smart Objects Technology The use of knowledge processing systems in Use of Smart Objects (RFID) Technology for localizing of medical equipment medicine is aimed at optimizing the quality of medical care by prospective measures (decision support and decision monitoring). Numerous studies (e.g. the publications of the American and processing data from electronic health files Selected Publications Institute of Medicine “To err is human.”) have for clinical research, being member of various Andreassen HK, Bujnowska-Fedak MM, Chronaki CE, revealed a considerable potential for improve- workgroups and participant in projects of the Dumitru RC, Pudule I, Santana S, Voss H, Wynn R (2007) ments. In this context, the research projects German Platform for Telematics for Medical Re- European citizens‘ use of E-health services: a study of seven countries. BMC Public Health, 7: 53 of the Chair for Medical Informatics primarily search Networks. concentrate on knowledge modeling for drug Klein A, Prokosch HU, Mueller M, Ganslandt T (2007) Ex- periences with an interoperable data acquisition platform therapy and the implementation of standard- for multi-centric research networks based on HL7 CDA. ized knowledge modules to be used within the Teaching Methods Inf Med, 46: 580-5 context of drug prescription, e.g. to reduce ad- Lang M, Kirpekar N, Buerkle T, Laumann S, Prokosch HU verse side effects. The Chair for Medical Informatics is committed (2007) Results from data mining in a radiology department: to the study of Medicine (Medical Informat- the relevance of data quality. Medinfo, 12: 576-80 IT-infrastructure applications for medical ics, Biometry and Epidemiology), Informatics Buerkle T, Beisig A, Ganslmayer M, Prokosch HU (2008) A randomized controlled trial to evaluate an electronic scoring research (subsidiary subject Medical Informatics) and tool in the ICU. Stud Health Technol Inform, 136: 279-84 Project manager: H.-U. Prokosch, T. Ganslandt the new main subject Medical Process Manage- Kummervold PE, Chronaki CE, Lausen B, Prokosch HU, Ras- Medical research is increasing based on close- ment (Master-Degree). In this context, 10 final mussen J, Santana S, Staniszewski A, Wangberg SC (2008) ly connected multicentric structures, which re- theses and 6 preparatory theses were written eHealth trends in Europe 2005-2007: a population-based quire a productive, efficient and safe IT-infra- in 2007 and 2008. survey. J Med Internet Res, 10: e42 structure. Internet portals for secured com- All lectures are based on the concept of blend- Prokosch HU, Ganslandt T (2009) Perspectives for medical muncation and collaboration as well as for ed learning. The Chair for Medical Informatics informatics. Reusing the electronic medical record for clinical research. Methods Inf Med, 48: 38-44 web-based recording of patient-related re- introduced and evaluated the study manage- search data at various workstations have been ment system Moodle in the winter semester International Cooperation designed and provided by the Chair for Medi- 2008/2009, paving the way for the rest of the Prof. Dr. Patrice Dégoulet, Hôpital Européen George Pom- cal Informatics for the Research Network Epi- Faculty of Medicine. The system is currently pidou, Paris, France dermolysis Bullosa and for the Competence being administered by the office of the Dean Prof. Isaac Kohane, M.D., Ph.D., i2b2 National Centre for Network Adipositas. Similar platforms have for Academic and Student Affairsof the Faculty Biomedical Computing, Boston, USA been developed e.g. for the exchange of image of Medicine. The design, implementation and Prof. Dr. Elske Ammenwerth, Private Universitaet fuer data in clinical studies for the Department of procurement of a web-based portal for search- Medizinische Informatik und Technik (UMIT), Hall near Ophthalmology of the Erlangen University Hos- ing and navigating medical image data bases Innsbruck, Austria pital. The Chair for Medical Informatics is cur- was another point of emphasis of the Chair for rently providing IT-support for bio-databases Medical Informatics.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 25 Clinical Theoretical Institutes

Institute of the History of Medicine and Medical Ethics Chair of the History of Medicine

Address A larger joint project combining history and by the Staedtler-foundation and the commis- Glueckstrasse 10 und Universitaetsstrasse 40 ethics, commissioned by the governing body sion of universities, and accomplished in part 91054 Erlangen of the university and the medical faculty, re- with the aid of the study group of universi- Phone: +49 9131 8526430 searched and documented, e.g., the issue of ty collections in Erlangen’s Metropolitan Mu- Fax: +49 9131 8522852 doctor’s titles being revoked during the “Third seum, was the special exhibition “Unpacked. www.igem.med.uni-erlangen.de Reich” (R. Wittern-Sterzel, A. Frewer). The Collections of the Erlangen-Nürnberg Uni- Head of Institute The Professorship for Medical Ethics is partic- versity,” along with the publication “U. Andr- ularly active in the areas of clinical ethics and aschke, M. M. Ruisinger (eds.): Die Sammlun- Prof. Dr. phil. Dr. med. habil. Renate ethics counseling. It also has a research focus gen der Universität Erlangen-Nürnberg. Nürn- Wittern-Sterzel in medicine and human rights. The research berg 2007.“ Contact program “clinical ethics” deals with the basic Dr. phil. Fritz Dross moral questions surrounding proper care for The social history of the hospital and the Phone: +49 9131 8526433 patients, with the justification of actions un- sanatorium Fax: +49 9131 8522852 dertaken by physicians in everyday medicine, Project manager: F. Dross [email protected] and with conflict situations in the hospital Ever since the leprosaria of the High Middle and private practice. Core questions concern Ages, specialized care and isolation facilities Research Focus clinical problem cases from the beginning of have existed in Europe. Since the beginning of • History of Scientific Collection life (prenatal diagnostics, pregnancy conflicts, the modern period, intensive scrutiny has been • The social history of the hospital and the neonatology, etc.) ethical questions in crisis paid to the close connection between pover- sanatorium situations (oncology, genetic counseling, psy- ty and illness. At the beginning, for instance chiatry, transplantation) to controversies about in the case of sanatoria for plague victims, the the end of life (euthanasia, care for the dying). concern was to isolate the ill, but by 1800 the Structure of the Institution Important instruments of clinical ethics are ar- notion had arisen that the hospital could be- gumentation analyses of the counseling given come a publicly funded facility for the care of The Institute of the History of Medicine and by committees in applied medical and bioeth- the indigent that could prevent poverty by cur- Medical Ethics consists of a Chair for the Histo- ics as well as empirical research studies. ing illness. Nevertheless, quick and efficient ry of Medicine and a Professorship for Medical The research area “medicine and human medical treatment in the specialized surround- Ethics. The institute also houses the “Forum for rights” deals with the various levels and aspects ings known as the “hospital” was only avail- Medicine and Human Rights,” established in of human rights questions in the fields of medi- able after the revolution of modern surgery in 2006 and the office of the Clinical Ethics Com- cine and biological sciences. This research focus the late 19th century. The concept of the mod- mittee. In addition it is charged with the care is the only one of its kind in German medical ern hospital is thus far older than the medicine for the Medical Collection in the city of Erlan- faculties; its institutional anchor is the “Forum that could breathe life into the concept. The regen. Fourteen associates are in the institute’s for Medicine and Human Rights.” search project investigates the social, political employ. Research is conducted by 12 scholars, and regulatory debates, as well as the medical seven of which are part-time. Currently 18 dis- debates in history since the Late Middle Ages. sertations on the history and ethics of medicine Research At the point where these debates converged are being supervised under the auspices of the there emerged a specialized sanatorium for the institute. Six scientific book series are overseen History of Scientific Collection prevention of poverty by means of medical ser- by members of the institute. Project manager: U. Andraschke, M. M. Ruis- vices as a hospital avant la lettre. (The Inven- The Chair of the History of Medicine research- inger tion of a Medical Institution? The Discussion es questions associated with ancient medicine Collecting, ordering, and systematizing the on Hospitals Around 1800. In: M. Dinges (ed.), and its reception in the Renaissance and the world of objects has numbered among the cen- Health and Health Care between Self-Help, In- Enlightenment (R. Wittern-Sterzel), the social tral practices in the production of knowledge termediary Organizations and Formal Poor Re- history of medicine in early modernity with a since the Renaissance. Collections were assem- lief (1500-2005), Lisbon 2007, S. 133-144). focus on the history of anatomy and surgery, bled at universities and were a core element of as well as patient history (M. M. Ruisinger). research and instruction in many disciplines. Further research examines networks of medi- The history of these collections therefore re- Teaching cal correspondence (also the subject matter of flects the history of academic disciplines in several dissertations) as well as the pre-history terms of their founding and their internal differ- The Institute of the History of Medicine and and early history of the health and hospital entiation. The collections that still exist today Medical Ethics is responsible for instruction systems (F. Dross). Finally, projects on the his- are an important resource for inquiries into the in medical terminology, as well as the history, tory of medicine and health in the region (ho- history of science and the universities. They theory and ethics of medicine. In the HTE semi- meopathy in Franconia by M. M. Ruisinger and also offer the possibility of communicating re- nars students learn the foundations of medical F. Dross) and in particular on the history of the search findings to a larger public in an appeal- history, the theory of medicine and medical medical faculty of the Friedrich-Alexander Uni- ing and immediately comprehensible manner. ethics by examining specific topics such as the versity Erlangen-Nürnberg are also underway. One result of the research project, sponsored history of the plague, the concept of health or

26 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) questions of medical ethics. Teaching methods include the interpretation of texts, cases discussion, roll-playing, short presentations, multi- media presentations and class excursions. The topical seminar “medicine and aging” is the institutes’ contribution to the module “dealing with age in the past and present.” Moreover, the institute is responsible for the area of ethics as a part of the introduction to clinical medicine. As an elective, the course “skills in ethical communication,” is offered as a subdivision of the modules “breaking bad news,” “speaking about death and dying,” and “intercultural communication.” Innova- tive techniques in instruction are utilized such as working with simulated patients. As a part of the major in molecular medicine students also study the subject “history of science and ethics.” In cooperation with the philosophy faculty courses are offered to deepen the students’ knowledge in the subjects of medical and bioethics. Beyond this, a survey lecture course is offered Wittern, R./Frewer, A. (2008): on questions of the history and ethics of medi- Erlanger Forschungen, Sonderreihe Band 12. cine and six series of scientific books are edited Verlag: Universitätsbund Erlangen-Nürnberg e. V. by members of the institute.

Selected Publications Ruisinger M M (2007) Surgery in letters. The example of Lorenz Heister‘s epistolary consultation. Med Ges Gesch, 29: 131-42, 266 Dross F (2008) “Battlefield of love”: the Fronberg-Hospital of the Deaconry Motherhouse Kaiserswerth. Medizinhist J, 43: 149-82

International Cooperation Prof. Dr. Laurinda Abreu, PhoenixTN European Thematic Network on Health and Social Welfare Policy, Universidade de Évora, Portugal Deutsch-Polnische Gesellschaft fuer Geschichte der Medizin e.V., TU Dresden, Germany/Poland

Meetings and International Training Courses 11.–13.07.2008: Medizintechnik – Sammeln, Forschen, Ausstellen: Symposium Medizinhistorische Museologie, Erlangen

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 27 Clinical Theoretical Institutes

Institute of the History of Medicine and Medical Ethics Professorship for Medical Ethics

Address of the university and the medical faculty, re- human rights in the area of medical and bio- Glueckstrasse 10 und Universitaetsstrasse 40 searched and documented, e.g., the issue of ethical controversy. From a theoretical per- 91054 Erlangen doctor’s titles being revoked during the “Third spective the possibilities and limits of a rights- Phone: +49 9131 8526430 Reich” (R. Wittern-Sterzel, A. Frewer). based medical and bioethics are considered Fax: +49 9131 8522852 The Professorship for Ethics in Medicine is par- and the dimensions of the concept of human www.igem.med.uni-erlangen.de ticularly active in the areas of clinical ethics and rights are investigated in this context (M. Roth- Head of Institute ethics counseling. It also has a research focus haar). In a practical vein this area of research inin medicine and human rights. The research volves questions of medical investigation and Prof. Dr. med. Andreas Frewer, M.A. program “clinical ethics” deals with the basic the documentation of human rights violations Contact moral questions surrounding proper care for (translation and edition of the Istanbul Protocol Dr. phil. Markus Rothhaar patients, with the justification of actions under- of the United Nations for the Documentation Phone: +49 9131 8526436 taken by physicians in everyday medicine, and of Torture), but also the participation of physi- Fax: +49 9131 8522852 with conflict situations in the hospital and pri- cians in human rights violations (M. Mylius, S. [email protected] vate practice. Core questions concern clinical Kolb). Not least of all it inquires into the the problem cases from the beginning of life (pre- rapy and “prophylaxis” of human rights viola- Research Focus natal diagnostics, pregnancy conflicts, neona- tions such as wartime sexual violence, torture, • Clinical Ethics and Ethics Counseling tology, etc.), ethical questions in crisis situa- recruitment of children as soldiers, and female • Medicine and Human Rights tions (oncology, genetic counseling, psychia- genital mutilation (K. Krása). In connection try, transplantation) to controversies about the with this area of research the reference book end of life (euthanasia, care for the dying). Im- series “Medicine and Human Rights” appears. Structure of the Institution portant instruments of clinical ethics are argu- On the occasion of the 60th anniversary of the mentation analyses of the counseling given by Universal Declaration of Human Rights the Pro- The Institute of the History of Medicine and committees in applied medical and bioethics as fessorship for Ethics in Medicine has organized Medical Ethics consists of a Chair for the His- well as empirical research studies. in 2008 a special issue of the Human Rights tory of Medicine and a Professorship for Medi- The research area “medicine and human Magazine (Potsdam University) on the topic of cal Ethics. The institute also houses the “Forum rights” deals with the various levels and aspects “Medicine and Human Rights.” for Medicine and Human Rights,” established of human rights questions in the fields of medi- in 2006, and the office of the Clinical Ethics cine and biological sciences. This research focus Committee. In addition it is charged with the is the only one of its kind in German medical Teaching care for the Medical Collection in the city of Er- faculties; its institutional anchor is the “Forum langen. Fourteen associates are in the institute’s for Medicine and Human Rights.” The Institute of the History of Medicine and employ. Research is conducted by 12 scholars, Medical Ethics is responsible for instruction seven of which are part-time. Currently 18 dis- in medical terminology, as well as the history, sertations on the history and ethics of medicine Research theory and ethics of medicine. In the HTE semi- are being supervised under the auspices of the nars students learn the foundations of medical institute. Six scientific book series are edited by Clinical Ethics and Ethics Counseling history, the theory of medicine and medical members of the institute. Project manager: A. Frewer, U. Fahr ethics by examining specific topics such as the The Chair of the History of Medicine research- Particular emphasis is placed on the investi- history of the plague, the concept of health or es questions associated with ancient medicine gation of clinical ethical counseling, which is questions of medical ethics. Teaching methods and its reception in the Renaissance and the conducted by the Professorship of Ethics in include the interpretation of texts, cases discus- Enlightenment (R. Wittern-Sterzel), the social Medicine in close association with the Clinical sion, roll-playing, short presentations, multi- history of medicine in early modernity with a Ethics Committee. Topics of research include media presentations and class excursions. focus on the history of anatomy and surgery, the theoretical foundations of ethical coun- The topical seminar “medicine and aging” as well as patient history (M. M. Ruisinger). seling, the evaluation of ethics counseling in is the institutes’ contribution to the module Further research examines networks of medi- hospitals, questions of narrative theory and “dealing with age in the past and present.” cal correspondence (also the subject matter of the documentation of ethics counseling (U. Moreover, the institute is responsible for the several dissertations) as well as the pre-history Fahr, T. Ramsauer, L. Kovács, A. Frewer). The area of ethics as a part of the introduction to and early history of the health and hospital framework afforded by this research includes clinical medicine. As an elective, the course systems (F. Dross). Finally, projects on the his- the “Day of Ethics” conference and “Yearbook “skills in ethical communication,” is offered as tory of medicine and health in the region (ho- Ethics in the Clinic” (YEC) [Jahrbuch Ethik in a subdivision of the modules “breaking bad meopathy in Franconia by M. M. Ruisinger and der Klinik]. news,” “speaking about death and dying,” F. Dross) and in particular on the history of the and “intercultural communication.” Innova- medical faculty of the Friedrich-Alexander Uni- Medicine and Human Rights tive techniques in instruction are utilized such versity Erlangen-Nürnberg are also underway. Project manager: A. Frewer as working with simulated patients. A larger joint project combining history and This branch of research bears on problems of As a part of the major in molecular medicine ethics, commissioned by the governing body determining the place of human dignity and students also study the subject “history of sci-

28 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) ence and ethics.” In cooperation with the Fac- ulty of Philosophy courses are offered to deepen the students’ knowledge in the subjects of medical and bioethics. Beyond this, a survey lecture course is offered on questions of the history and ethics of medicine and six series of scientific books are edited by members of the institute.

Selected Publications Frewer A, Fahr U (2007) Clinical Ethics and Confidentiality: Opinions of Experts and Ethics Committees. HEC Forum, 19: 277-291 Saefken C, Frewer A (2007) The Duty to Warn and Clinical Ethics: Legal and Ethical Aspects of Confidentiality and HIV/ AIDS. HEC Forum, 19: 313-326

International Cooperation Prof. J. D. Moreno, Ph.D., Centre of Medical Ethics and the History and Sociology of Science, University of Pennsyl vania, USA Prof. U. Schmidt, Ph.D., Rutherford College, University of Kent, Canterbury, Great Britain

Meetings and International Training Courses 24.11.2007: 7. Ethiktag des Klinischen Ethikkomitees und der Professur fuer Ethik in der Medizin: Patientenverfuegung und Ethikberatung in der Praxis, Erlangen 22.11.2008: 8. Ethiktag des Klinischen Ethikkomitees und der Professur fuer Ethik in der Medizin: Ethik im klinischen Alltag, Erlangen

Series of lectures on “Medicine, Ethics and Human Rights” Source: Prof. Dr. A. Frewer

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 29 Clinical Theoretical Institutes

Institute of Pathology Chair of General Pathology and Pathological Anatomy

Address Research The subject of a further research project are Krankenhausstrasse 12 the molecular changes in tumors in the head 91054 Erlangen Molecular Pathology of Urological Tumors and neck region (Dr. S. Schwarz, cooperation Phone: +49 9131 8522286 Project manager: A. Hartmann, R. Stoehr, C. with the Department of Ear, Nose and Throat- Fax: +49 9131 8524745 Hammerschmied Head and Neck Surgery, Prof. Dr. H. Iro and www.pathologie.uk-erlangen.de The research group investigates the basic mo- the Department of Oral and Maxillofacial Sur- Head of Institute lecular principles of the development of uro- gery, Prof. Dr. Neukam, Prof. Dr. Nkenke). This Prof. Dr. med. Arndt Hartmann thelial carcinoma of the urinary bladder and research project has two objectives: one is to renal cell carcinoma. There is a close cooper- compile a molecular-pathological and histo- Contact ation with the Department of Urology of the pathological classification of salivary gland tu- Karola Rudelt University Erlangen-Nürnberg at the hospital mors with low and high risk of relapse and pro- Phone: +49 9131 8522877 Waldkrankenhaus and also with numerous na- gression and the second one is to detect early Fax: +49 9131 8524745 tional and international cooperating partners. molecular markers to identify dysplastic chang- [email protected] The objective is the identification of genomic es as tumor precursors in the mucosa of the and epigenetic changes in urothelial carcino- head and neck region. Research Focus mas of the urinary bladder and kidney tumors • Molecular pathology of urological tumors to identify new markers for early diagnosis and Pathology of immune and inflammatory • Experimental tumor pathology new therapeutic target molecules. In addition reactions • Pathology of immune and inflammatory one of the priorities of the work is the correla- Project manager: M. Buettner reactions tion of clinical-pathological findings with the This topic examines the interaction between in- • Clinical and predictive molecular pathology molecular changes. fection and B cell differentiation in primary and persistent EBV infection and the mechanisms Experimental tumor pathology and interactions between the immune sys- Structure of the Institution Project manager: R. Schneider-Stock, A. Hart- tem and tumor cells in different tumors (pros- mann, S. Schwarz, A. Agaimy tate carcinoma, renal cell carcinoma, Hodgkin The Institute of Pathology includes also the Di- The first focus is the molecular characterization lymphoma). The objective is the identification vision of Nephropathology. A total of 75 mem- of maligant gastrointestinal tumors. Research of mechanisms through which the tumor cells bers of staff work in the Institute of Pathology, projects for the molecular regulation of apop- could escape the immune response of the or- 22 are medical professionals or scientists. Of tosis in colorectal carcinomas and adeno-car- ganism. these 8 are currently financed by third-party cinomas of the lower oesophagus (Barrett-car- funding. cinoma) are an important topic of the research Clinical and predictive molecular The Institute of Pathology is responsible for all work. Other areas deal with the basic molec- pathology pathology diagnostics within the University ular principles of chronic gastritis and Barrett Project manager: R. Stoehr, A. Hartmann Hospital Erlangen and for more than 30 exter- metaplasia and the significance of epigenetic The objective of this research topic involving nal hospitals and physicians. The pathology di- changes in the genesis of malignant tumors molecular examination of numerous tumor agnoses are carried out using the latest micro- (Dr. T. Rau) and with molecular genetics and types is the identification of molecular mark- scopic, immunohistochemical and molecular prognosis assessment in gastrointestinal stro- ers that can predict the response of malignant methods. In addition to the histological evalu- mal tumors (PD Dr. A. Agaimy, Prof. Dr. R. Sch- tumors to traditional radio- or chemothera- ations of approx. 35,000 samples more than neider-Stock). Another research project investi- pies or to new targeted molecular therapies. 1,500 molecular pathology investigations are gates the basic molecular principles of tumori- The Department of Molecular Pathology Diag- carried out. genesis in patients with Colitis ulcerosa. nostic (Head Dr. R. Stoehr) examines genetic The diagnostics specialities of the institute are The second main focus is in cooperation with changes (e.g. through specific mutation analy- urogenital and gynecological pathology as well the Department of Obstetrics and Gynaecol- sis) and epigenetic modifications in the tumor as breast pathology. Other focuses are the di- ogy (Prof. Dr. M. Beckmann, PD Dr. P. Fasch- (e.g. specific promoter-hypermethylation anal- agnosis of soft part tumors and gastrointestinal ing) and with the West German Study Group ysis). A further focus is the diagnosis of hered- tumor pathology. The clinical focuses are very (Prof. Dr. U. Nitz, Dr. O. Gluz) and the Insti- itary tumors. closely linked to the research topics of the In- tute of Pathology of RWTH Aachen (Prof. Dr. E. stitute of Pathology, with associate professor- Dahl) in the discovery of genetic and epigene- ships in “Experimental Tumor Pathologie” and tic changes in breast cancer and ovarian carci- Teaching “Diagnostic Molecular Pathology”. nomas (Prof. Dr. A. Hartmann, Dr. D. Wachter). The objective of the research here is to discov- The Institute of Pathology has an essential role er prognostic markers and to identify molecular in the teaching of students of human, den- markers that could be used in the clinical-path- tal and molecular medicine and in delivering ological differential diagnosis and therapeutic the study course “medical process manage- stratification of breast cancer. ment”. In addition to traditional teaching for-

30 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) mats (main lectures, block seminars) the Insti- tute also offers integrated and interdisciplinary courses. In particular the teaching course in the autopsy ward and the interdisciplinary course “conference of clinical pathology” has to be mentioned. In the study course “molecular medicine” we offer teaching courses such as “basic principles of pathology”, “basic principles of tumor biology” (literature seminar) and other subjects of molecular pathology.

Selected Publications Agaimy A, Wuensch PH, Hofstaedter F, Blaszyk H, Ruemmele P, Gaumann A, Dietmaier W, Hartmann A (2007) Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol, 31: 113-20 Dahl E, Wiesmann F, Woenckhaus M, Stoehr R, Wild PJ, Veeck J, Knuechel R, Klopocki E, Sauter G, Simon R, Wieland WF, Walter B, Denzinger S, Hartmann A, Hammerschmied CG (2007) Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter General renovation of the historic building of the Institute of Pathology methylation in renal cell carcinoma. Oncogene, 26: 5680-91 Source: University Hospital Erlangen Hafner C, López-Knowles E, Luis NM, Toll A, Baselga E, Fernández-Casado A, Hernández S, Ribé A, Mentzel T, Stoehr R, Hofstaedter F, Landthaler M, Vogt T, Pujol RM, Hartmann A, Real FX (2007) Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci U S A, 104: 13450-4 Wild PJ, Giedl J, Stoehr R, Junker K, Boehm S, van Oers JM, Zwarthoff EC, Blaszyk H, Fine SW, Humphrey PA, Dehner LP, Amin MB, Epstein JI, Hartmann A (2007) Genomic aberrations are rare in urothelial neoplasms of patients 19 years or younger. J Pathol, 211: 18-25 Gluz O, Wild P, Meiler R, Diallo-Danebrock R, Ting E, Mohrmann S, Schuett G, Dahl E, Fuchs T, Herr A, Gaumann A, Frick M, Poremba C, Nitz UA, Hartmann A (2008) Nuclear karyopherin alpha2 expression predicts poor survival in patients with advanced breast cancer irrespective of treatment intensity. Int J Cancer, 123: 1433-8 Wassermann S, Scheel SK, Hiendlmeyer E, Palmqvist R, Horst D, Hlubek F, Haynl A, Kriegl L, Reu S, Merkel S, Brabletz T, Kirchner T, Jung A (2009) p16(INK4a) Is a beta-Catenin Target Gene and Indicates Low Survival in Human Colorectal Tumors. Gastroenterology, 136: 196-205.e2

International Cooperation Ellen Zwarthoff, Erasmus MC Rotterdam, Netherlands Torben Ornthoft, MOMA Aarhus, Denmark Version Pathology - Finished in 2010 Paco Real und Nuria Malats CNIO, Madrid, Spain Source: State Building Authority Erlangen-Nürnberg W. EL-Rifai, Vanderbilt University, Memphis, USA

Research Equipment PALM Laser-Mikrodissektions-Mikroskop

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 31 Clinical Theoretical Institutes

Institute of Pathology Division of Nephropathology

Address Research Interdisciplinary Centre for Clinical Krankenhausstrasse 12 Research 91054 Erlangen Clinical and experimental nephro Project manager: K. Amann Phone: +49 9131 8522291 pathology 1. Cardiovascular changes in experimental sys- Fax: +49 9131 8522601 Project manager: K. Amann temic Lupus erythematodes. Here in coopera- www.nephropathologie.uk-erlangen.de There is extensive clinical and experimental co- tion with Prof. Thomas Winkler (Chair of Ge- Head of Division operation with clinical partners (Department netics) and PD Dr. Reinhardt Voll (Department Prof. Dr. med. Kerstin Amann of Medicine 4 and pediatric nephrology of the of Medicine 3) the hypothesis is explored that Department of Pediatrics) as well as numerous in the case of systemic Lupus erythematodes Contact task groups of the University Hospital and the independent carciovascular changes develop Judith Wagner University Erlangen-Nürnberg which are active that are independent of the degree of the kid- Phone: +49 9131 8522605 in the area of kidney research. The task of the ney participation in the disease and which are Fax: +49 9131 8522600 Division of Nephropathology is predominantly a considerable clinical problem in particular in [email protected] the testing of molecular hypotheses on mate- younger patients. This hypothesis is evaluated rial of animal experiments and human kidneys. in different animal models of systemic Lupus Research Focus In addition, equipment is available to carry out erythematodes using morphological and mo- • Clinical and experimental nephropathology methods of quantitative tissue analysis for renal lecular methods. • Collaborative Research Centre (SFB) 423 phenotyping of transgenic and knock-out ani- 2. Proteases inhibition as a new therapeutic kidney damage mal models. intervention in inflammatory kidney diseases. • Interdisciplinary Centre for Clinical Research In cooperation with PD Dr. Reinhardt Voll (De- Collaborative Research Centre (SFB) 423 partment of Medicine 3) and PD Dr.Michael kidney damage Wiesner (Department of Medicine 4) it is ex- Structure of the Institution Project manager: K. Amann plored whether proteases inhibition constitutes Within the framework of the Collaborative Re- a new therapeutic option in the treatment of The Division of Nephropathology together search Centre (SFB) 423 renal injury: “Patho- Lupus-nephritis and also other immuno-com- with the chair of General Pathology constitutes genesis and regeneration” established in 1999 plex mediated inflammatory kidney diseases. the Institute of Pathology. The Department em- at the Medical Faculty of the University Er- To test this hypothesis, medicational interven- ploys a total of 12 members of staff of which langen-Nürnberg, the Division of Nephro tions for proteases inhibition in standard mod- six are financed by third-party funds. Research pathology makes the central project Z2 “Quan- els of systemic Lupus erythematodes and other is carried out by two Ph.D. students and four titative morphology” available by putting at inflammatory kidney diseases are investigated. technical staff. the disposal of the other projects of the Col- The Department of Nephropathology is re- laborative Research Centre (SFB) morphometric sponsible for the kidney biopsy diagnosis of the and sterologie methods of tissue analysis and in Teaching University Hospital Erlangen (Department of particular the laser-assisted micro dissection. In Medicine 4 and Pediatric nephrology of the De- respect of the mentioned technologies an in- The Department of Nephropathology partici- partment of Pediatrics) and of further 42 exter- tensive induction does take place and surrance. pates in the teaching of the Institute of Pathol- nal biopsy senders. The kidney biopsy diagnosis ogy. In addition, nephropathological confer- is carried out using the latest light-microscopic, ences with the clinical departments of the Uni- immunohistological, electron microscopic and versity Hospital and external biopsy senders molecular methods. In this field there are close are regularly held. Furthermore, twice a year a links with the corresponding structures of the kidney pathology course takes place for both Institute of Pathology. staff of the University Hospital and staff of external hospitals.

32 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Aigner T, Neureiter D, Câmpean V, Soder S, Amann K (2008) Expression of cartilage-specific markers in calcified and non- calcified atherosclerotic lesions. Atherosclerosis, 196: 37-41 Boor P, Casper S, Celec P, Hurbánková M, Beno M, Heidland A, Amann K, Sebeková K (2008) Renal, vascular and cardiac fibrosis in rats exposed to passive smoking and industrial dust fiber amosite. 2008 Oct 6. [Epub ahead of print] Câmpean V, Karpe B, Haas C, Atalla A, Peters H, Rupprecht H, Liebner S, Acker T, Plate K, Amann K (2008) Angiopoi- etin 1 and 2 gene and protein expression is differentially regulated in acute anti-Thy1.1 glomerulonephritis. Am J Physiol Renal Physiol, 294: F1174-84 Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE (2008) The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med, 14: 748-55 Amann K, Haas CS, Zeiler GA, Benz K, Bader BL, Hartner A, Hilgers KF (2009) Lack of nidogen-2 increases blood pressure, glomerular and tubulointerstitial damage in DOCA-salt hypertension. Eur J Clin Invest, 39: 116-25 Benz K, Amann K (2009) Pathological aspects of membra- noproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP). Thromb Haemost, 101: 265-70

International Cooperation Prof. Dr. J. Kanwar, Pathologisches Institut, North Western University, Chicago, USA Prof. Dr. S. Rostand, Nephrologie, University of Birming- ham, Alabama, England Dr. Ingeborg Bajema, Pathologisches Institut, Universitaet Leiden, Netherlands

Research Equipment PALM Laser-Mikrodissektions-Mikroskop

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 33 Clinical Theoretical Institutes

Institute of Neuropathology Chair of Neuropathology

Address terization of transgenic mouse models for the The European EpiCure Consortium (funded Schwabachanlage 6 IBMPFD disease (Inclusion Body Myopathy as- by EC) has established an Epilepsy Brain Bank 91054 Erlangen sociated with Pagets disease of bone and Fron- (www.epicure-bank.org), which is associated Phone: +49 9131 8526031 totemporal Dementia) and the desmin myop- to our institution, to achieve the following Fax: +49 9131 8526033 athy and cardiomyopathy. The clinical, mor- goals: (1) To standardize histopathological di- www.epilepsie-register.de phological, biochemical and molecular analy- agnosis among European countries. (2) To stan- Head of Institute sis of these mouse models shall provide deeper dardize sampling and long-term storage of sur- Prof. Dr. med. Ingmar Bluemcke insights into the molecular “sequence” that gical tissue specimens for research purpose. (3) leads to pathological protein aggregation and Colleagues with rare expertise in examining Contact progressive muscle damage in these disorders. epilepsy-surgical specimens can request for a Prof. Dr. med. Ingmar Bluemcke This work will be the basis for novel targeted consultant opinion (free of charge). (4) Regular Phone: +49 9131 8526031 treatment strategies. workshops are organized to achieve common Fax: +49 9131 8526033 diagnosis and classification schemes within Eu- [email protected] Focal human epilepsies / european epi- ropean countries. lepsy brain bank Research Focus Project manager: I. Bluemcke Neuro-oncology • Molecular myopathology This research topic focuses on therapy-refrac- Project manager: R. Buslei • Focal human epilepsies / european epilepsy tory focal epilepsies in humans. To unravel the Neuro-oncology plays an important role in brain bank molecular pathogenesis of major entities asso- our clinico-neuropathological surveillance. • Neuro-oncology ciated with chronic epilepsies, e.g. hippocam- With the international reputation of the De- • Adult stem cells of the human brain pal sclerosis, glio-neuronal tumours and focal partment of Neurosurgery in Erlangen and cortical dysplasias, we performed systematic its emphasis on the treatment of neuroendo- analysis using surgically resected brain spec- crine tumors (e. g. pituitary adenomas, cranio- Structure of the Institution imens and correlated them with clinical his- pharyngeomas) an unique collection of surgi- tories and post surgical follow-up data. Dur- cal tissue samples is available for a systematic The Institute has become part of the Universi- ing this research period, major advances result molecular-neuropathological examination. Our ty Hospital in 2007. A total of 20 collaborators from improved classification systems for mesial research topics address three major questions: were employed (7 paid from external grants): temporal sclerosis. (1) molecular tumorigenesis (2) pathogene- 5 academic staff, 8 post-graduate students and Research of human epilepsies and histopatho- sis of brain invasiveness (3) molecular genetic 6 technicians. Different research units address logically well-characterized surgical specimens analysis as a tool for evaluating prognosis and the molecular pathomechanisms of CNS and obtained from patients with temporal lobe ep- therapy. For our molecular-biological and ge- skeletal muscle disorders. Particular focus is ilepsy opens also new avenues to study higher netical analysis we have access to a tissue bank paid to epilepsy surgery, neuro-oncology and brain function in humans, i.e., the hippocam- comprising more than 500 unique tumors of neuromuscular disorders. We have established pus serves a major role in memory formation. the pituitary gland as well as craniopharyngeo- the neuropathological reference centre for epi- In addition, our finding of epilepsy-induced mas. Major improvements result from the anal- lepsy surgery and the European Epilepsy Brain neurogenesis in the human hippocampus of- ysis of β-catenin mutations in craniopharyngio- Bank (supported by EU). fers the possibility to unravel molecular signals mas and its impact for the differential diagno- for the recruitment, proliferation and differen- sis of cystic tumours of the sellar region. Future tiation of adult stem cells in the human brain. work will address the development of novel Research animal models and in vitro cultures to unravel the molecular pathogenesis of this peculiar tu- Molecular myopathology mour entity. Project manager: R. Schroeder A central research topic is the molecular char- Adult stem cells of the human brain acterisation of progressive skeletal muscle and Project manager: R. Coras cardiac diseases, which are morphologically Numerous regions of the adult brain maintain characterized by pathological protein aggrega- neural progenitor cells (“adult stem cells“), tion. These adult onset protein aggregate my- which are able to generate new neurons under opathies are clinically characterized by a pro- physiological as well as pathophysiological con- gressive course leading to severe disability and ditions (neurogenesis). These intriguing pre- premature death. To date, no causative treat- cursor cells may gain outstanding importance ment is available for these disorders. The main in regenerative neurobiological treatment mo- focus of our current research work (funded by Adult human brain stem cells dalities and constitute an alternative approach Induced neuronal differentiation in a stem cell obtained the German Research Foundation, the Federal to embryonic stem cells. Basic mechanisms from the adult human hippocampus (epilepsy surgery). Ministry of Education and Research; Fritz-Thys- Fluorescence microscopy of MAP2 immunoreactivity (in of recruitment, proliferation and differentia- sen Foundation) is the generation and charac- green). Hoechst nuclear staining in blue. tion of adult stem cells remain, however, un-

34 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) known. The identification of these mechanisms is a major topic of our project. To address this question, we have access to unique models: or- ganotypic slice cultures of rat and mice hippocampus, but also from epilepsy surgical specimens are available resources. Furthermore, we are able to isolate adult stem cells from acute brain slices and proliferate them clonally. The possibility to generate high numbers of differentiated neurons or glia cells from autologues stem cells of the brain may unravel novel treat- Craniopharyngioma ment strategies in apoplexia, Parkinson‘s dis- Left Image: H&E staining in a craniopharyngeoma reveals the characteristic epithelial architecture ease but also epilepsies or multiple sclerosis with enamel dots and wet ceratin deposits. Right image: the majority of craniopharyngeomas carry (supported by the Bavarian Research Consor- mutations in the β-catenin gene, which lead to nuclear β-catenin protein accumulation and activa- tium ForNeuroCell). tion of the wnt signalling pathway.

Teaching

Our Department in enroled in pathology training and lectures.

Selected Publications Blumcke I, Pauli E, Clusmann H, Schramm J, Becker A, Elger C, Merschhemke M, Meencke HJ, Lehmann T, von Deim- ling A, Scheiwe C, Zentner J, Volk B, Romstock J, Stefan H, Hildebrandt M (2007) A new clinico-pathological classification system for mesial temporal sclerosis. Acta Neuropathol Desminopathy (Berl), 113: 235-44 Intracellular protein aggregates (arrowheads) present a characteristic finding in desmin myopa- Kley RA, Hellenbroich Y, van der Ven PF, Fuerst DO, Huebner thies. Upper image: Gomori staining. Lower image: Fluorescence microscopic analysis of desmin A, Bruchertseifer V, Peters SA, Heyer CM, Kirschner J, Schro- immunoreactivity. eder R, Fischer D, Mueller K, Tolksdorf K, Eger K, Germing A, Brodherr T, Reum C, Walter MC, Lochmueller H, Ketelsen UP, Vorgerd M (2007) Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain, 130: 3250-64 International Cooperation Hoelsken A, Kreutzer J, Hofmann BM, Hans V, Oppel F, Bu- chfelder M, Fahlbusch R, Bluemcke I, Buslei R (2008) Target Prof. Gerhard Wiche, Max F. Perutz Laboratories, Univer- Gene Activation of the Wnt Signaling Pathway in Nuclear sitaet Wien, Austria beta-Catenin Accumulating Cells of Adamantinomatous Prof. Dr. Roberto Spreafico, Department of Epilepsy Clinic Craniopharyngiomas. Brain Pathol Epub 2008 May 29. and Experimental Neurophysiology, Fondazione IRCCS Huttner HB, Janich P, Koehrmann M, Jászai J, Siebzehnrubl Istituto Neurologico “Carlo Besta”, Milano, Italy F, Bluemcke I, Suttorp M, Gahr M, Kuhnt D, Nimsky C, Krex Prof. Dr. Dennis Steindler, McKnight Brain Institute, Uni- D, Schackert G, Loewenbrueck K, Reichmann H, Juettler E, versity of Florida, Gainsville, USA Hacke W, Schellinger PD, Schwab S, Wilsch-Braeuninger M, Marzesco AM, Corbeil D (2008) The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells, 26: 698-705 Konieczny P, Fuchs P, Reipert S, Kunz WS, Zeoeld A, Fischer I, Paulin D, Schroeder R, Wiche G (2008) Myofiber integrity depends on desmin network targeting to Z-disks and costa- meres via distinct plectin isoforms. J Cell Biol, 181: 667-81 Siebzehnrubl FA, Jeske I, Mueller D, Buslei R, Coras R, Hahnen E, Huttner HB, Corbeil D, Kaesbauer J, Appl T, von Hoersten S, Bluemcke I (2008) Spontaneous In Vitro Transformation of Adult Neural Precursors into Stem-Like Cancer Cells. Brain Pathol Epub 2008 Jul 10

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 35 Clinical Theoretical Institutes

Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Chair of Microbiology and Immunology of Infection

Address PCR machines, analytical fluorescence activat- mechanisms of action of adjuvants. Another Wasserturmstrasse 3-5 ed cell sorters (FACS), sequencing and imag- research avenue focuses on the question how 91054 Erlangen ing systems. the inflammatory response of macrophages is Phone: +49 9131 8522551/22552 The main clinical work of the institute is fo- terminated in order to prevent collateral tis- Fax: +49 9131 851001 cussed on the diagnostics of bacterial, fungal sue damage. In this context one central aspect www.klimi.med.uni-erlangen.de and parasitic infectious diseases, the hospital is the in vitro and in vivo analysis of the “dual Head of Institute hygiene and the prevention of infectious dis- specificity phosphatases”.T hese inhibit various Prof. Dr. med. Christian Bogdan eases by immunization. The institute runs the kinases that are essential for the production of university outpatients´ clinic for vaccination proinflammatory cytokines and chemokines. Contact and travel medicine. For bacteriological, sero- Christine Kubik logical and mycological diagnostic procedures Phone: +49 9131 8522281 the institute functions as reference centre for Fax: +49 9131 851001 the country-wide quality control and profi- [email protected] ciency tests. Research Focus • Innate immunity and myeloid cells Research • Innate immunity and natural killer cells • Signal transduction of interleukin-4 receptor Innate immunity and myeloid cells signaling Project manager: H.U. Beuscher • Bacterial virulence factors In cooperation with the Department of Medi- • Innate immunity and antimicrobial proteins cine 3 and a Junior Research Group of the IZKF • New methods of diagnostic microbiology the survival strategies, the immunoregulatory Leishmania infantum (green) is endocytosed by myeloid functions and the production of inflammatory dendritic cells (red surface with blue nucleus) (Schleicher mediators by neutrophils from patients with et al. J Exp Med 2007) Structure of the Institution rheumatoid arthritis will be investigated. The study aims to characterize an anti-apoptot- The Institute of Microbiology – Clinical Micro- ic factor and its mechanism of action as well biology, Immunology and Hygiene houses the as possible therapeutic applications. A second Innate immunity and natural killer cells Chair of Microbiology and Immunology of In- project analyses, how mast cells interact with B Project manager: U. Schleicher fectious Diseases (Head: Prof. Dr. med. C. Bog- lymphocytes, modulate the antibody synthesis The early phase of Leishmania infections is dan), the Diagnostic Laboratories for Clinical and thereby optimize the specific immune de- characterized by the rapid activation of natural Microbiology and Hospital Hygiene (Head: OA fense of the host organism. killer (NK) cells. The group investigates, which Dr. med. Dipl. Chem. C. Schoerner) and, since Project manager: C. Bogdan receptors (e.g. toll-like receptors, TLR), cyto- November 1, 2008, the newly installed Division The interferon (IFN)-γ inducible nitric oxide kines and cell-types (macrophages, myeloid of Infection Biology. The institute employs 84 synthase (iNOS), which generates nitric oxide and plasmacytoid dendritic cells) are required coworkers, of which 29 are payed by extramu- from the amino acid L-arginine, is essential for for NK cell activation. As activated NK cells ral funding sources. The research is carried out several functions of the immune system and contribute to the control of pathogens, exper- by 14 scientists with a M.D. or Ph.D. degree, the defense against intracellular microorgan- iments are carried out to unravel the underly- 16 Ph.D. students und 12 technical assistants. isms (e.g. Leishmania spp.). In macrophages, ing direct or indirect effector mechanisms. For The different research groups of the institute the mechanism underlying the suppression of the functional analysis of NK cells in vivo during study the innate and adaptive immune re- iNOS protein synthesis by L-arginine-deficien- cutaneous (L. major) and visceral leishmaniasis sponse during infectious diseases, investigate cy, which occurs following induction of the ar- (L. infantum) a transgenic mouse model, which mechanisms of microbial virulence and analyse ginine-metabolizing enzyme arginase, will be allows for the selective deletion of NK cells, and the regulation of basic inflammatory process- studied. Another area of research is the auto- novel NK cell activators will be applied. es, using immunological, cell-biological and activation of macrophages via endogenously molecular techniques. Various infectious dis- produced IFN-β and the effect of hypoxic con- Signal transduction of interleukin-4 recep- ease models are studied, which include Lyme ditions in inflamed tissues on the antimicrobial tor signaling arthritis (Borrelia burgdorferi), gastrointestinal function of myeloid cells. Project manager: A. Gessner infections (Salmonella typhimurium, Yersinia Project manager: R. Lang T-helper lymphocytes exist as different sub- enterocolitica), pulmonary infections (Pseu- The group explores, which receptors are used types and therefore contribute both to the domonas aeruginosa), cutaneous (Leishmania by macrophages to detect pathogenic micro- control as well as to the pathogenesis of infec- major) and visceral leishmaniasis (Leishmania organisms and their products (e.g. the myco- tious diseases. For the induction and function infantum). The institute is fully equipped with bacterial cord-factor trehalose-dimycolate) and of type 2 T-helper cells interleukin (IL)-4 is of BSL2- and BSL3-laboratories, fluorescence and how these receptors signal to elicit immune pivotal importance. Using various biochemi- confocal laser scanning microscopes, real-time reponses. The project aims to eludicate the cal approaches as well as a number of newly

36 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) established knock-out and knock-in mice the of antimicrobial proteins by toll-like receptors Selected Publications signalosom that is recuited to the IL-4 receptor (TLR). Emphasis will be given to the “bacte- Auer J, Blaess M, Schulze-Koops H, Russwurm S, Nagel T, as well as the subsequent signaling cascades ricidal/permeability-increasing protein” (BPI), Kalden JR, Roellinghoff M, Beuscher HU (2007) Expression will be defined. For functional in vivo analyses, which facilitates the phagocytosis and the lysis and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res Ther, 9: R94 the elucidation of inflammatory processes and of Gram-negative bacteria. In cooperation with the evaluation of novel immunotherapeutic ap- the group of A. Gessner the phenotype of BPI- Gerlach RG, Jaeckel D, Stecher B, Wagner C, Lupas A, Hardt WD, Hensel M (2007) Salmonella Pathogenicity Island 4 proaches infectious disease mouse models will deficient transgenic mice will be characterized. encodes a giant non-fimbrial adhesin and the cognate type be used (Leishmania major, Borrelia burgdor- Finally, the expression of TLR and antimicrobial 1 secretion system. Cell Microbiol, 9: 1834-50 feri, Pseuodomonas aeruginosa). proteins in trophoblasts and placental tissue is Schleicher U, Liese J, Knippertz I, Kurzmann C, Hesse A, Heit investigated in order to gain novel insights into A, Fischer JA, Weiss S, Kalinke U, Kunz S, Bogdan C (2007) Bacterial virulence factors the immunsuppressed status and susceptibility NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid Project manager: M. Hensel to infection of fetuses and newborns. DCs. J Exp Med, 204: 893-906 The ability of bacterial pathogens to evade the Groer GJ, Haslbeck M, Roessle M, Gessner A (2008) Structur- immune system and to cause disease are a con- New methods of diagnostic microbiology al characterization of soluble E-Syt2. FEBS Lett, 582: 3941-7 sequence of the expression of virulence factors, Project manager: W. Geißdoerfer, F. Albert, B. Wittmann I, Schoenefeld M, Aichele D, Groer G, Gessner some of which are encoded by pathogenicity Kunz, C. Schoerner A, Schnare M (2008) Murine bactericidal/permeability- islands. Using the gastrointestinal pathogen Aim of the project is the development and eval- increasing protein inhibits the endotoxic activity of lipo- Salmonella typhimurium, the group investi- uation of new microbiological diagnostic pro- polysaccharide and gram-negative bacteria. J Immunol, 180: 7546-52 gates the molecular mechanisms of adhesion, cedures that are highly specific, sensitive, fast Werninghaus K, Babiak A, Gross O, Hoelscher C, Dietrich invasion and intracellular replication of the and cost-efficient. The group focuses on the H, Agger EM, Mages J, Mocsai A, Schoenen H, Finger K, bacteria, the genetic basis for the adaptation establishment of novel real-time polymerase- Nimmerjahn F, Brown GD, Kirschning C, Heit A, Andersen of the bacterial metabolism to the intracellular chain-reactions, the utilization of mass spec- P, Wagner H, Ruland J, Lang R (2009) Adjuvanticity of a life and the (immuno)modulatory impact of the trometry (MALDI-TOF) for direct identification synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-de- bacterial effector molecules on the host cells. of bacterial and fungal species, the routine ap- pendent innate immune activation. J Exp Med, 206: 89-97 Further projects aim to optimize the use of Sal- plication of rapid screening procedures for monella as recombinant carriers for prophy- multi-resistant pathogens and the implemen- International Cooperation lactic and therapeutic vaccines and to develop tation of a new electronic data processing sys- Larry Keefer, National Cancer Institute, Bethesda, USA new methods for the efficient genetic manipu- tem that offers online accessibility for placing Peter Murray, St. Jude Children‘s Research Hospital, lation of bacterial pathogens. orders and viewing results. The spectrum of Memphis, USA infectious pathogens, for which the diagnostic Dipshikha Chakravortty, Indian Institute of Science, Ban- procedures have been improved, range from galore, India bacteria (e.g. MRSA, C. trachomatis, L. pneu- Pavel Kovarik, Max F. Perutz Laboratories, University of mophila, T. whipplei) to fungi and protozoa (T. Vienna, Austria gondii, Leishmania spp.). Research Equipment Applied Biosystems DNA-Sequenzierautomat Teaching Applied Biosystems ABI Prism 7900 Taqman sequence detector BD Biosciences FACS Canto II The coworkers of the institute teach students of human medicine, dental medicine, molecular medicine, biology and pharmaceutical sciences in clinical and molecular microbiology, in im- Salmonella (red) adhere to the apical side of polarized munology, in infectious disease research and in epithelial cells (using a SPI4-encoded adhesin), induce the field of clinical infectious disease diagnos- the elimination of microvilli and invade the host cells tics and tropical diseases. The training takes (image provided by Dr. Manfred Rohde, HZI, Braun- place in form of seminars, practical courses, lec- schweig). tures, laboratory rotations, as well as bachelor, master, M.D. and Ph.D. theses. Together with the Institute of Clinical and Molecular Virology Innate immunity and antimicrobial the institute organizes an interdisciplinary lec- proteins ture series on the diagnosis and treatment of in- Project manager: M. Schnare fectious diseases, which serves as a continuous Antimicrobial proteins are essential compo- medical education program of medical doctors nents of the immune response against infec- in the region. tious pathogens. The focus of the project is the analysis of the function and the regulation

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 37 Clinical Theoretical Institutes

Institute of Virology – Clinical and Molecular Virology Chair of Clinical Virology

Address Schlossgarten 4 91054 Erlangen Phone: +49 9131 8523563 Fax: +49 9131 8522101 www.virologie.uni-erlangen.de

Head of Institute Prof. Dr. med. Bernhard Fleckenstein

Contact Dr. rer. nat. Monika Groene Phone: +49 9131 8525790 Fax: +49 9131 8522101 [email protected]

Research Focus • HIV and other retroviruses Confocal Laser Scanning Microscopy for determination of intracellular localization of viral pro- • Expert Laboratory for Beta-Herpesviruses teins in infected cells. • Research Network on DNA tumor viruses Source: Foto Fuchs Design, Erlangen

Structure of the Institution Research (human T cell leukemia virus). They investigate the molecular function of the Tax oncoprotein The research focuses of the institute are patho- HIV and other retroviruses of the virus. genic Retroviruses, Human Cytomegalovirus Several basic research projects in the institute and Oncogenetic Herpesviruses. The research have a close connection to the task of the Na- Expert Laboratory for Beta-Herpesviruses fields range from infection biology, tumor vi- tional Reference Centre for Retroviruses. The The broad research activity of the institute rology, vector development, therapy research, group of Prof. Dr. U. Schubert is studying the focuses on the immune defense and on the immunology to clinical diagnostics. Altogeth- interaction of host and virus proteins on the molecular mechanisms of replication of the er the institute has about 130 staff members. molecular level in order to define interface re- clinically relevant human cytomegalovirus The majority are students of biology, medicine, gions of binding partners that can be used (HCMV). The research group of Prof. Dr. M. biochemistry and molecular medicine who are as target structures for anti-viral strategies. A Mach defines in collaboration with Prof. Th. working on their dissertation or master thesis major focus of their research encompasses gen- Winkler, Chair of Genetics (Faculty of Natu- in one of the 14 research groups. Head of the eral aspects of HIV-1 biology, including the role ral Science), the key factors providing protec- project groups are full, associate and assistant of cellular factors in retrovirus assembly. Those tive humoral immunity following HCMV infec- professors and junior scientists. 15 technical studies are focused on the role of the ubiqui- tion using a mouse model. They disprove the assistants support the research groups. The tine-proteasome-system (UPS) in late process- still ongoing opinion that antibodies are irrel- majority of the research staff is supplied by re- es of the HIV replication cycle. The group of evant for protection from CMV infection in risk search supporting organizations. PD B. Schmidt surveys the role of plasmacy- groups. The group of Prof. T. Stamminger char- The renovations and extension of the north toid dendritic cells in innate immune defens- acterizes the functional mechanism of viral reg- wing of our institute was completed in mid- es against HIV. Dr. Dr. H. Reil is engaged in the ulatory proteins that exert an essential function 2008. This construction measure provided ade- interference of flavivirus GB Virus C (GBV-C) for efficient viral replication and are thus attrac- quate security standards for the majority of the and immunodeficiency viruses. Dr. H. Walter tive novel target molecules for antiviral thera- scientific laboratories. Furthermore, the insti- and Dr. K. Korn are working on the develop- py. Prof. Stamminger’s research group could re- tute has five security labs of security level three. ment of methods for the detection of HIV recently identify a novel intrinsic immune mech- The diagnostic labs offer a modern spectrum of sistance against new drug classes. In close con- anism against herpes viruses that could be rel- diagnostic tests for all relevant viral infections. nection, PD Dr. K. Metzner investigates the evant for the regulation of herpesviral latency. The focus lies on retrovirus diagnostic for HIV/ pathology of the development of drug resis- Furthermore, they are working together with AIDS and Human T-cell-Leukemia virus. Very tance in immunodeficiency viruses under the Prof. Ensminger (cardiac surgery) on a mouse important in this field is the resistance test for aspect of appearance of HIV viral quasispecies. xenotransplantation model on the mechanism HIV to determine the susceptibility to antiretro- Prof. R. Grassmann was the head of the HTLV of CMV induced transplant arteriosclerosis. The viral drugs. In addition, the institute offers HIV group until July 2008, when he suddenly died. research group of Prof. Dr. M. Marschall inves- reference material in its role as National Refer- His group studied the molecular biology of the tigates the roles of viral and cellular protein ki- ence Centre for Retroviruses. development of ATLL (adult T cell Leukemia/ nases in herpesviral replication and herpes virus Lymphoma) caused by the retrovirus HTLV-1 pathogenicity. This area of his work serves the

38 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) purpose to develop novel antiviral drugs of pro- Master of Science (M.Sc.) degree program for tein kinase inhibitors (including inhibitors of biology students are currently established. Fur- cellular signal transduction). thermore the members of the institute are es- sentially involved in the weekly seminars, pe- Research Network on DNA tumor viruses riodic workshops and biannual retreats of the This network is coordinated by Prof. Dr. B. graduate training program 1071 ‘Viruses of the Fleckenstein and is focused on the mecha- immune system’. nism of cellular growth transformation by Selected Publications DNA tumor viruses. The Kaposi´s sarcoma-associated human herpesvirus type 8 (HHV-8) Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU (2007) is also associated with B-cell lymphoprolifera- Living cells on a slide during confocal laser scanning TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG- tion. The growth promoting and immunoreg- microscopy. I-mediated antiviral activity. Nature, 446: 916-920 Source: Foto Fuchs Design, Erlangen ulatory properties of different HHV-8 proteins Klenovsek K, Weisel F, Schneider A, Appelt U, Jonjic S, Mes- are studied by the group of PD Dr. F. Neipel. serle M, Bradel-Tretheway B, Winkler TH, Mach M (2007) In 2008, they identified novel ligands for two Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells. Blood, 110: 3472-9 viral glycoproteins. The binding of the viral glycoproteins to the new receptor induces signal Teaching Goldwich A, Hahn SS, Schreiber S, Meier S, Kaempgen E, Wagner R, Lutz MB, Schubert U (2008) Targeting HIV-1 Gag transduction pathways known to be involved into the defective ribosomal product pathway enhances in the tumorigenic process by vascularization. In cooperation with the microbiology col- MHC class I antigen presentation and CD8+ T cell activation. Thus, HHV-8 encounters and activates cellular leagues, the Institute of Virology offers curric- J Immunol, 180: 372-82 genes contributing to oncogenesis at the ear- ular lectures and practical courses in infectiol- Pichler K, Kattan T, Gentzsch J, Kress AK, Taylor GP, Bang- liest stages of infection. The group of Prof. A. ogy and immunology. These general infectiol- ham CR, Grassmann R (2008) Strong induction of 4-1BB, a growth and survival promoting costimulatory receptor, Ensser narrowed down transformation-relevant ogy courses have been expanded to students in HTLV-1-infected cultured and patients‘ T cells by the viral domains and the function of the herpesviral ef- of pharmaceutics, dentistry and life science Tax oncoprotein. Blood, 111: 4741-51 fector oncoprotein Tip of Herpesvirus saimiri engineering. Furthermore, our institute is in- Tavalai N, Papior P, Rechter S, Stamminger T (2008) Nuclear (H. Saimiri). H. Saimiri induces tumors in non- volved in the four-year full-time degree pro- domain 10 components promyelocytic leukemia protein human primates and, like HHV-8, belongs to gram in molecular medicine. The lectures for and hDaxx independently contribute to an intrinsic antiviral defense against human cytomegalovirus infection. J Virol, the family of rhadinoviruses. The second focus the students mediate basics of general virol- 82: 126-37 is the analysis of viral episomal replication and ogy like clinical aspects and pathogenetis of Wies E, Mori Y, Hahn A, Kremmer E, Sturzl M, Fleckenstein chromatin structure in eukaryotic cells, par- viruses, viral replication and gene regulation, B, Neipel F (2008) The viral interferon-regulatory factor-3 is ticularly in human T-cells. The group of PD viral transformation, viral vectors, immune de- required for the survival of KSHV-infected primary effusion B. Biesinger studied T-cellular signaling path- fense and antiviral therapy. In the advanced lymphoma cells. Blood, 111: 320-7 ways regulated by the viral oncoproteins StpC seminar for students of molecular medicine, International Cooperation and Tip from Herpesvirus saimiri C488 as well the students are introduced to original scien- Prof. Dr. J. Sinclair, Addenbrooke‘s Hospital, Cambridge, UK as Tio from Herpesvirus ateles. Via the regula- tific publications. The fundament of our viral tion of gene expression, DNA methylation and/ education is a F1 practical course that lasts Dr. Jeffery Kopp, Kidney Disease Section, NIDDK, NIH, Bethesda, MD, USA or histone modification have been document- four weeks. Groups of two to three students of ed to affect many biomedical processes. Prof. medicine, molecular medicine or biology work Dr. Ashok Balasubramanyam, Baylor College of Medicine, Houston, TX, USA W. Doerfler’s laboratory characterizes different under direct instruction of the team leaders on Dr. David Ott, SAIC Frederick, NCI FCRDC, NIH, Frederick, aspects of DNA-methylation in transgenic cells current research projects in the lab. Insight into MD, USA and in the human genome. the actual research project of the institute is Prof. Jae Ung Jung, Molecular Microbiology & Immunology, provided in the weekly seminar on methods in University of Southern California, Los Angeles, CA, USA molecular virology. A seminar on current topics in clinical virology is also offered weekly. For Meetings and International Training the scientific education of biology students, the Courses Institute for Virology provides a basic lecture 01.–05.09.2007: Third European Congress of Virology, Nürnberg, Germany of virology, as well as the above-mentioned F1 practical course and method seminars. Be- 17.–19.10.2008: Second International Symposium, Er- langen, Germany, GRK 592, GRK 1071, Forschergruppe side this the biology students should attend FOR 832 a couple of the special lectures like molecular and immunopathogenicity, viral and cellular Research Equipment signal transduction, strategies of viral replica- BD Biosciences Durchflusscytophometer LSR II tion, development of antiviral therapy, innate Leica konfokales Mikroskop TCS SP5 immune defense against viruses and bioinfor- ABI Prism 3100 Genetic Analyzer u. Datenbank matics. Courses for the recently introduced

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 39 Clinical Theoretical Institutes

Institute of Clinical and Molecular Virology Franz-Penzoldt-Centre of Experimental Biomedicine

Address genes on all systems within an organism. Con- Selected Publications Palmsanlage 5 sequently, the field of comprehensive pheno- von Hoersten S, Schmitt I, Nguyen HP, Holzmann C, 91054 Erlangen typing rapidly evolves and bridges a “post-ge- Schmidt T, Walther T, Bader M, Pabst R, Kobbe P, Krotova Phone: +49 9131 8523501 nomic-gap” between genomics and phenom- J, Stiller D, Kask A, Vaarmann A, Rathke-Hartlieb S, Schulz JB, Grasshoff U, Bauer I, Vieira-Saecker AM, Paul M, Jones Fax: +49 9131 8523502 ics. Due to these developments in the field, sci- L, Lindenberg KS, Landwehrmeyer B, Bauer A, Li XJ, Riess O www.fpz.uni-erlangen.de entists are frequently challenged by the task of (2003) Transgenic rat model of Huntington‘s disease. Hum detecting discrete differences in mice and rats. Mol Genet, 12: 617-24 Head of Department The Franz-Penzoldt-Centre provides all prereq- Nguyen HP, Kobbe P, Rahne H, Woerpel T, Jaeger B, Prof. Dr. med. Stephan von Hoersten uisites not only for genetic manipulations but Stephan M, Pabst R, Holzmann C, Riess O, Korr H, Kántor O, Petrasch-Parwez E, Wetzel R, Osmand A, von Hoersten S also for comprehensive phenotyping of trans- (2006) Behavioral abnormalities precede neuropathological Contact genic models for human diseases. markers in rats transgenic for Huntington‘s disease. Hum Dr. med. vet. Kerstin Raber Within several European projects and collabo- Mol Genet, 15: 3177-94 Phone: +49 9131 8523505 rations, the research group at the Section for Bode FJ, Stephan M, Suhling H, Pabst R, Straub RH, Raber Fax: +49 9131 8523502 Experimental Therapy characterizes and use KA, Bonin M, Nguyen HP, Riess O, Bauer A, Sjoberg C, Petersén A, von Hoersten S (2008) Sex differences in a [email protected] transgenic models of neurological diseases, transgenic rat model of Huntington‘s disease: decreased which are world wide unique. 17beta-estradiol levels correlate with reduced numbers of Research Focus Neurodegenerative disorders including Alz DARPP32+ neurons in males. Hum Mol Genet, 17: 2595-609 Comprehensive Phenotyping of transgenic heimer´s disease, Parkinson´s disease, as well as Forssmann U, Stoetzer C, Stephan M, Kruschinski C, Skripu- mice and rats the polyglutamine disease such Huntington´s letz T, Schade J, Schmiedl A, Pabst R, Wagner L, Hoffmann T, Kehlen A, Escher SE, Forssmann WG, Elsner J, von Hoersten S disease and Spinocerebellar ataxias can nei- (2008) Inhibition of CD26/dipeptidyl peptidase IV enhances ther be cured nor treated in a satisfactory way. CCL11/eotaxin-mediated recruitment of eosinophils in vivo. Structure of the Institution Transgenic rodent models are needed to more J Immunol, 181: 1120-7 rapidly study pathogenesis and therapeutic ap- Kruschinski C, Skripuletz T, Bedoui S, Raber K, Straub RH, The lab occupies dedicated space within the proach. Our group presently characterizes rat Hoffmann T, Grote K, Jacobs R, Stephan M, Pabst R, von Hoersten S (2008) Postnatal life events affect the severity of newly build Franz-Penzoldt-Centre (FPZ) in Er- and mouse models of HD, SCA, PD, and AD. asthmatic airway inflammation in the adult rat. J Immunol, langen, which compromises in a central animal 180: 3919-25 facility and corresponding lab space. Present- Frerker N, Raber K, Bode F, Skripuletz T, Nave H, Klemann ly a small animal-imaging centre is additional Teaching C, Pabst R, Stephan M, Schade J, Brabant G, Wedekind D, build and small animal PET is already running. Jacobs R, Joerns A, Forssmann U, Straub RH, Johannes S, Hoffmann T, Wagner L, Demuth HU, von Hoersten S (2009) In the lab we have established molecular biol- Seminars contribute to the curricula in clini- Phenotyping of congenic dipeptidyl peptidase 4 (DP4) de- ogy equipment including quantitative real time cal and experimental biomedicine including ficient Dark Agouti (DA) rats suggests involvement of DP4 PCR machine, histology lab, cell culture lab, anatomy, pharmacology, reproductive biol- in neuro-, endocrine, and immune functions. Clin Chem various microscopes including centrifuges, in- ogy, and laboratory animals sciences. We em- Lab Med, 47: 275-87 cubators etc; a dedicated rat and mouse behav- ploye modern educational technologies in sev- International Cooperation iour floor combining space for automated and eral seminars and practical courses, which also Bertrand Tavitian, EU-Projekt “RatStream”, Orsay, France classical behavioural equipment is available. have repeatedly been evaluated. The seminars Prof. A. van der Linden, Bio Imaging Lab, Universitaet Automated home-cage-phenotyping systems are part of the B.Sc./M.Sc. of Molecular Medi- Antwerpen, Belgium (TSE-Phenomaster, NewBehavior-IntelliCage) cine at Friedrich-Alexander University Erlan- Prof. Hans-Peter Lipp, Anatomisches Institut, ETH Zuerich, run since very recently. gen-Nürnberg and integrated in postgraduate Switzerland research programs. Alexander P. Osmand, Ph.D., Research Centre – Graduate School of Medicine, Universitaet Tennessee, Knoxville, USA Research Takashi Yamamura MD, PhD, Department of Immunology, National Institute of Neuroscience, Tokio, Japan Comprehensive Phenotyping of transgenic mice and rats Research Equipment The use of transgenic animal models is central TSE Systems GmbH PhenoMaster for modern biomedical research. Advances in New Behavior AG IntelliCage transgenic technology nowadays more readily allow bridging the gap from genes to physiology and behaviour. The human, rat and mouse genome projects, coupled with an impressive array of molecular genetic technologies to manipulate expression of individual genes within an organism, have provided unprecedented opportunities for investigating the influence of

40 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Franz-Penzoldt-Centre entrance

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 41 Clinical Theoretical Institutes

Institute of Experimental and Clinical Pharmacology and Toxicology Chair of Pharmacology and Toxicology

Address Research to expectations, brain specific HCN4-KOs do Fahrstrasse 17 not show absence epilepsy, but a resistance 91054 Erlangen Rhythm generation in the sinoatrial node towards seizures provoked by GABAA antago- Phone: +49 9131 8522771 Project manager: J. Stieber, S. Herrmann, A. nists. In addition we could show that HCN4 is Fax: +49 9131 8522774 Ludwig involved in the control of motor function dur- www.pharmakologie.uni-erlangen.de The role of various ion channels for the gen- ing demanding motor tasks. Head of Institute eration of rhythmic cardiac activity is studied. Prof. Dr. med. Andreas Ludwig One focus is the function of HCN pacemaker Immunological mechanisms in inflamma- channels. These channels underly the If current tory liver and kidney injury Contact and are thought to be essential for the genera- Project manager: G. Tiegs, G. Sass Prof. Dr. med. Andreas Ludwig tion of action potentials in the sinoatrial node. The group addresses immunological mecha- Phone: +49 9131 8522220 Since global deletion of HCN4-channels turned nisms and signal transduction pathways in in- Fax: +49 9131 8522774 out to be embryonic lethal, we now deleted flammatory liver and kidney disease. Based on [email protected] HCN4 selectively in the heart. If was severly TNFα- and TNFα-receptor signals which in- reduced leading to the disturbed generation duce apoptosis but also cell proliferation, liver Research Focus of action potenials and sinus pauses (Fig.). In regeneration and the expression of “survival • Rhythm generation in the sinoatrial node contrast to earlier assumptions we found that factors”, the group worked on the identifica- • HCN-channels in nociceptors and other HCN4 is not required for the sympathetic up- tion of cytoprotective liver proteins. These pro- neurons regulation of heart rate. We currently attempt teins including heme oxygenase-1 exert most- • Immunological mechanisms in inflammatory the complete deletion of sinoatrial If by gener- ly anti-apoptotic effects and are important for liver and kidney injury ating double (HCN2/4) and triple (HCN1/2/4) the protection of organ function but can also • Pharmacological imaging and image knockout mice. promote tumor growth. The RNAi-technology analysis In addition, we generated the mouse line for the knockdown of genes in vitro and in vivo HCN4-KiT by “knock-in” of a Cre recombinase was established and used to downregulate the into the HCN4 locus. By using this line we are expression of pro- and antiapoptotic proteins. Structure of the Institution able to delete any gene selectively in the sino- Another research area focused on the mecha- atrial and atrioventricular node in a temporal- nisms guiding the differentiation of adaptive The Chair of Pharmacology and Toxicology, ly controlled manner (Fig.). The line is current- tolerogenic T cells (Tregs and NKT cells) which the Chair of Clinical Pharmacology and Clinical ly used to analyse the exact mechanisms of ac- can induce immune tolerance in the liver. Toxicology and the Doerenkamp-Foundation tion potenial generation in the cardiac conduc- The group also studied interactions between professorship for Innovations in animal and tion system. We focus on the physiological role immune and nervous system in animal models consumer protection form together the Insti- of voltage-gated calcium channels and ryano- of hepatitis and nephritis. Based on the immu- tute of Experimental and Clinical Pharmacol- dine-receptors. nological mechanisms involved and the mod- ogy and Toxicology. Another project deals with the generation of ulation of these mechanisms by neuropeptides The position of executive director of the insti- arrhythmias in the hypertrophied heart. It was and neurotransmitters new approaches for im- tute rotates between the chair of Pharmacology proposed that increased activtity and upregu- munotherapy were developed. and Toxicology (Prof. A. Ludwig) and the chair lation of ventricular HCN channels contributes of Clinical Pharmacology and Clinical Toxicol- to arrhythmogenesis. We study this hypothe- Pharmacological imaging and image ogy (Prof. M. Fromm) on a two-year basis.The sis by induction of cardiac hypertrophy in HCN analysis chair has a staff of 31 employees. Research is deficient mice. Project manager: A. Hess carried out by 8 PhD graduates, 7 postgraduate The group uses non-invasive magnetic reso- student and 6 research technicians. HCN-channels in nociceptors and other nance tomography to study plastic nocicep- Main areas of research are the function of neurons tive processes in the central nervous system of various ion channels (HCN pacemaker chan- Project manager: S. Herrmann, A. Ludwig rodents. Further details can be found in the re- nels, calcium channels, ryanodine receptors) in Various ion channels are involved in the gener- port of the Doerenkamp-Foundation professor- heart, brain and dorsal root ganglions, immu- ation and transmission of painful stimuli. Sev- ship. In addition, various topics ranging from nological mechanisms in liver injury and func- eral reports suggest that HCN channels may cardiology to lipid metabolism, imaging of ves- tional MR-Imaging. These areas are explored play an important role in neuropathic and in- sels and in- vivo-tracing of marked cells are an- by combining methods from molecular biolo- flammatory pain. We found in earlier work that alysed in different cooperations (IZKF, DFG FG gy, mouse genetics, electrophysiology, immu- HCN1 and HCN2 are strongly expressed in dor- 661 Praeklinische Bildgebung, DFG KFG Post- nology and whole-animal studies. Research is sal root ganglions. We now study the exact role operativer Schmerz). The combination of non- supported by various grants from the DFG, EU of these isoforms by generation of nociceptor- invasive MR imaging with the delineation of and BMBF. In 2008 Prof. Gisa Tiegs left the in- specific deletion mutants of HCN1 and HCN2. soft-tissue contrasts and state-of-the art image stitute to take over a position as director of the We also generated a brain-specific deletion analysis proves to be highly effective and mini- unit for experimental immunology and hepa- of HCN4. In thalamocortical neurons of these mizes animal stress. tology at the University Medical Centre Ham- mice, Ih was reduced by about 50 %. Contrary burg-Eppendorf.

42 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Teaching

Pharmacology and Toxicology is taught to medical students, students of molecular medicine and pharmacy students. The pharmacology course for medical students consists of lectures and a problem-based small group tutori- sinoatrial node al. Students of molecular medicine are trained aorta by lectures, a seminar focusing on the molecular mechanisms of drug actions and laboratory internships. In addition, the chair provides the complete training in pharmacology for pharmacy students (as required to acquire the license to practice pharmacy). This includes lectures covering pharmacology and pathophysiology, seminars and laboratory internships.

Selected Publications Erhardt A, Biburger M, Papadopoulos T, Tiegs G (2007) IL- lf(HCN4) 10, regulatory T cells, and Kupffer cells mediate tolerance sinus pauses in concanavalin A-induced liver injury in mice. Hepatology, 45: 475-85 Herrmann S, Stieber J, Stoeckl G, Hofmann F, Ludwig A (2007) HCN4 provides a ‚depolarization reserve‘ and is not required for heart rate acceleration in mice. EMBO J, 26: 4423-32 David R, Brenner C, Stieber J, Schwarz F, Brunner S, Vollmer M, Mentele E, Mueller-Hoecker J, Kitajima S, Lickert H, Rupp R, Franz WM (2008) MesP1 drives vertebrate cardiovascular sinoatrial node - specific. wild type differentiation through Dkk-1-mediated blockade of Wnt- HCN4-knockout signalling. Nat Cell Biol, 10: 338-45 Hoesl E, Stieber J, Herrmann S, Feil S, Tybl E, Hofmann F, Feil Temporally controlled gene deletion in the sinoatrial node R, Ludwig A (2008) Tamoxifen-inducible gene deletion in Top, A target gene is deleted selectively in the sinoatrial node after administration of tamoxifen to HCN4- the cardiac conduction system. J Mol Cell Cardiol, 45: 62-9 KiT mice. Blue staining indicates successful recombination (left, whole-mount; right, section). Middle, Lack of HCN4 channels in the sinoatrial node results in disturbed action potential generation and sinus Knabl J, Witschi R, Hoesl K, Reinold H, Zeilhofer UB, Ahmadi pauses. Bottom, Diagram of proposed mechanism. HCN4-deficient animals have difficulties counter- S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy JM, balancing hyperpolarizing currents. Rudolph U, Moehler H, Zeilhofer HU (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature, 451: 330-4

Ludwig A, Herrmann S, Hoesl E, Stieber J (2008) Mouse International Cooperation Meetings and International Training models for studying pacemaker channel function and sinus Courses node arrhythmia. Prog Biophys Mol Biol, 98: 179-85 Prof. Kenneth Chien, Harvard Medical School, Boston, USA 01.08.2008: DFG Forschergruppe 923 – Molecular Dissec- Prof. L. Cervetto, Dipartimento di Scienze Fisiologiche, tion of Cardiovascular Functions, Erlangen Università di Pisa, Italy Dr. Ming Lei, Cardiovascular Research Group, University of Research Equipment Manchester, Great Britain Bruker 4,7 Tesla Kleintier-MRT G. Fishman, MD, Division of Cardiology, NYU Department Zeiss Konfokales Laserscanning-Mikroskop LSM 5 of Medicine, New York, USA Prof. Jeffrey Holt, Department of Neuroscience, University of Virginia, Charlottesville, USA

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 43 Clinical Theoretical Institutes

Institute of Experimental and Clinical Pharmacology and Toxicology Chair of Clinical Pharmacology and Clinical Toxicology

Address The following topics, which are funded e.g. and OATP1B3-mediated pravastatin uptake. Fahrstrasse 17 by the German Research Council (DFG) and In vivo, this reduced hepatic uptake may lead 91054 Erlangen the German Cancer Aid, are in the focus of to elevated pravastatin plasma concentrations Phone: +49 9131 8522772 our studies: uptake and efflux transporters for with an increased risk of adverse drug reac- Fax: +49 9131 8522773 drugs, genetic determinants of drug effects tions. A second study showed that frequently www.pharmakologie.uni-erlangen.de (pharmacogenomics), drug metabolism (cyto- prescribed oral antidiabetic drugs inhibit OATP- Head of Institute chrome P450 enzymes), drug uptake in tumors, mediated pravastatin uptake. Prof. Dr. med. Martin F. Fromm cardiovascular pharmacology and risk factors, alterations of the L-arginine-NO-metabolism. Expression and function of uptake trans- Contact porters in gastrointestinal tract Prof. Dr. med. Martin F. Fromm Project manager: H. Glaeser, M. F. Fromm Phone: +49 9131 8522772 Research The knowledge on the importance of OATP up- Fax: +49 9131 8522773 take transporters for drug transport, physiolo- [email protected] Molecular characterization of drug gy and pathophysiology in the human gastro- transporters intestinal tract is still limited. Therefore, stud- Research Focus Project manager: J. Koenig, M. F. Fromm ies regarding the expression and function of • Molecular characterization of drug trans- Transporter proteins located in distinct plas- OATPs in human stomach and intestine were porters ma membrane domains are important for up- performed. In collaboration with the University • Expression and function of uptake transport- take, distribution and excretion of drugs and of Kentucky, (Lexington, KN, USA), the Univer- ers in gastrointestinal tract drug metabolites. Therefore, modulation of sity of Western Ontario (London, Ontario, Can- • Pharmacogenetics of cardiovascular drugs transport function may result in adverse drug ada) and the Vanderbilt University (Nashville, • Molecular and clinical characterisation reactions (ADR). Two molecular mechanisms TN, USA; Prof. W. Lee und Prof. R. B. Kim) the of therapeutic targets in the can account for such modulations of transport expression of the OATP1B3 in multiple colon L-arginine-NO-nitrate pathway function. First, variations in transporter genes carcinoma samples was detected. Moreover, (polymorphisms) may result in mutated trans- OATP1B3 mediated apoptosis resistance in sev- porter proteins with altered transport kinet- eral colon carcinoma cell lines after treatment Structure of the Institution ics. Second, one drug can influence the trans- with the antineoplastic agents oxaliplatin and port kinetics of a second coadministered drug camptothecin. The Chair of Clinical Pharmacology and Clini- if both are substrates for one transport pro- A further member of the human OATP-family cal Toxicology forms together with the Chair tein (transporter-dependent drug-drug inter- is the prostaglandin transporter OATP2A1. The of Pharmacology and Toxicology and the Do- actions). The molecular characterizations of transport of prostaglandins from the extracel- erenkamp-Professorship of Innovations in Ani- both processes are in the focus of our studies. lular space to the cytosol by OATP2A1 contrib- mal and Consumer Protection the Institute of Organic Anion Transporting Polypeptide 1B1 utes to the termination of prostaglandin ef- Experimental and Clinical Pharmacology and (OATP1B1) is an important uptake transport- fects. In collaboration with the Institute of Pa- Toxicology. The position of the executive direc- er located in the basolateral hepatocyte mem- thology (Prof. K. U. Amann, Dr. T. Rau) it was tor of the Institute rotates between the Chair brane mediating the uptake of several endoge- possible to show the localization of OAT2A1 in of Pharmacology and Toxicology (Prof. A. Lud- nous compounds and drugs from the portal ve- parietal cells and deep glands of corpus and an- wig) and the Chair of Clinical Pharmacology nous blood into the liver. In a cooperation with trum of human stomach, respectively. Further- and Clinical Toxicology (Prof. M. Fromm) on a the University of Greifswald we could demon- more, using OATP2A1-overexpressing cell lines two-year basis. strate that the cholesterol-lowering drug ezet- we were able to demonstrate that NSAIDs (non 35 persons are working at the Chair with 10 of imibe inhibited OATP1B1-mediated uptake and steroidal anti-inflammatory drugs) can stimu- them being funded by extramural sources. In that the metabolite ezetimibe-glucuronide is a late or inhibit the function of OATP2A1. Such July 2008 a Professor of Clinical Pharmacology substrate of this transporter. Furthermore, we functional modifications may contribute to (W2) was appointed. Research is conducted by have demonstrated that a frequent polymor- NSAID-induced side effects such as ulcerations 6 scientists with 4 of them being specialists in phism of the OATP1B1 protein (variant OAT- or bleeding in the human gastric mucosa. clinical pharmacology, 10 MD or PhD students P1B1*5) is associated with reduced uptake rates and 10 technicians. for ezetimibe-glucuronide compared to the Pharmacogenetics of cardiovascular drugs The groups at the Chair of Clinical Pharmacol- wild type protein. These results are in agree- Project manager: O. Zolk, M.F. Fromm ogy and Clinical Toxicology investigate mech- ment with results from a clinical study con- Cardiovascular diseases are the most common, anisms underlying interindividual differences ducted in parallel. and cardiovascular drugs belong to the most in drug effects using molecular and cellular bi- OATP1B1, together with the OATP family mem- frequently prescribed drugs. Their use contrib- ology as well as clinical studies. The Chair has bers OATP1B3 and OATP2B1 that are also ex- utes to reduced mortality from cardiovascular excellent opportunities for drug analytics and pressed in human hepatocytes were in the events, for example dual antiplatelet inhibition a clinical trial unit. In addition, a drug informa- focus of studies investigating transporter-me- with ASS and clopidogrel significantly reduces tion service is available for the physicians of the diated drug-drug interactions. First, we could the risk of fatal coronary stent thrombosis after University Hospital and for external physicians. demonstrate that macrolides inhibit OATP1B1- PCI. However, there are marked differences in

44 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) the treatment effects between individual patients with treatment failure or enhanced toxicity occurring in some patients. In this project genetic variations in genes involved in drug transport or metabolism that cause interindividual differences in response to cardiovascular drugs are investigated. In a collaborative project with the Heart Centre Bad Krozingen the as- Expression of the human uptake transporter OCT2 (green) in HEK293 cells sociation of polymorphisms in drug transporters and cytochrome P450 enzymes with the inhibitory effect of clopidogrel on platelet aggregation was investigated. Another study focused on the impact of gender and genetic differences in genes involved failure in cardiovascular medicine, with a spe- Lieb W, Benndorf RA, Benjamin EJ, Sullivan LM, Maas R, in transport and metabolism of drugs on the cial focus on the prevention of thromboembol- Xanthakis V, Schwedhelm E, Aragam J, Schulze F, Boeger RH, Vasan RS (2009) Plasma asymmetric dimethylarginine, pharmacokinetics of the diuretic torasemide. ic events. Related health services research proj- L-arginine and left ventricular structure and function in Moreover, in a collaborative project with the ects are directed at real life problems in trans- a community-based sample. Atherosclerosis, 204: 282-7 Department of Medicine 4 – Nephrology and lating knowledge and implementing guidelines Hypertensiology (University Hospital Erlangen) into clinical practice. International Cooperation we investigate a potential association of poly- Prof. Carmine Zoccali, Renal Dialysis Transplantation and morphisms in catecholamine transporter genes Hypertension Unit & Institute of Bio-Medicine of the Na- with the diagnosis of essential hypertension. Teaching tional Research Council, Reggio Calabria, Italy Prof. Ramachandran Vasan, Framingham Heart Study, USA Molecular and clinical characterisation The Chair coordinates the interdisciplinary lec- Prof. Jean-Luc Cracowski, INSERM Grenoble, France of therapeutic targets in the ture series and seminar Clinical Pharmacology L-arginine-NO-nitrate pathway / Pharmacotherapy for medical students apply- Research Equipment Project manager: R. Maas ing problem-based learning. In addition, we Applied Biosystems API 4000 MS/MS System Package A major focus of the group is the experimental teach students of dental medicine, molecular Zeiss LSM 5 Pascal and clinical characterization of new cardiovas- medicine, pharmacy and medical process man- cular risk factors as potential targets for ther- agement in Clinical Pharmacology by lectures, apeutic interventions. Presently we study the seminars and practical exercises. Students of regulation of the L-arginine-NO-nitrate path- pharmacy are welcome to work with us during way by endogenously formed compounds such their final year. as ADMA and L-NMMA and the metabolic fate of these compounds. For in vitro and in vivo investigations new isotope- and mass spectrom- Selected Publications etry-based methods are developed. In a DFG Zolk O, Jacobi J, Pahl A, Fromm MF, Schmieder RE (2007) funded project and in cooperation with col- MDR1 genotype-dependent regulation of the aldosterone leagues at the Department of Medicine 4 – Ne- system in humans. Pharmacogenet Genomics, 17: 137-44 phrology and Hypertensiology (University Hos- Bachmakov I, Glaeser H, Fromm MF, Koenig J (2008) pital Erlangen) we investigate the biologic ef- Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypep- fects of disturbed methylarginine metabolism tides and organic cation transporter 1. Diabetes, 57: 1463-9 on vascular function in animal models and ex- Gradhand U, Lang T, Schaeffeler E, Glaeser H, Tegude H, perimental studies. The experimental inves- Klein K, Fritz P, Jedlitschky G, Kroemer HK, Bachmakov I, tigations are complemented by clinical and Anwald B, Kerb R, Zanger UM, Eichelbaum M, Schwab population-based studies performed in coop- M, Fromm MF (2008) Variability in human hepatic MRP4 expression: influence of cholestasis and genotype. Pharma- eration with the Department of Medicine 2 – cogenomics J, 8: 42-52 Cardiology and Angiology and international Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Har- partners at the Framingham Heart Study (USA) ris EI, Washington MK, Brunt EM, Zaika A, Kim RB, El-Rifai and at the Institute of Bio-Medicine of the Na- W (2008) Overexpression of OATP1B3 confers apoptotic tional Research Council (Italy). With these part- resistance in colon cancer. Cancer Res, 68: 10315-23 ners we presently investigate causes and long Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, term clinical effects of elevated plasma con- Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, Buettner HJ, Neumann FJ (2008) Cytochrome P450 2C19 681G>A centrations of ADMA and related substances. polymorphism and high on-clopidogrel platelet reactivity In further projects we study genetic and bio- associated with adverse 1-year clinical outcome of elective chemical/pharmacological causes of treatment percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol, 51: 1925-34

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 45 Clinical Theoretical Institutes

Institute of Experimental and Clinical Pharmacology and Toxicology Doerenkamp-Chair of Innovations in Animal and Consumer Protection

Address Research Development of cell culture systems to Krankenhausstrasse 9 detect new drugs 91054 Erlangen Analgesics and anti-rheumatics These projects lead to the funding of two large Phone: +49 9131 8522293 Cyclooxygenase (COX) inhibitors (analgesics, pieces of equipment, i.e. the total remodelling Fax: +49 9131 8526898 anti-rheumatics) are the most widely used and modernisation of the existing animal MRT www.pharmakologie.uni-erlangen.de/ drugs. They are effective, but also prone to as well as the funding of a modern MRT-im- doerenkamp cause unwanted drug effects. Together with proved resolution. Head of Institute B. Hinz, we analysed PK/PD of the most com- Together with PD Dr. Pahl we tried to develop mon drugs, including acetaminophen, aspirin, cell culture systems to detect new drugs, possi- Prof. Dr. med. Dr. h.c. Kay Brune diclofenac, etoricoxib, ibuprofen, lumiracoxib, bly useful in chronic obstructive pulmonary dis- Contact etc. by applying an ex vivo technique in volun- ease (COPD). The work lead to the employment Ursula Niederweis, M.A. teers. We could show that acetaminophen is a of PD Dr. Pahl as head of a research group with Phone: +49 9131 8522293 selective (preferential) inhibitor of COX-2, as- Nycomed, Hamburg. Due to the change of em- Fax: +49 9131 8526898 sociated with unrelated serious hepatotoxicity. ployment of PD Dr. Pahl, this approach will not [email protected] The data accrued are presently used as argu- be persued further within the next years. ments to eliminate acetaminophen from the Finally, the chairholder was and still is engaged Research Focus OTC-market. in many research and pharmaco-political ac- • Analgesics and anti-rheumatics We found that most new and old inhibitors are tivities. Some of the insights gained have re- • Non-invasive functional imaging chronically overdosed in most patients. With sulted in essays related to health politics, sci- • Development of cell culture systems to the aid of our ex vivo PK/PD, analysing con- ence in Europe and animal protection (see also detect new drugs cepts for tissue, toxicity sparing doses were publications). developed. The analysis of older drugs, including (aside of Structure of the Institution acetaminophen) metamizol (dipyrone), showed Teaching that dipyrone is overdosed under clinical con- This professorship is one of three full professor- ditions. The engagement of Prof. Brune as speaker at in- ships implemented at the Institute of Experi- Recently, COX-inhibitors were shown to cause ternational conferences, his membership in sev- mental and Clinical Pharmacology and Toxicol- cardiac infarctions and accelerated arthero- eral administrative bodies and advisory struc- ogy. The acting directorship is rotating among sclerosis in certain patients. Using NTproBNP, tures has led to many additional invitations to the professors. a new biomarker, we could show that deter comment on timely problems of drug therapy The Doerenkamp professorship will be ending ming the NTproBNP level is helpful in singling in man. In addition, Prof. Brune is engaged in on 31 March 2011. Funds, donated by the per- out patients at risk. the production of many national and interna- son the professorship is named after, are used Finally, it is helpful to connect individual data of tional guidelines, textbooks, etc. A sample of to finance the chair holder, one administrative/ patients in the clinic of internal medicine with publications related to these activities is to be academic management person and up to three information about the drugs applied in order to on the homepage of the Department. academic co-workers. In addition, there is close detect unwanted drug effects in time. collaboration of this chair with researchers of the other two professorships. Together with Non-invasive functional imaging these senior scientists, grants finance up to Non-invasive functional imaging employing 4 post-doctoral and 6 doctoral collaborators. magnet resonance tomography in rats and The research goals of the Doerenkamp profes- mice demonstrated that nociceptive inputs in sorship are persued in close collaboration with experimental animals can be detected, local- Prof. Dr. Burkhard Hinz (formerly senior scien- ized and quantified despite the fact that the tist at the institute, presently chairman of the animals are in anaesthesia. Consequently, this Department of Toxicology and Pharmacology approach allows for measuring antinociceptive at the University of Rostock), PD Dr. Andreas effects, locating new pathways of pain pro- Pahl (formerly member of the Chair of Phar- cessing in the brain of mammals and defining macology and Toxicology, presently head of new targets for pain therapy, in particular for research division of Nycomed, Hamburg), and chronic pain. This approach has been applied PD Dr. Andreas Hess (member of the Chair of successfully to rats and is presently also used in Pharmacology and Toxicology at the institute). genetically modified strains of mice allowing to In collaboration with these senior co-workers, define the role of distinct pain mediators and the following results were achieved. their antagonists in nociception (figure).

46 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Fig.: Activation of the pain matrix of the mouse, rat and man following the applica- Haeupl T, Burmester GR, Giannitsis E, Rohrlach T, Spanuth tion of a nociceptive stimulus to the skin E, Parsch H, Brune K (2007) N-terminal prohormone brain Despite the differences in size (comp. 1 cm), it is natriuretic peptide: a biomarker for detecting cardiovascular evident that similar brain structures are activated risks in patients with rheumatoid arthritis or osteoarthritis? Ann Rheum Dis, 66: 838-9 by the stimulus. The development of highly sensitive fMRI-technology is the basis of non-invasive Hinz B, Cheremina O, Bachmakov J, Renner B, Zolk O, pain research in rodents. The options of this tech- Fromm MF, Brune K (2007) Dipyrone elicits substantial nology are further enhanced by the use of genetic inhibition of peripheral cyclooxygenases in humans: new modifications of the mouse genome. a: mouse, insights into the pharmacology of an old analgesic. FASEB b: rat, c: man J, 21: 2343-51 Puljic R, Benediktus E, Plater-Zyberk C, Baeuerle PA, Szelenyi S, Brune K, Pahl A (2007) Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF. Eur J Pharmacol, 557: 230-5 Brune K, Katus HA, Moecks J, Spanuth E, Jaffe AS, Giannit- sis E (2008) N-terminal pro-B-type natriuretic peptide concentrations predict the risk of cardiovascular adverse events from antiinflammatory drugs: a pilot trial. Clin Chem, 54: 1149-57 Hinz B, Cheremina O, Brune K (2008) Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J, 22: 383-90 Knabl J, Witschi R, Hoesl K, Reinold H, Zeilhofer UB, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy JM, Rudolph U, Moehler H, Zeilhofer HU (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature, 451: 330-4

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 47 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Institute of Human Genetics Chair of Human Genetics Clinical Theoretical Institutes

Address Research of a DFG-funded project they now investigated Schwabachanlage 10 the cellular and systemic effects resulting from 91054 Erlangen Molecular basis of monogenic traits and a loss of UBR1 enzyme activity. In addition, the Phone: +49 9131 8522318 genotype-phenotype correlation group was able to identify SOS1 as the second Fax: +49 9131 8523232 Project manager: A. Reis, A. Rauch, M. Zenker most common gene affected in Noonan syn- www.humangenetik.uk-erlangen.de The main scientific focus of the institute is the drome and was able to publish several findings Head of Institute elucidation of the molecular basis of inherited on a genotype-phenotype correlation for this Prof. Dr. med. André Reis disease. Major approaches used include posi- disease. Dr. Kraus and her group worked on the aetiology and pathogenesis of neuromuscu- Contact lar disorders using the mdf mouse as a model. Prof. Dr. med. André Reis During the report period the group identified Phone: +49 9131 8522318 mutations in the Scyl1 gene as the cause of Fax: +49 9131 8523232 this murine phenotype in collaboration with [email protected] Prof. Bittner. Research Focus Genetics of complex diseases • Molecular basis of monogenic traits and Project manager: A. Reis genotype-phenotype correlation Complex and multifactorial diseases are caused • Genetics of complex diseases by a combination of mostly unknown envi- • Developmental genetics ronmental and genetic factors. The group of Prof. André Reis carries out genetic association Cell division in a healthy human fibroblast cell line: the studies with large patient cohorts, especial- Structure of the Institution pericentrin protein, which is missing in MOPDI patients ly for psoriasis vulgaris, psoriatic arthritis and is marked in red, chromosomal material green in blue glaucoma with and without pseudoexfoliation The Institute is active in teaching, research and and spindle fibers, which are formed properly during syndrome. The projects were funded within anaphase, in green. health care. At the end of 2008 a total of 64 the Collaborative Research Centre (SFB) 539 persons were working at the Institute: 19 scien- (glaucoma and pseudoexfoliation syndrome) tists (natural scientists and physicians), 13 PhD- and the IZKF. In collaboration with partners students, 24 technical and administrative em- tional cloning strategies and the detection of from England and the Netherlands the group ployees and 8 graduate students. 25 colleagues copy number variations using molecular karyo- was able to demonstrate a significant associ- were funded through grants. The Institute runs typing. Using the latter strategy the group of ation between an increased copy number of a genetic clinic for ambulatory care and ge- Prof. Rauch recently identified the molecular the β-defensin gene cluster on chromosome 8 netic counselling of patients as well as diag- cause of Pitt-Hopkins syndrome, a severe form and the risk to develop psoriasis. Moreover, the nostic laboratories for highly specialised cyto- of mental retardation with characteristic respi- group performed several association studies for genetic and molecular genetics investigations. ratory apnea. In the context of the BMBF proj- psoriatic arthrtitis in functional and position- Research activities are organised in 5 research ect “rare diseases network: skeletal dysplasia al candidate genes. For secondary glaucoma groups. Members of the Institute participate in (SKELNET)” the group also identified the mo- with pseudoexfoliation the group was able to various collaborative research groups (SFBs and lecular defect in MOPD II (microcephalic os- replicate an association of common polymor- “Forschergruppen”). The head of institute Prof. teodysplastic primordial dwarfism type II).T his phism in the LOXL1 gene (originally described Reis coordinates a collaborative research net- disease is characterized by the most extreme in Scandinavian patients) also in German and work on the genetic basis of mental retardation form of short stature in man. Patients are viable Italian patients and to recognise it as predispos- (MRNET) funded by the Federal Ministry of but their final height ranges between 70 and ing to exfoliation syndrome rather than glau- Research (BMBF) within the National German 90 cm. Using linkage studies the group discov- coma. In collaboration with Prof. Schloetzer- Genome Research Network (NGFNplus). He ered biallelic loss-of-function mutations in the Schrehardt (Department of Ophthalmology) is also the Speaker of Interdisciplinary Centre centrosomal pericentrin gene on chromosme the involvement of the LOXL1 gene product for Clinical Research (IZKF) at the Medical Fac- 21 (figure) underlying this disorder. In addition, in disturbed fibrogenesis, the primary cause of ulty. In addition, he was elected in 2008 presi- using homozygosity mapping they succeeded the disease, could be demonstrated. dent of the German Society of Human Genet- in collaboration with the group of Prof. Reis to ics (GfH). The Institute runs 2 IZKF-core units, identify mutations in the STRA6 gene under- Developmental genetics “Z3 Genomic Platform” for microarray analysis lying Mathew-Woods syndrome, a pleiotropic Project manager: A. Winterpacht and “Z4 DNA Extraction Platform (Biobank)”; malformation syndrome with anophthalmia. The group is interested in the molecular basis of for quality controlled DNA extraction of blood The group of PD Dr. M. Zenker mainly focus- developmental processes and their individual samples especially for clinical studies. es on the molecular basis of the Johanson-Bliz- variability. This includes elucidation of regula- zard (JBS) and the Noonan syndromes. Previ- tory networks of organogenesis and cell differ- ously the group had identified mutations in the entiation as well as the identification of variants UBR1 gene as the cause of JBS. In the context in specific components of these networks. For

48 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) most of the projects the group works on mouse Teaching International Cooperation or chicken as model organisms. The projects Prof. John Armour, Institute of Genetics, University of comprise work on: 1. the skeletal system, which The Institute is involved in curricular teach- Nottingham, UK aims at the global and systematic identification ings at the medical school and in the diploma, Prof. Yves Barde, Biozentrum, University of Basel, Swit- and molecular characterisation of novel genes bachelor- and master programmes in molecu- zerland and gene networks involved and cartilage/ lar medicine as well as biology and molecular Dr. Anne Barton, arc-Epidemiology Unit, University of bone formation. In the context of this proj- and cellular biology, respectively. During the Manchester, UK ect UCMA, a novel secreted factor and highly report period 17 diploma theses in biology and Prof. Reginald Bittner, Centre of Anatomy and Cell Biology, specific marker of distal chondrocytes, could molecular medicine were finished at the insti- Neuromuscular Research Department, Medical University of Vienna, Austria be identified, which probably plays an impor- tute. In addition doctoral theses in medical and tant role in early stages of chondrocyte differ- natural sciences were supervised. Prof. Marco Tartaglia, Istituto Superiore di Sanità, Università La Sapienza, Rome, Italy entiation. 2. the nervous system, where the group focuses on cognitive processes, which Meetings and International Training were investigated using the example of Wolf- Selected Publications Courses Hirschhorn syndrome. In addition, in collabora- 15.–17.06.2007: “Cardinal symptoms in differential di- Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach agnosis of syndromal disorders”. 16. Symposium of the tion with the Departments of Anaesthesiology G, Fitzpatrick DR, Nuernberg G, Brasch F, Schirmer-Zim- Arbeitsgemeinschaft Klinische Genetik in der Paediatrie, mermann H, Tolmie JL, Chitayat D, Houge G, Fernández- and Surgery the group worked on the identifi- (Chairperson Prof. Anita Rauch), Kloster Banz, Arbeitsge- Martínez L, Keating S, Mortier G, Hennekam RC, von der cation of susceptibility genes for post-operative meinschaft Klinische Genetik in der Paediatrie Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, pain perception. This work is supported by the Nuernberg P, Reis A, Rauch A (2007) Mutations in STRA6 DFG in the context of the “Klinische Forscher- cause a broad spectrum of malformations including anoph- Research Equipment gruppe 130 (KFO 130)”. 3. tumor development thalmia, congenital heart defects, diaphragmatic hernia, Applied Biosystems DNA-Sequenzierautomat alveolar capillary dysplasia, lung hypoplasia, and mental and progression, where the group investigated retardation. Am J Hum Genet, 80: 550-60 Affymetrix Genomik-Chip-Plattform the novel gene SPOC1 (PHF13). Expression of Schmidt WM, Kraus C, Hoeger H, Hochmeister S, Ober- SPOC1 in tumours is associated with survival ndorfer F, Branka M, Bingemann S, Lassmann H, Mueller time in patients with ovarian cancer. The group M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE was able to show that the gene plays a role in (2007) Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar germ cell development. neurodegeneration. EMBO Rep, 8: 691-7 Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton- Smith J, Reardon W, Saraiva J, Cabral A, Gohring I, Devriendt K, de Ravel T, Bijlsma EK, Hennekam RC, Orrico A, Cohen M, Dreweke A, Reis A, Nurnberg P, Rauch A (2007) Haploinsuf- ficiency ofT CF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet, 80: 994-1001 Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D, van de Kerkhof PC, Traupe H, de Jongh G, den Heijer M, Reis A, Armour JA, Schalkwijk J (2008) Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet, 40: 23-5 Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Doerfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Doerr HG, Reis A (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science, 319: 816-9 Tagariello A, Luther J, Streiter M, Didt-Koziel L, Wuelling M, Surmann-Schmitt C, Stock M, Adam N, Vortkamp A, Winterpacht A (2008) Ucma--A novel secreted factor represents a highly specific marker for distal chondrocytes. Matrix Biol, 27: 3-11

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 49 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Institute of Forensic Medicine Chair of Forensic Medicine

Address performed in body fluids of dead and living Study on the incorporation of drugs in Universitaetsstrasse 22 persons. Many findings are used in diagnos- hair – comparison between consumers and 91054 Erlangen tic procedures and for the control of therapies job-related exposition Phone: +49 9131 8522272 applied by different hospitals as well as medi- Project manager: G. Eckardt Fax: +49 9131 8522274 cal practices. Hair analysis is a well established procedure for www.recht.med.uni-erlangen.de a variety of problems, such as retrospective es- Head of Institute timation of criminal responsibility, evidence of abstinence but also for the evidence of han- Prof. Dr. med. Peter Betz Research dling of drugs. However, the significance of Contact Comparison of laser and mercury-arc lamp hair analysis results, especially for the differen- PD Dr. med. Thomas Lederer for the detection of body fluids on differ- tiation between past drug abuse and external Phone: +49 9131 8522294 ent substrates contamination remains controversal. Fax: +49 9131 8522272 Project manager: S. Seidl All in all 24 hair samples of persons with job- [email protected] The performance of two detection techniques related contact to drugs were collected and for body fluids, theS pectra-Physics Reveal por- analyzed parallel to hair samples of drug con- Research Focus table forensic laser system and the mercury- sumers. • Comparison of laser and mercury-arc lamp arc lamp Lumatec Superlite 400, was evaluat- All samples were decontaminated and the de- for the detection of body fluids on different ed with various biological stains on different contamination solution as well as the crushed substrates substrates. Serial dilutions of neat, 1/10, 1/100 hair material were analyzed with gas chroma- • Impairment of driving skills after intravenous and 1/1,000 using fluid semen, saliva, urine tography/ mass spectroscopy (GC-MS) for res- administration of propofol and blood were applied on glazed tiles, glass, idues of cannabinoids, amphetamines, benzo- • Study on the incorporation of drugs in PVC, wood, metal, stone, formica, carpet and ylecgonin and opiates. The ratios between the hair – comparison between consumers and cotton. Apart from the fact that blood traces absolute amount of substance in the hair sam- job-related exposition were not detectable with the laser, both light ple itself and in the decontamination solution • Development and validation of PCR-multi- sources showed comparable results regarding were compared. An external contamination plex systems for forensic DNA analysis their detection capability. Clear advantages of leads usually to lower concentrations in the the Lumatec Superlite 400, however, are its hair, but the applied methods did not allow a lower size, weight and purchase costs as well definite differentiation between external con- Structure of the Institution as the possibility to operate this light source tamination and drug consume. Although an es- by battery. timation by trend could be possible. The Institute of Forensic Medicine with its divisions forensic medicine, forensic genetics and Impairment of driving skills after intrave- Development and validation of PCR-multi- forensic toxicology belongs to the clinical the- nous administration of propofol plex systems for forensic DNA analysis oretical institutes of the Friedrich-Alexander Project manager: S. Seidl Project manager: T. Lederer University. Beside responsibilities in the field of The severity and duration of cognitive perfor- Since the beginning of the development of mo- research and education official expertises are mance capacity deficits after intravenous ad- lecular methods for forensic stain analysis and made for other medical facilities and by order ministration of propofol were determined using paternity testing in 1985, in particular the PCR- of justice, prosecution and police authorities in the validated psychological test procedure SKT based typing of STR-polymorphisms has been the North Bavarian region. Moreover – even (Syndrome Short Test), a simple reaction test spread around the world. Not only due to a though less frequently – services are offered and original driving license exam questions. large number of successful investigations which to private persons, lawyers, probation officers The test battery was performed before, imme- can be put down to the establishment of na- and insurance companies. Predominantly, ex- diately after as well as 1 and 2 h after propo- tional and international databases, DNA analy- pertises are related to forensic investigations fol administration in 23 persons. Immediately sis can be regarded as an indispensable tool in on injury patterns including crime reconstruc- after propofol anaesthesia, 6 individuals had a forensic casework analysis. In 1998, the feder- tion in the case of home violence, child abuse slight performance loss and 4 subjects showed al criminal police office of Germany (BKA) es- and criminal assault. In the case of deceased mild deficits, consistent with medium organic tablished a central genetic database of offend- the expertises include statements on the cause neuropsychologic disorder or dementia. The ers and suspects to facilitate comparisons with of death as well as on specific questions (acci- status of the subjects rapidly changed for the biological samples of future criminal offences. dent? suicide? homicide?). Genetic analyses are better and 2 h after propofol anaesthesia only In our recent work a variety of PCR-mutliplex carried out for clarification of personal identi- one person (4%) showed slight deficits of mem- systems were established which allow the sity, for the individual assignment of biological ory and attention. Therefore it is suggested that multaneous amplification of up to 12 autoso- specimen and in paternity cases. Toxicological patients refrain from any participation in road mal STR markers. It could be shown that all analyses are done to ascertain poisoning and to traffic for at least 2 h after propofol anaesthe- multiplexes are robust and reliable typing tools evaluate personal capacities at a definite time sia. Driving a car should not be admitted until for a diversity of forensic specimen and are well (fitness to drive? criminal responsibility?). The an interval of 6 h has elapsed. suited in the case of paternity testing. determination of the alcohol concentration is

50 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) It has already been mentioned that national and international databases for genetic profiles and a cross-national usage of these data are an important tool of investigations by the police. A European-wide standardization and extension of the respective databases as well as the establishment of new typing systems is in the focus of current discussions and developments. Therefore, within our work the existing multiplex systems should be expanded by five more STR-loci (“European recommended loci”). Fur- thermore, population data of the new markers should be surveyed. Beside autosomal polymorphisms gonosomal localized systems play an upcoming role in the forensic diagnostic. In particular y-chromosom- Selective preparation of spermatozoa by laser-catapulting al DYS-systems have to be mentioned in this context. These systems are well qualified for stain and paternity testing. However, the basis of a further distribution of these systems will be the establishment of worldwide databases containing haplotype frequencies and the development of PCR-multiplex systems. By that reason different analysis-systems for these mark- Selected Publications ers were established. Hausmann R, Seidl S, Betz P (2007) Hypoxic changes in Purkinje cells of the human cerebellum. Int J Legal Med, 121: 175-83 Teaching Lederer T, Braunschweiger G (2007) Commentary on: Coble MD, Butler JM. Characterization of new miniSTR loci to aid analysis of degraded DNA. J Forensic Sci 2005;50:43-53. J The Institute of Forensic Medicine performs Forensic Sci, 52: 493; author reply 494 the education given by the by the Statutes of Peters AS, Schwarze B, Tomandl B, Probst-Cousin S, Lang the medical act (AeAppO) for students residing CJ, Hilz MJ (2007) Bilateral striatal hyperintensities on dif- in the clinical part of the study course human fusion weighted MRI in acute methanol poisoning. Eur J medicine. This includes lectures, seminars and Neurol, 14: e1-2 specific activities. In addition, courses are held Seidl S, Hausmann R, Neisser J, Janisch HD, Betz P (2007) Severity and duration of mental deficiency symptoms after for students of the faculty of justice and the intravenous administration of propofol. Int J Legal Med, faculty of natural sciences as well as for medi- 121: 281-5 cal students from the University of Regensburg. Lederer T, Braunschweiger G, Dunkelmann B, Betz P (2008) Although research associations with other fa- Characterization of two unusual allele variants at the STR cilities of the university do not exist in the clas- locus ACTBP2 (SE33). Forensic Sci Med Pathol, 4: 164-6 sical sense due to the specific character of the Seidl S, Hausmann R, Betz P (2008) Comparison of laser subject “forensic medicine”, many smaller co- and mercury-arc lamp for the detection of body fluids on different substrates. Int J Legal Med, 122: 241-4 operations with clinical and theoretical disciplines are maintained. Furthermore students Research Equipment are welcome during the whole year to sit in on Applied Biosystems DNA Sequencer autopsies, court trials and practical courses in the field of forensic analytic.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 51 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine Chair of Occupational and Social Medicine

Address German Research Foundation (DFG). The insti- All the scientific projects focussing on skin pen- Schillerstrasse 25/29 tute also houses the scientific offices of these etration examine influence factors to dermal 91054 Erlangen work groups. penetration by using in vitro models (static dif- Phone: +49 9131 8522312 Next to this the institute is in charge of Ger- fusion chamber, microdialysis on freshly ex- Fax: +49 9131 8522317 man External Quality Assessment Scheme (G- cised human skin) and in vivo models (micro- www.arbeitsmedizin.uni-erlangen.de EQUAS) which has been carried out since dialysis of volunteers). These projects are sub- Head of Institute 1982 on behalf of the German Association stantially promoted by the DFG and the Euro- Prof. Dr. med. Hans Drexler for Occupational and Environmental Medicine (DGAUM). Contact The laboratories of the institute serve as refer- PD Dr. rer. nat. Thomas Goeen ence laboratories for G-EQUAS and other inter- Phone: +49 9131 8526121 national quality assessment schemes. Fax: +49 9131 8522317 [email protected] Research Research Focus • Molecular markers of exposure to hazardous Molecular markers of exposure to hazard- substances ous substances • Dermatoxicology This research area develops and validates pro- • Work related health research cedures for the quantitative assessment of mo- • Population related health studies lecular markers of individual exposure to haz- • Quality assurance of Biomonitoring methods ardous substances (dose monitoring), for the • Quality assurance of health promoting disposition for hazardous substances in the me- actions In vivo studies of dermal penetration of hazardous sub- tabolism (susceptibility monitoring) and the ef- stances by microdialysis fects of hazardous substances (biological effect monitoring). The research is mainly promoted Structure of the Institution by the DFG. A special focus is on the biological pean Union. Furthermore one work group of effect monitoring which particularly quantifies the institute deals with the evaluation of skin The Institute and Outpatient Clinic of Occupa- reaction products of mutagenous substances, penetration for the establishment of occupational, Social and Environmental Medicine be- covalently bound as adducts to macromole- tional medical threshold limit values for the longs to the clinical theoretical institutes. The cules like proteins or DNA. The valency of the Commission of Investigation of Health Hazards institute has 37 employees (12 of them are fi- single biomarkers is examined in studies which of Chemical Compounds in the Work Area of nanced by third-party funds). Research is car- give information about the specificy, sensitiv- the DFG. The ad hoc group “skin absorption” ried out by 11 PhD scientist, 6 PhD students ity and toxicokinetic behaviour of the different has developed a systematic approach for la- and 12 technical assistants. parameters. belling hazardous substances which can pene- Different work groups develop molecular mark- An important pre-requisite for sensitive and trate via skin. The DFG work group headed by ers of exposure to hazardous substances as well specific biomonitoring is the use of very sensi- Dipl.-Ing. K. H. Schaller is responsible for label- as procedures to quantify skin penetration of tive and molecular-structural distinguishing an- ling chemical substances with a skin designa- hazardous substances and to standardize di- alyzing techniques. The institute therefore pos- tion in Germany. agnostical pre medical findings. Furthermore sesses very good technical equipment which is Additionally, procedures to early diagnose pre- the institute examines work-related exposure modernized on a regular basis. Gas chromato- clinical skin damages and irritations like the Er- of employees and the exposure of the general graphic techniques as well as high performance langer Haut-Score are developed and validated. population. liquid chromatographic systems belong to the The department of the university’s medical equipment which are particularly connected Work related health research officers belongs to the institute. It carries out to one-dimensional and multiple-dimension- Field studies, taking into account the work- the preventive medical checkups of all the uni- al mass spectrometry (GC-MS/MS and LC-MS/ place conditions, aiming for the detection of versity’s employees and the students. It also MS) and to modern analytical techniques for physiological and pathophysiological changes gives advice to the head of the university and the determination of metals in body fluids (GF- before manifest diseases appear. Diseases as a the university hospitals regarding occupational AAS und ICP/MS). response to an exposure in workplaces of the health protection and offers actions for health last decades are still a scientific field of activity promotion. Dermatoxicology of clinical occupational medicine. For example, The institute directs the work groups “Biologi- At the institute different research projects deal substantial social-medical problems can result cal limit values”, “Analysis in biological mate- with procedures to determine dermal penetra- from asbestos-induced malignoms of the respi- rials” and “Skin absorption” of the Commis- tion of chemicals and to standardize preclini- ratory tract system. Current questions always sion of the Investigation of Health Hazards of cal skin damages. arise when new technologies or working ma- Chemical Compounds in the Work Area of the terials are introduced. Exemplarily new weld-

52 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) ing techniques used in the aluminium process- Quality assurance of health promoting Selected Publications ing industry, or the replacement of classical sol- actions Broding HC, Schettgen T, Göen T, Angerer J, Drexler H vents by alternative solvents with a higher risk This research area develops concepts to exam- (2007) Development and verification of a toxicokinetic of skin irritation of the exposed employees are ine the effectivity and sustainability of health model of polychlorinated biphenyl elimination in persons working in a contaminated building. Chemosphere, 68: named. Furthermore allergically mediated dis- promotion in companies and uses them in 1427-34 eases at the workplace, with clearly improved practice. The network “Erlangen model of Korinth G, Weiss T, Penkert S, Schaller KH, Angerer J, Drexler hygienic conditions, are still a problem. There- workplace health promotion” aims at initiating H (2007) Percutaneous absorption of aromatic amines in fore an important topic for the institute is the a sustainable culture in the enterprises. Health rubber industry workers: impact of impaired skin and skin assessment of exposure and effect of toxic, promotional behaviour is to be brought not barrier creams. Occup Environ Med, 64: 366-72 mutagenous and sensitizing working materi- only temporarily limited into companies and Hartmann EC, Boettcher MI, Schettgen T, Fromme H, als in Germany and abroad. Many field stud- should be preserved after an initiation phase Drexler H, Angerer J (2008) Hemoglobin adducts and mercapturic acid excretion of acrylamide and glycidamide ies qualitatively assess the uptake which can in the entire enterprise. Carriers of the current in one study population. J Agric Food Chem, 56: 6061-8 be absorbed percutaneously by taking into ac- network are public health authorities, the city Kuetting B, Uter W, Drexler H (2008) The association count the workplace conditions. These studies of Erlangen, the Siemens health insurance as between self-reported acrylamide intake and hemoglobin are often carried by the by the German Social well as different clubs and associations. Partic- adducts as biomarkers of exposure. Cancer Causes Control, Insurance or the German Ministry of Labor and ipating companies are divisions of large-scale 19: 273-81 Social Affairs. companies, as well as small and medium-sized Schmid K, Merkl K, Hiddemann-Koca K, Drexler H (2008) companies of the region. The Institute and Out- Obligatory occupational health check increases vaccination rates among medical students. J Hosp Infect, 70: 71-5 Population related health studies patient Clinic of Occupational, Social and En- Wellner T, Lueersen L, Schaller KH, Angerer J, Drexler H, Environmental medicine relates to occupation- vironmental Medicine and the Interdisciplinary Korinth G (2008) Percutaneous absorption of aromatic al medical questions by critically proving expo- Institute for Philosophy and History of Science amines - A contribution for human health risk assessment. sure and possible effects. The institute in par- evaluate the network. Task of the evaluation is Food Chem Toxicol, 46: 1960-8 ticular has to offer fast and adequate help if to verify the goals of the initiative on its consis- International Cooperation the public is postulated with high exposure to tency and feasibility and to judge the assigned chemical agents like PCB in schools, plasticizer means for the objectives fitness and efficien- Nadine Fréry, Institut de Veille Sanitaire, Franz. Gesund- heitsbehoerde, 94415 St. Maurice, France in pharmaceuticals or toys, aromatic amines in cy, as well as the whole network for its sustain- ACGIH – American Conference of Governmental Industrial fabric. These studies are often carried by local ability. The evaluation results are communicat- Hygienists, Cincinnati, USA authorities, the Bavarian State Ministry of the ed regularly to the carriers and participants of Patrick J. Parsons, DOH, Department of Health, Albany, Environment and Public Health and the Ger- the network and continuously serve as a qual- New York, USA man Federal Environment Agency. ity control and further project optimization. Biomonitoring Team, Finnish Institute of Occupational Health, Helsiniki, Finland Quality assurance of Biomonitoring Alain LeBlanc, Institut national de santé publique du methods Teaching Québec, Centre de toxicologie, INSPQ, Québec, Canada On behalf of the German Association for Oc- Dr. S. Kezic, Coronel Institute of Occupational Health, cupational and Environmental Medicine Professor Drexler is the dean of the students Universitaet Amsterdam, Academic Medical Centre, Am- (DGAUM) the institute currently organizes ex- in the clinical phase since 2006. The lessons in sterdam, Netherlands ternal quality assessment schemes worldwide the Occupational-, Social- and Environmental Larry Needham, CDC, Atlanta, USA for the evaluation of occupational and environ- Medicine (lectures, practical courses and E- Research Equipment mental biomarkers. The 42nd round robin test learning) are carried out according to the stat- of G-EQUAS was finished within the report pe- utes of the medical act. Varian GC-MS/MS-System 2100 riod. At the moment G-EQUAS comprises 122 Sciex API 2000 LC-MS/MS-System analysis parameters; 150 to 200 laboratories worldwide (2/3 international) take part in G- EQUAS every six months.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 53 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Institute of Medical Physics Chair of Medical Physics

Address medical imaging. The acquisition of the unit Henkestrasse 91 was supported with about 1.5 million Euros in 91052 Erlangen the framework of the orthoMIT main project. Phone: +49 9131 8522310 From 01/2005 to 12/2007 the European Union Fax: +49 9131 8522824 supported a major project to investigate the www.imp.uni-erlangen.de safety and efficacy of computed tomogra- Head of Institute phy (CT) in the 6th Research Framework. The technological advances of the previous years Prof. Dr. habil. Dr. med. h. c. Willi A. Kalender have enormously improved the performance Contact of computed tomography and strengthened Prof. Dr. habil. Dr. med. h. c. Willi A. Kalender its role as an important tool for non-invasive Phone: +49 9131 8522310 The C-arm system allows almost unlimited freedom of diagnostics. All body regions or organs can be Fax: +49 9131 8522824 movements. (Picture: Kurt Fuchs, IMP, Erlangen) scanned three-dimensionally on modern CT [email protected] scanners in only a few seconds and in excep- tional quality. However, many times it is not the Research Focus high performance that is in the focus of discus- Development and application of imaging tion of imaging procedures in medical diag- sions but the assumed high patient dose in CT procedures in medical diagnosis and image- nosis and image-guided therapy. In particular examinations. The main objective of the whole guided therapy the achievements in the field of computed to- project in which 10 european institutes partici- mography (CT) receive great recognition; the pated was to provide recommendations for the institute has gained a leading position here. use of CT to optimize the examination proce- Structure of the Institution Four selected research projects are described dure and, in particular, to reduce dose. At the in the following: institute the focus of the research lay on devel- In addition to the chair and full professorship From July 2005 to July 2010 the German Fed- oping methods for optimization and dose effi- of Medical Physics, the Institute of Medical eral Ministry of Research and Technology sup- ciency of CT and on validating and providing Physics comprises the professorship of Medi- ports a major project to minimally invasive sur- the results for clinical use in cooperation with cal Imaging (held by Prof. Dr. M. Kachelrieß gery methods in orthopedics. More than one the industry. The introduction of an automat- since 07/2005) and the professorship of Medi- million patients have to undergo orthopedic ic exposure control (AEC) for CT allows to de- cal Optics (held by Prof. Dr. A. Langenbucher surgery every year. The main objective of or- termine the minimal dose automatically. Tak- until 09/2009). thoMIT is to develop an integrated platform for ing into account that children are more sensi- In all the Institute employs 62 persons, where- the “gentle” operative therapy in orthopedics tive to higher radiation exposure than adults it of 43 are financed by third-party funds. The and traumatology with particular emphasis on is particularly necessary to adapt the scan pa- researchers, 35 of them are doctoral students, hip, knee and spinal column surgery. The Insti- rameters conscientiously to the relative body are working on a wide range of topics in the tute of Medical Physics (project director: W. A. size in examinations with children. DoseTutor, area of medical physics. The projects focus on Kalender) participates in the orthoMIT project a software program, enables the user to dem- different issues of the following research areas: by working on the implementation of 3D CT onstrate the relation between scan parameters, medical imaging, medical image processing, imaging in minimally invasive interventions. image quality and patient dose without having computer assisted surgery, medical optics, ra- The aim of this subproject is to provide high to carry out several CT scans with different scan diation therapy, dosimetry and radiation pro- image quality with significantly improved spa- parameter settings. tection, osteoporosis research. tial resolution and an acceptable radiation ex- In the 7th Research Framework the European An important basis for the research at the Insti- posure in the operating room. The main focus Union supports with 2.05 million Euros from tute is fundraising: Public grants by the Europe- lies on the implementation of artificial joints 01/2008 to 06/2010 the research on dedicated an Union, the German Federal Ministry of Re- and surgical procedures at the spine. CT of the female breast (project director and search and Technology, the German Research In January 2008 the new unit Artis zeego speaker: W. A. Kalender). Foundation, the Bavarian Research Foundation (Siemens Healthcare) was installed, a device Three academic partners representing inter- and cooperations with industrial partners reach equipped with a worldwide unique robot arm nationally renowned and well established cen- an amount of about one million Euros per year. that allows with only one device all x-ray exam- tres for modern radiological imaging at the inations from roentgenoscopy to CT-like scan- universities of Erlangen-Nürnberg, Leuven and ning. The combination of a C-arm with a pow- Rotterdam and one industrial partner, VAMP Research erful industrial robot provides the treating phy- GmbH from Erlangen, are working togeth- sician with almost unlimited freedom of move- er on the development of a special device for Development and application of imag- ment, even rotating around the patient. The scanning of the female breast with computed ing procedures in medical diagnosis and application of the new system enables work- tomography (CT) with focus on feasibility and image-guided therapy ing on improvement of image quality in prin- optimisation and in comparison to competing The focus of the 30 ongoing research proj- ciple and also new developments in the areas imaging modalities. Considering the incidence ects is on the development and the applica- of interventional radiology and intra operative rate of breast cancer in women accurate diag-

54 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Screenshot of DoseTutor (VAMP GmbH, Erlangen). A PC a) Concept of using robots in medical imaging and surgical interventions. [Kalender, Kyriakou 2007] program to simulate CT scans with a lower dose or an- b) Implementation of a KUKA light robot in experiment in a navigation and robot assisted intervention at the IMP other reconstruction kernel. When changing one of these parameters, the program interactively shows the effect on the dose and image quality.

nosis of this disease at an early state is a pend- Since 10/2006 the German Research Foun- Selected Publications ing challenge. Digital x-ray mammography is dation is supporting the Research Unit 661: Kalender WA, Kyriakou Y (2007) Flat-detector computed considered today’s state of the art in diagno- “Multimodal Imaging in Pre-clinical Research” tomography (FD-CT). Eur Radiol, 17: 2767-79 sis although severe insufficiencies are acknowl- (Speaker: W. A. Kalender). Deak P, van Straten M, Shrimpton PC, Zankl M, Kalender WA edged. It is a so called projection procedure in More information on this project is offered in (2008) Validation of a Monte Carlo tool for patient-specific which structures and details along the ray are the section describing special research areas or dose simulations in multi-slice computed tomography. Eur Radiol, 18: 759-72 displayed interfering with each other in the major research projects funded by the German Ertel D, Kroeber E, Kyriakou Y, Langner O, Kalender WA image. For this reason findings are often missed Research Foundation. (2008) Modulation transfer function-based assessment of – this is called a too small sensitivity – respec- temporal resolution: validation for single- and dual-source tively there are findings suspected although CT. Radiology, 248: 1013-7 there aren’t any – in this case this is called a too Teaching Kalender WA, Buchenau S, Deak P, Kellermeier M, Langner small specificity. To improve image quality the O, van Straten M, Vollmar S, Wilharm S (2008) Technical approaches to the optimisation of CT. Phys Med, 24: 71-9 significant advantages of 3D imaging for the The institute participates in the education of examination of the female breast is generally the medical students in the area of medical Lapp RM, Kyriakou Y, Kachelriess M, Wilharm S, Kalender WA (2008) Interactively variable isotropic resolution in acknowledged. In eight different subprojects imaging by offering lectures and seminars. computed tomography. Phys Med Biol, 53: 2693-713 the potential of a dedicated CT scanner for the The course on the basics of medical physics Vollmar SV, Kalender WA (2008) Reduction of dose to the female breast is to be scrutinized and its per- including a tutorial gives students of natural female breast in thoracic CT: a comparison of standard-pro- formance features are to be characterized. Be- science the opportunity to learn more about tocol, bismuth-shielded, partial and tube-current-modulated sides the specification of a dedicated breast CT this field of physics. Besides these elementary CT examinations. Eur Radiol, 18: 1674-82 scanner another aim is to evaluate the role of courses the institute regularly offers lectures International Cooperation the different competing methods to diagnose and seminars on special subjects of medical Prof. CA Mistretta, Dept. of Medical Physics, University of breast cancer. The main objective is above all physics, medical optics, medical imaging and Wisconsin, Madison, WI, USA to make breast tumors detectable as early as medical image processing and of osteoporo- Profs. S Napel, G Rubin, Dep. of Radiology, Stanford Uni- possible. From this point of view the different ses research. versity, Palo Alto, CA, USA alternative imaging procedures are to be ex- An essential part of the education program at Prof. J.M. Boone, Dep. of Radiology, UC Davis Medical plored and evaluated. the institute is the supervision of diploma the- Centre, Sacramento, CA, USA sis of different fields and of doctoral studies to Dep. of Ophthalmology, Semmelweis University, Budapest, graduate as Dr. rer. biol. hum. Ungarn Prof. Dr. Hilde Bosmans, Radiologie, Katholieke Universiteit Leuven, Belgium Prof. Gabriel P. Krestin, Erasmus Medical Centre, Rotterdam, Netherlands Dr. J. Geleijns, Medical Centre, Leiden University, Leiden, Netherlands Dr. P. Shrimpton, Radiation Protection, Health Protection Agency, Chilton, United Kingdom Prof. Dr. J. Damilakis, University Of Crete, Iraklion, Crete, Greece

Research Equipment Siemens SOMATOM Definition Dual Source CT Siemens MR-Scanner Magnetom Vision VAMP GmbH In-vivo Mikro-CT-Scanner Siemens C-Bogen-CT-Scanner Axiom Artis zeego In dedicated breast CT a multitude of projection images from all directions on a circular path are taken with low x-ray dose. Calculations indicate that we will be able to display microcalcifications as well or even better than standard mammography does. However, in addition we will be able to clearly see soft tissue lesions which are often obscured by overlaying tissue in mammography. Fig.: Inst. f. Med. Physik

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 55 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Nikolaus-Fiebiger-Centre of Molecular Medicine Chair of Experimental Medicine I (Connective Tissue Research) Clinical Theoretical Institutes

Address ed control of endochondral ossification is an binds to cartilage collagens and contains ty- Glueckstrasse 6 absolute requirement. Similar processes also rosine sulphate and γ-carboxyl glutamic acid 91054 Erlangen occur during fracture callus healing and devel- (Gla), indicating that it maybe involved in ma- Phone: +49 9131 8529100 opment of osteophytes in osteoarthritic joints. trix assembly and/or calcification. A UCMA Fax: +49 9131 8526341 Therefore, elucidation of factors and mecha- knockout mouse was generated and is currently www.em1.molmed.uni-erlangen.de nisms involved in endochondral ossification is being investigated in order to get insight into Head of Institute essential not only for our understanding of the the possible function of UCMA in cartilage de- Prof. Dr. rer. nat. Klaus von der Mark regulation of normal skeletal growth and skel- velopment and homeostasis. etal dysplasias, but also for the development of Contact new tools in the diagnosis and therapy of joint Molecular mechanisms of endochondral Prof. Dr. rer. nat. Klaus von der Mark degeneration, fracture healing, and cartilage ossification in skeletal development Phone: +49 9131 8529104 and bone repair. The analysis of these factors Coordinated turnover of fetal cartilage and its Fax: +49 9131 8526341 by means of in vitro techniques, cell-and organs replacement by bone in the growth plate long [email protected] culture systems and transgenic mouse models bones, ribs and vertebrae requires a precise is currently the major focus of the workgroup control by numerous growth factors and their Research Focus of Prof. von der Mark. receptors. In order to investigate the specif- • Structure, function and gene regulation of ic role of growth factors, receptors and tran- extracellular cartilage matrix proteins Structure, function and gene regulation of scription factors identified in growth plate • Molecular mechanisms of endochondral os- extracellular cartilage matrix proteins cartilage, we generated various transgenic sification in skeletal development Project manager: M. Stock, C.Surmann-Schmitt mouse models in which selected factors such • Cell-matrix interactions in biomimetic titan- By subtractive suppression hybridization we as TSG, UCMA and Wif1 were specifically over- dioxide nanotubes were able to identify novel genes involved in expressed in cartilage under the collagen II pro- the regulation of chondrocyte differentiation moter Col2a1. The development of a collagen by subtractive hybridization of mRNA obtained 10-specific targeting vector for recombination Structure of the Institution from distinct chondrocyte populations of the into BACs (bacterial artificial chromosomes) growth plate. One of them, twisted gastrula- allowed the specific expression of transgenes The Chair of Experimental Medicine I is locat- tion (TSG), an antagonist of bone morphogen- such as lacZ reporter genes, cre-recombinase ed in the Nikolaus-Fiebiger Centre of Molecu- ic proteins (BMPs) is expressed predominantly as well as the transcription factor Sox9 in the lar Medicine and is responsible together with in hypertrophic cartilage and inhibits BMP-1 – hypertrophic zone of the murine growth plate. the Chair of Experimental Medicine II for the induced collagen II-and- X synthesis. Transgen- Overexpression of Sox 9 significantly blocked organisation and administration of the Centre. ic models in which TSG is overexpressed under resorption of hypertropic cartilage, capillary in- In 2007-2008 about 15 persons were involved a cartilage specific promoter, have been devel- vasion and bone marrow formation in the de- in research and teaching at the department Ex- oped to analyse the function of this protein in veloping long bones, resulting in impaired skel- perimental Medicine I, among them 5 postdoc- skeletal development. Two further genes seem etal growth and reduced bone length (Fig.2). toral and senior scientists, 3 graduate students, to be involved in the regulation of early carti- This demonstrated for the first time a novel role 3 undergraduate students and 4 technicians. lage and bone development: the Wnt inhibito- of Sox9 as angiogenic inhibitor of cartilage vas- Half of the staff was financed through grants. ry factor Wif-1 is expressed exclusively in the cularization. Since October 2008 the department chair is upper zone of articular cartilage and seems to The generation of Col10-specific Cre-deleter advertised for reneweal. control wnt-induced chondrocyte dedifferen- mice opened the possibilities for specific dele- tiation during joint development (Fig.1). While tion of floxed genes in the hypertrophic zone of Wif-1 has so far been only investigated in con- the growth plate. Mating the Col10-Cre mice Research text of its potential role as tumor supressor, we with conditional beta-catenin mice (R.Kemler, have shown that its major expression site is in Freiburg) with floxed catenin alleles resulted in Cartilage cells (chondrocytes) have two rath- cartilage, and that witf-1 is able to neutralize transgenic mice lacking trabelcular bone in the er adverse properties and functions in the fetal wnt3a –induced inhibition of chondrogene- suchondral zone of the diaphysis. Several co- and the adult skeleton: A transient role in dur- sis. The putative role of Wif-1 as a stabilizer of operation were started with laboratories in Vi- ing skeletal development, and a permanent articular cartilage and its role in degenerative enna (C. Hartmann), Boston (B. Lanske) and in in adult cartilages of the joint, trachea and in joint diseases is currently being investigated in Houston (B. de Crombrugghe ) and Freiburg elastic cartilages of nose and ear. During de- collaboration with Prof. Schett, Department of (B. Zabel) for specific gene inactivation stud- velopment of the vertebral skeleton chondro- Medicine 3. ies the hypertropic zone using the Col10-Cre cytes shape the cartilage model of the subse- A novel cartilage-specific gene was discovered deleter mouse. quent bony skeleton. They grow and differen- which codes for a small extracellular cartilage tiate rapidly and will be replaced by bone cells protein (UCMA), a secreted protein. It is ex- in a complex process called “endochondral os- pressed only in juvenile, distal chondrocytes sification”. For reproducible skeletal growth of fetal epiphyseal and vertebral cartilage. The a precise spatially and temporally coordinat- protein is processed by a furin -like protease,

56 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) a b c

A a b

tg wt tg wt P14 P14 d wt e wt

Pulldown: Wif-1 Sepharose B

Fig.1: The Wnt-inhibitor Wif-1 is strongly expressed in the upper Fig.2: Overexpression of Sox9 in hypertrophic chondrocytes of the zone of articular cartilage (14 d mouse knee joint), suggesting a growth plate under a BAC Col10promoter causes substantial retar- protective function against degenerative actions of Wnt factors. dation of bow marrow formation in transgenic (tg) mice (a), impairs resorption of hypertrophic cartilage (b,c) and bone growth (d,e ; Mi- croCT image: A.Hess, Pharmacology, Friedrich-Alexander-University Erlangen-Nürnberg)

Cell-matrix interactions in biomimetic The size of 15 nm corresponds to the size of Selected Publications titandioxide nanotubes the extracellular domain of integrin receptors Brachvogel B, Pausch F, Farlie P, Gaipl U, Etich J, Zhou Z, Project manager: J. Park which are responsible for cell-matrix interac- Cameron T, von der Mark K, Bateman JF, Pöschl E (2007) Isolated Anxa5+/Sca-1+ perivascular cells from mouse Critical features of biomimetic materials used tions of all cells. We postulate that the surface meningeal vasculature retain their perivascular phenotype for vascular grafts and stents are surface geom- geometry of 15 nm allows a maximum of inin vitro and in vivo. Exp Cell Res, 313: 2730-43 etry and chemical features of the implant ma- tegrin receptor clustering on the cell surface, Gebhard S, Hattori T, Bauer E, Bösl MR, Schlund B, Pöschl terial supporting adhesion, proliferation, and thus initiating intracellular signalling and cy- E, Adam N, de Crombrugghe B, von der Mark K (2007) BAC constructs in transgenic reporter mouse lines control differentiation of endothelial cells and smooth toskeletal reorganisations. This hypothesis was efficient and specific LacZ expression in hypertrophic chon- muscle cells, the major cell types of blood ves- supported by immunohistological and elec- drocytes under the complete Col10a1 promoter. Histochem Cell Biol, 127: 183-94 sels. Recently increasing experimental evidence tronmicroscopical analysis of cells after adhe- Park J, Bauer S, von der Mark K, Schmuki P (2007) Nanosize has accumulated showing that nanoscale to- sion to nanotubes of various diameters. These and vitality: TiO2 nanotube diameter directs cell fate. Nano pography is an important factor for cellular studies were supplemented by experimental Lett, 7: 1686-91 recognition and cell behaviour on biomimet- animal implantation experiments performed in von der Mark H, Pöschl E, Lanig H, Sasaki T, Deutzman R, ic material used for vascular grafts, stents, or collaboration with Dr. Schlegel and Prof Neu- von der Mark K (2007) Distinct acidic clusters and hydro- phobic residues in the alternative splice domains X1 and X2 bone implants. Prof. P. Schmuki Dr. Sebastian kam, Department of Oral and Maxillofacial of alpha7 integrins define specificity for laminin isoforms. J Bauer at the Department of Material Sciences, Surgery, Friedrich-Alexander University Erlan- Mol Biol, 371: 1188-203 Friedrich-Alexander University Erlangen-Nürn- gen-Nürnberg. Gebhard S, Hattori T, Bauer E, Schlund B, Bösl MR, de Crombrugghe B, von der Mark K (2008) Specific expression berg, developed a procedure to coat titanium of Cre recombinase in hypertrophic cartilage under the surfaces with vertically aligned Titanium diox- control of a BAC-Col10a1 promoter. Matrix Biol, 27: 693-9 ide nanotubes by anodizing Ti sheets in a phos- Teaching Surmann-Schmitt C, Dietz U, Kireva T, Adam N, Park J, Taga- phate-fluoride electrolyte with defined lumen riello A, Onnerfjord P, Heinegård D, Schlötzer-Schrehardt U, Deutzmann R, von der Mark K, Stock M (2008) Ucma, a diameters ranging between 15nm and 100 nm. The Departments of Experimental Medicine I Novel Secreted Cartilage-specific Protein with Implications In collaboration with this group cell behaviour and II organize lectures, seminars and experi- in Osteogenesis. J Biol Chem, 283: 7082-93 of various cell type including osteoblasts, bone mental classes in cell, molecular and develop- International Cooperation marrow mesenchymal stem cells (BMSC), and mental biology at basic and advanced levels endothelial cells on Ti02 nanotubes was inves- for students of molecular medicine, human Benoit de Crombrugghe, MD Anderson Cancer Centre, Texas University, Houston, USA tigated with respect to adhesion, proliferation, medicine and biology. Special lectures includ- Takako Hattori, Graduate School of Dentistry and Medicine, migration, differentiation and cell death. Sur- ing tumor biology and oncology, molecular Okayama University, Japan prisingly, all cell types showed a maximum re- mechanism of celldifferentiation and develop- Christine Hartmann, Institut of Molecular Pathology, IMP, sponse to nanotubes with a lumen diameter ment, cell-cell and cell-extracellular matrix in- Wien, Austria of 15 nm, whereas on 100nm nanotubes cells teractions are given. Beate Lanske, Department of Cell Biology, Havard Medical tended toward enhanced apoptosis. On 15 nm School, Boston, USA nanotubes osteoblasts showed a maximum mineralisation tendency, BMSC the highest Research Equipment rate of osteogenic differentiation, and endo- Leica Konfokales Laserscanning Mikroskop thelial cells high expression of PECAM (CD31). Biacore Surface Plasmone Resonance

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 57 CLINICALClinical THEORETICAL Theoret INSTITUTESical Institutes

Nikolaus-Fiebiger-Centre of Molecular Medicine Chair of Experimental Medicine II (Molecular Oncology) Clinical Theoretical Institutes

Address tion. In colorectal tumours, mutations of APC Glueckstrasse 6 or conductin, or mutations of the serine/threo- 91054 Erlangen nine phosphorylation sites of β-catenin lead to Phone: +49 9131 8529110 stabilisation of β-catenin and trigger constitu- Fax: +49 9131 8529111 tive signalling to the nucleus. Such β-catenin www.molmed.uni-erlangen.de mutations are also found in a multitude of other Head of Institute tumour types suggesting that aberrant activation of wnt signalling is a key mechanism of on- Prof. Dr. rer. nat. Juergen Behrens The localisation of exogenous AP in MCF-7 cells was an- cogenic transformation. During the report pe- alysed by immunofluorescence. APC is localised along Contact riod we have investigated the consequences of microtubules in control cells (A, siGFP). Knock-down of Prof. Dr. rer. nat. Juergen Behrens APC mutations on wnt signalling in tumours, Amer1 leads to a redistribution of APC t othe tips of mic- trotubules in cellular protrusions (B, siAmer1c). Expres- Phone: +49 9131 8529109 and we have identified a new interaction part- sion of Amer1 leads to the recruitment of APC to the Fax: +49 9131 8529111 ner of APC, which recruits APC to the plasma plasma membrane (c, siAmer1c+rAmer1). [email protected] membrane. A further focus of our studies is on the regulation and consequences of -catenin Research Focus β dependent transcription. • Molecular oncology of wnt signalling Membrane Recruitement 1). Amer1 is associ- • Tumour suppressor APC Tumour suppressor APC ated to the plasma membrane through inter- • Transcriptional regulation by -catenin β Project manager: A. Grohmann, K. Tanneberg- action with phosphatidylinositol lipids and re- • Functional genomics of renal cell carcinoma er, A. Alzner, J. Schneikert, E. Kohler cruits APC from the microtubules to the plas- Mutations of the APC gene result in trunca- ma membrane. Conversely, loss of Amer1 by tions of the APC protein. The “mutation clus- siRNA leads to an increased association of APC Structure of the Institution ter region (MCR)” is located approximately in to the tips of microtubules (see Figure). In ad- the middle of the APC gene and overlaps with dition we observed a loss of cell-cell contacts The Chair of Experimental Medicine II is situ- the region that binds to β-catenin . To investi- in epithelial cells when Amer1 is down regulat- ated at the Nikolaus-Fiebiger-Centre for Mo- gate the functional relevance of truncated APC ed. It turned out that Amer1 is identical to the lecular Medicine. There are 16 staff members, proteins, we have introduced tumour-associat- tumour suppressor WTX, which is mutated in 9 of them scientists financed by third-party ed mutations into the APC cDNA and analyzed Wilms tumours. funds. During the reported period there were the effects on the binding to β-catenin and on 6 PostDocs, 6 PhD students, 3 technicians and β-catenin destruction. We found that in most Transcriptional regulation by β-catenin one secretary. cases truncated APC retains reduced, but still Project manager: V. Stemmer, M. Dehner, M. Our main target is to investigate the molecular significant binding to β-catenin as well as the Hadjihannas mechanisms of tumour development and pro- capacity of negative regulation of wnt signal- Using DNA microarray we have identified gression by cell and molecular biological meth- ling. β-Catenin binding is mediated by the first genes whose expression is modulated by acti- ods to find new ways for diagnosis, prognosis of in total seven 20 amino acid repeats. This re- vation of wnt signalling in cell lines. We found and therapy. peat is always retained in the APC fragments. that the expression of SGK1 (serum and gluco- Furthermore, upon closer analysis we found corticoid-inducible kinase 1) is induced after that a domain within the MCR is essential for knock-down of APC or stimulation with wnt- Research the activity of the APC fragments. Deletion of conditioned medium. Promoter analysis and this domain, which we have called β-catenin chromatin immunoprecipitation showed that Molecular Oncology of Wnt Signalling inhibitory domain (CID), results in a complete SGK1 is a direct target gene of β-catenin. SGK1 The Wnt signalling pathway regulates vari- loss of APC activity. Altogether we have come can inhibit the transcription factor FoxO3a ous processes during embryonic development to a functional definition of the MCR: Muta- through phosphorylation. We found, that wnt and can lead to cancer. Wnts are secreted tions in tumours are selected for the presence signalling leads to the exclusion of FoxO3a glycoproteins, which induce the accumula- of the first 20 amino acid repeats, lack of the from the nucleus in a SGK1 dependent manner. tion of β-catenin in cytoplasm and nucle- third repeat and frequent inactivation of the Furthermore, wnt signalling inhibited FoxO3a us by binding to frizzled and LRP receptors. CID domain. Our data also indicate that a cer- transcription and apoptosis. Altogether we β-Catenin interacts with TCF transcription fac- tain control of activity of wnt signalling needs have identified a novel negative crosstalk be- tors and activates target genes. The destruc- to be retained in colon tumours to allow for tween the oncogenic wnt signalling pathway tion of β-catenin is induced by phosphoryla- “just-right-signalling”. and the pro-apoptotic action of FoxOs. tion in a multi-protein complex, which con- Besides its function as a negative regulator of We found that the transcriptional repressor sists of the scaffold component conductin, the the wnt signalling pathway APC plays also a snail acts as a positive regulator of β-catenin serine/threonine kinase GSK3β, and the tu- role in the organization of microtubules and dependent transcription. Snail can bind to mour suppressor APC (Adenomatous Polyposis of cell contacts. In a yeast-two-hybrid screen β-catenin and is required for efficient activa- Coli). The wnt signal inhibits phosphorylation we have identified a novel interaction part- tion of wnt target genes. As snail has been de- of β-catenin and thereby leads to its stabilisa- ner of APC, which we have called Amer1 (APC scribed as a target gene of the wnt pathway,

58 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) this could result in positive feedback for stimu- Selected Publications lation of signalling. Grohmann A, Tanneberger K, Alzner A, Schneikert J, Behrens J (2007) AMER1 regulates the distribution of the tumor Functional genomics of renal cell suppressor APC between microtubules and the plasma membrane. J Cell Sci, 120: 3738-47 carcinoma Project manager: I. Wacker, M. Sachs Schneikert J, Behrens J (2007) The canonical Wnt signalling pathway and its APC partner in colon cancer development. We have established gene expression patterns Gut, 56: 417-25 of renal cell carcinomas using DNA microar- Dehner M, Hadjihannas M, Weiske J, Huber O, Behrens J rays in order to identify genes relevant for the (2008) Wnt signaling inhibits Forkhead box O3a-induced tumour biology and clinical course of this dis- transcription and apoptosis through up-regulation of ease. The von Hippel Lindau tumour suppressor serum- and glucocorticoid-inducible kinase 1. J Biol Chem, 283: 19201-10 is mutated in clear cell renal carcinoma, which Kohler EM, Derungs A, Daum G, Behrens J, Schneikert J leads to constitutive activation of hypoxia in- (2008) Functional definition of the mutation cluster region ducible factor (HIF) transcription factors and to of adenomatous polyposis coli in colorectal tumours. Hum expression of its target genes. We found that Mol Genet, 17: 1978-87 Activin B, a member of the TGFβ family, is high- Stemmer V, de Craene B, Berx G, Behrens J (2008) Snail ly over expressed in kidney tumours as com- promotes Wnt target gene expression and interacts with pared to normal kidneys. Furthermore, expres- beta-catenin. Oncogene, 27: 5075-80 sion of Activin B is stimulated by hypoxia via Wacker I, Sachs M, Knaup K, Wiesener M, Weiske J, Huber O, Akçetin Z, Behrens J (2009) Key role for activin B in cellular HIFs and repressed by VHL. Functional studies transformation after loss of the von Hippel-Lindau tumor showed that Activin B reduces adhesion of RCC suppressor. Mol Cell Biol, 29: 1707-18 cells to extracellular matrix and promotes invasion of tumour cells in vitro. Importantly, knock- International Cooperation down of Activin B inhibited tumour growth of Dr. Geert Berx, VIB Department for Molecular Biomedical kidney tumour cells in nude mice. Collectively, Research, Universitaet Gent, Belgium the data show that the loss of Activin B has sim- Research Equipment ilar consequences as the reconstitution of wild- Dako Cytomation MoFlo – Zellsortiergeraet type VHL in kidney tumour cells. Our results in- Applied Biosystems Genetic Analyzer ABI 3130 dicate that Activin B is a major oncogenic factor in kidney tumours.

Teaching

Training of students of molecular medicine in cell biology in cooperation with Chair of Experimental Medicine I.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 59 CLINICALClinical THEORETICAL Chairs addi INSTITUTEStionally to the University Hospital

Institute of Biomedicine of Aging Chair of Internal Medicine - Geriatrics

Address Research Metabolism and nutrition in old age Heimerichstrasse 58 (Sarcopenia – frailty) 90419 Nürnberg Acute poisoning in old age: most frequent Project manager: J. M. Bauer Phone: +49 911 300050 and most dangerous drugs in an analysis During the past two years the working group Fax: +49 911 3000525 of the Poison Control Centre Nürnberg on nutrition, sarcopenia and frailty realized sev- www.geriatrie-nuernberg.de Project manager: W. Muehlberg, H.-J. Heppner eral projects that were supported by research Head of Institute Although acute poisoning in old age is asso- grants from charitable foundations and from ciated with an increased morbidity and mor- the industry. The Else Kroener-Fresenius-Foun- Prof. Dr. med. Cornel C. Sieber tality, only few literatures exist to this topic. In dation sponsored a one year follow-up study Contact a retrospective study of 37,124 poison emer- on 200 nursing home residents, which was Prof. Dr. med. Cornel C. Sieber gency calls which arrived from 1995 to 2006 carried out in cooperation with the Council of Phone: +49 911 3982434 at the Poison Control Centre Nürnberg, the Nürnberg. In this study a multitude of param- Fax: +49 911 3982117 age of the patents, kind of poison (i. e. drugs), eters has been analysed for their relevance with [email protected] symptoms of the poisoning at the time of the regard to functionality and mortality in this telephone call, and the “ad hoc” therapy ad- population. It could be shown that obese resi- Research Focus vice were recorded in a data base. Statisti- dents had a better survival than residents with • Acute poisoning in old age: most frequent cal evaluation (comparison between expected underweight and than those who were with- and most dangerous drugs in an analysis of and observed frequencies) was done by cross in the normal weight range (BMI 20 – 25 kg/ the Poison Control Centre Nürnberg tables using the SPSS for Windows software. m2). In addition, the obese residents did not • Metabolism and nutrition in old age (Sarco- Results: Acute poisoning (accidental/suicidal) differ from the other groups with regard to penia – frailty) with drugs (p < 0.001) and with commercial functionality. In this study the working group • The GerontoNet feasibility study – A descrip- chemicals was much more frequent in older also tested the applicability and prognostic vative study of older people among a network patients (age ≥ 65 yrs) as compared to young- lidity of several nutritional screening tools. The of European research Centres er patients. Statistically significant less frequent Mini Nutritional Assessment (MNA) proved to • Use of the interRAI emergency department in old age were intoxications with plant or ani- be the best suited instrument for the nursing screener to improve hospital and communi- mal poisons, with illegal drugs, and with house- home setting. Nestlé supported the working ty-based care for frail elderly individuals hold chemicals. Severe intoxication needing group in a project that reevaluated the MNA • Health economics and medical supply al- rapid admission to a hospital were more fre- on the basis of an internationally pooled da- location in the elderly quent in the older patients (p < 0.001). In ad- tabase. In addition, a modified composition of dition, symptoms of the central nervous sys- the MNA short form (MNAsf) was tested. This tems, the gastrointestinal tract, and the heart/ project was realized with the help of the Insti- Structure of the Institution circulation system occurred earlier and more tute of Medical Informatics, Biometry and Epi- frequent in the older patients (p<0.001). No demiology of the University of Erlangen-Nürn- The Institute for Biomedicine of Aging of the such age difference could be observed for ven- berg. The new MNAsf is supposed to facilitate Friedrich-Alexander-University is characterized tilation symptoms. Looking at single drugs, the screening of the nutritional status in older by a close cooperation with the Internal Medi- poisonings with bromazepam (p<0.05) and persons without compromising sensitivity and cal Clinic 2, Clinical Centre Nürnberg, which with zopiclon/zolpidem (p<0.001) were much specifity. In cooperation with the Else-Kroen- includes the Acute Geriatric Hospital and the more frequent in old patients (≥ 65 yrs) as com- er-Fresenius Centre of Nutritional Medicine at Geriatric Day Hospital. Head of the Chair of pared to the young. Statistically significant the Technical University of Munich the working Internal Medicine – Geriatrics, of the institute less poisonings in the elderly patients were group analysed the basal and postprandial se- and of the hospital is Professor Cornel C. Sieber. observed for acetylic salicylic acid, ibuprofen cretion of appetite regulating hormones ghre- Scientific projects with a medical focus can be and paracetamol. Discussion: zolpidem/zop- lin, leptin and insulin in young and old study realized in close cooperation between experts iclon were announced as less dangerous for participants. Older test persons showed a re- of the institute and the hospital. The different older patients (as compared to benzodiaze- duced feeling of hunger and an increased feel- research groups are mainly funded by third- pines), but with respect to the risk of poisoning of satiety while postprandial levels of ghre- party funds. The main research topics are clini- ing this was apparently not true. Neuroleptics lin did not decrease like in the younger group. cal pharmacology and toxicology in old age, (normal and atypic), antidepressants (TCA and This age-associated alteration of ghrelin secre- quality assurance and outcome parameters for SSRI) showed no increased risk of poisoning in tion has to be discussed as a contributing fac- geriatric treatment, rehabilitation in old age, old age. As somehow surprising result, poison- tor in the anorexia of aging. health care and allocation of resources in the ings (not adverse drug effects) with NSAIDS elderly, metabolism in the elderly, molecular were less frequent in the old patients as com- and cellular aging, and nutrition in geriatrics. pared to the young patients. The research on malnutrition is not only focused to inpatients but also to nursing home residents. Therefore a close collaboration with the municipal nursing homes of Nürnberg was established in 2006.

60 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) The GerontoNet feasibility study – A Health economics and medical supply al- Selected Publications descriptive study of older people among a location in the elderly Bauer JM, Wirth R, Troegner J, Erdmann J, Eberl T, Heppner network of European research Centres Project manager: H.-J. Heppner HJ, Schusdziarra V, Sieber CC (2007) Ghrelin, anthropom- Project manager: W. Swoboda The demographic development generates new etry and nutritional assessment in geriatric hospital patients. Z Gerontol Geriatr, 40: 31-36 The Geriatric Minimum Data Set (GMDS) de- challenges in medical supply and management veloped by GerontoNet centres, is a consensus for older patients. Age-related functional re- Brosche T, Brueckmann M, Haase KK, Sieber C, Bertsch T (2007) Decreased plasmalogen concentration as a surrogate assessment tool dedicated to make data com- strictions and multi-morbidity in time of limit- marker of oxidative stress in patients presenting with acute parable across Europe. The GMDS needs to be ed resources need cost-effective modern ther- coronary syndromes or supraventricular tachycardias. Clin evaluated in clinical research in terms of dura- apies. Economic aspect gets more and more Chem Lab Med, 45: 689-91 tion, relevance and availability of scales in the important, so Dr. H.-J. Heppner works with Wirth R, Bauer J, Sieber C (2007) Erythrocyte volume is a different countries and languages in a feasibil- PD Dr. rer. pol. A. S. Esslinger (Department of poor predictor of cobalamin and folate deficiency in geriatric patients. J Am Geriatr Soc, 55: 2100-1 ity study. Frailty appears to be a new area of Management Science, University of Erlangen- Dragonas C, Wagner JT, Heppner HJ, Bertsch T, Muhlberg interest for pharmaceutical and biotech com- Nürnberg) on the problems of ageism and the W, Wicklein S, Pahl A, Diewald C, Bachmakov I, Sieber CC, panies around the world. The Food and Drug development of cost effective structures in the Fromm MF (2008) The association of ABCB1 polymorphisms Administration (FDA) and European Medicines health care of older patients. For a long time it and elevated serum digitoxin concentrations in geriatric Agency (EMEA) have expressed their inter- was not possible to describe the operating ex- patients. Eur J Clin Pharmacol, 64: 367-72 est to make an issue out of frailty. However, pense for required supply in this patient group Bauer JM, Kaiser MJ, Sieber CC (2008) Sarcopenia in nursing they underlined the need for better defini- and to work out and discuss changes in struc- home residents. J Am Med Dir Assoc, 9: 545-51 tion and knowledge. Although the frailty syn- ture and processing quality in clinical treat- Bauer JM, Sieber CC (2008) Sarcopenia and frailty: a clini- cian‘s controversial point of view. Exp Gerontol, 43: 674-8 drome seems easy to recognise in clinical prac- ment under economic aspects. Age dependent tice there is still no consensus-based definition priorisation of medical supply and its implica- International Cooperation or an assessment tool to define it. Preliminary tion for the health care system are critically dis- Prof. Bruno Vellas, GerontoNet, Toulouse, France results from 37 centres were presented at the cussed in this research group. Also rationing of Prof. Ian Hastie, United European Medicine Societies – Geri- 3 rd GerontoNet Meeting in Nürnberg in De- necessary medical supply for the ageing soci- atric Medicine Section (UEMS-GMS), London, Great Britain cember 2008. ety is critically questioned. In this context ex- Prof. Cornel Sieber, European Academy for Medicine of perts are consulted and relevant data of cross- Ageing (EAMA), Sion, Switzerland Use of the interRAI emergency department national evaluations are collected. For their re- screener to improve hospital and commu- search studies among quality of life in older age Meetings and International Training Courses nity-based care for frail elderly individuals against the background of narrow resources in Project manager: K. Singler, W. Swoboda in co- the health care system, the work group was 15.–17.11.2008: Alter als gesellschaftliche Herausforderung, Nürnberg, Germany, Deutsche Gesellschaft fuer Geriatrie operation with interRAI awarded with the Ignatius Nascher Award of The inter RAI ED screener functions as a com- Vienna (Austria) to Advance Geriatric Research. 12.–13.12.2008: GerontoNet Meeting, Nürnberg, Germa- ny, GerontoNet – europaeisches Konsortium fuer klinische patible assessment system in the interRAI fam- Representation of the German Geriatric Society Forschung in der Geriatrie ily of instruments and it employs the same clin- at the AMWF-S-3 guideline “non-invasive ven- ical logic as the interRAI contact assessment tilation” and the AMWF-S-2 guideline “wean- for identifying service urgency and need of as- ing” enabled the research group to point out sessment. Since 2008 a multicenter study is the strong medical distinctions of elderly pain progress including centres in Canada (John tients. Integration of those patients in innova- Hirdes), Australia (Len Gray), Iceland (Palmi tive treatment shows big chances in optimiz- Jonsson) and Germany. The project has the fol- ing health care systems as to effectiveness in lowing primary objectives: 1. to demonstrate medical supply, resulting in higher quality of the clinical utility of the interRAI ED screener life for the elderly. as a tool for identifying elderly persons with complex health needs in the emergency department; 2. to evaluate the ability oft the ED Teaching screener to support improved coordination between home care agencies and acute hospitals “Instant Aging” is a simulation model of aging. with respect to frail elderly persons discharged It was integrated in the practical Geriatric of from ED‘s to the community; 3. to pilot the ED the Medical Clinic 2, Clinical Centre Nürnberg. screener as a tool for triggering specialized ge- “Instant Aging” provides tools for medical stu- riatric assessment and intervention for frail el- dents to bodily experience different age- and derly persons admitted to hospital from ED; 4. illness-related limitations of activity. to track outcomes of care for persons admitted to hospital based on their baseline ED screener assessment.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 61 CLINICALClinical THEORETICAL Chairs addi INSTITUTEStionally to the University Hospital

Department of Orthopaedics in the Waldkrankenhaus Chair of Orthopaedics and Orthopaedic Surgery

Address The clinical focus of our clinic are: total hip-, vised with radiostereometric analysis after total Rathsbergerstrasse 57 knee- and shoulderarthroplasty, spine surgery, hip replacement in Erlangen since 1998. The 91054 Erlangen pedeatric orthopeadics, foot surgery, tumor- following examinations are carried out with this Phone: +49 9131 8223303 surgery, arthroscopic operations. clients in different studies: measuring of migra- Fax: +49 9131 8523565 tion of polyethelene cups after bone grafting www.orthopaedie.med.uni-erlangen.de and reinforcement acetabular ring with hook Head of Department Research for severe acetabular dysplasia; measuring of initial stability of acetabular components with Prof. Dr. med. Raimund Forst Radiostereoanalysis for quality control in alumina and polyethylen liner in a compari- Contact total hip arthroplasty son essay, measuring of migration of cement- PD Dr. med. Lutz Arne Mueller Project manager: R. Forst, L. Mueller ed femoral components into dependence of Phone: +49 9131 8220 Recent studies lead to the conclusion that a various cementing techniques in a comparison Fax: +49 9131 8523565 measurement of migration at 2 years forms a essay, measuring of migration of uncemented [email protected] basis for predicting the long-term outcome of femoral components after early load transfer.

Research Focus • Radiostereoanalysis for quality control in total hip arthroplasty • Computertomography-assisted periprosthetic osteodensitometry after total hip arthroplasty • Neuromuscular disorders • Computer assisted surgery of the hip joint

Structure of the Institution

17 medical doctors work in the departement of orthopaedic surgery. The research is accomplished by 5 postdoctorate medical doctors, 14 graduate students and 3 technical assistants. In the endoprosthesis working group, apart from the standardised clinical and radiologi- CT-Osteodensitometrie: proximal stress-shielding (-) after straight stem versus collum femoris pre- cal long-term investigations for quality control serving (C.F.P) cementless total hip arthroplasty. after navigated and non-navigated total hip and knee surgery, periprosthetic bone density measurements are accomplished by means of computer tomography (CT) – assisted osteodensitometrie and radiostereoanalysis (RSA) the acetabular and femoral component when Computertomography-assisted peripros- for the evaluation of the migration pattern of considered separately. The quality control is thetic osteodensitometry after total hip the prostheses. The influence of navigation, the achieved with thorough documentation and arthroplasty prosthesis design and the prosthesis coating on precise analysis of fixation. Project manager: R. Forst, L. Mueller the longevity of the implant is investigated by Measurements on conventional radiographs The reaction of the bone which occurs after these procedures. can have an accuracy of 1-5mm and 1°- 6° de- THA is important for the stability of the implant The research group for neuromuscular disor- pending on technique employed, the anatom- and thus the long term prognosis. This study ders is engaged in a study and evaluation of ic region investigated, and the number of ex- was designed to analyze the changes of fem- conservative and operative treatment in chil- aminers. Radio stereo analysis (RSA) has proved oral and periacetabular bone after THA intro- dren and adult patients with neuromuscular to be an accurate and safe method to objecti- ducing a novel method of computed tomogra- disorders (anterior horn cell diseases, spinal fy skeletal kinematics. RSA is based on radio- phy (CT) – assisted bone density measurement muscular atrophies, post polio syndrome, mus- graphic examinations of calibration cages and in vivo. A special software tool is used (CAPPA cular dystrophies). object markers implanted in the skeleton. Ac- postOP, CAS Innovations AG, Erlangen) which The common aim of research in care for pa- curate measurement of radiographs and com- allows a separate view of femoral and acetabu- tients with cerebral palsy is the evaluation of re- puter-assisted calculation can provide a three- lar bone. CT investigations are performed ten sults of botulinum toxin therapy and optimising dimensional motion analysis. RSA can be per- days, one, three and five years post-operatively. of orthopaedic treatment strategies to improve formed with an accuracy of 10-250 μm and Cortical and cancellous bone density as well as the quality of life of these patients. 0.03°-0.6°. Altogether 200 patients are super- bone area and bone-implant contact are mea-

62 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) sured. Bone demsity measurements are un- spective study in collective of more 500 pa- ducted which allow an exact comparison of dertaken to in respect to fixation methods (ce- tients with genetically confirmed diagnosis of the received data. 50 patients will be analysed. mented/uncemented), coating (e.g. hydroxy- DMD. Positive effect of this treatment could apatite) and design (collum femoris preserv- be proven and a stage-oriented therapy con- ing/ standard). cept developed. Teaching In close co-operation with the Department of Neuromuscular disorders Anaesthesiology the special features in anaes- Beside the traditional teaching forms (main lec- Project manager: J. Forst, A. Fujak, R. Forst thesia and pain therapy in patients with the ture and practical courses) hospitations and fel- The research group for neuromuscular disor- neuromuscular disorders are investigated. lowships can be undertaken anytime. ders is engaged in an evaluation of orthopaedic In common projects with the Division of Pedi- symptoms, conservative and operative treat- atric Cardiac Surgery and Institute of Radiolo- Selected Publications ment in children and adult patients with neu- gy the participation of the heart musculature Fujak A, Ingenhorst A, Heuser K, Forst R, Forst J (2005) romuscular disorders. The aim of research is the in DMD is examined. Treatment of scoliosis in intermediate spinal muscular atrophy (SMA type II) in childhood. Ortop Traumatol Rehabil, 7: 175-9 Schmidt R, Pitto RP, Kress A, Ehremann C, Nowak TE, Re- ulbach U, Forst R, Müller L (2005) Inter- and intraobserver assessment of periacetabular osteodensitometry after cemented and uncemented total hip arthroplasty using computed tomography. Arch Orthop Trauma Surg, 125: 291-7 Fujak A, Wollinsky KH, Forst R (2007) Proximal spinal muscular atrophy (SMA). Z Orthop Unfall, 145: 233-52 Mueller LA, Nowak TE, Mueller LP, Schmidt R, Ehrmann C, Pitto RP, Pfander D, Forst R, Eichinger S (2007) Acetabular cortical and cancellous bone density and radiolucent lines after cemented total hip arthroplasty: a prospective study using computed tomography and plain radiography. Arch Orthop Trauma Surg, 127: 909-17 Mueller LA, Voelk M, Kress A, Pitto RP, Schmidt R (2007) An ABJS Best Paper: Progressive cancellous and cortical bone remodeling after press-fit cup fixation: a 3-year followup. Clin Orthop Relat Res, 463: 213-20 Fujak A, Forst R, Forst J (2008) Outcome after Achilles tendon lengthening with a posterior capsulolysis according to Imhäuser in idiopathic congenital clubfoot. Ortop Traumatol Rehabil, 10: 367-76 Radiostereoanalysis after total hip arthroplasty is based on the radiographic evaluation of small tantalum markers and calibration cages which permit an accurate (1-250μm and 0.03-0.6°) International Cooperation three-dimensional analysis of the migration pattern of the prosthesis. Gaetano Conte Academy, Neapel, Italy Institute Duchenne de Boulogne, Poitiers, France

Meetings and International Training optimising of orthopaedic treatment, improve- Computer assisted surgery of the hip joint Courses ment of the medical care and of the quality of The aim of this study is to develop a navigation Repetitorium Orthopaedie und Unfallchirugie, Banz, life of these patients. The studies are particular- system for total hip arthroplasty and to use it Deutschland, Stiftung Akademie Deutscher Orthopaeden ly focused on anterior horn cell diseases, spinal for the surgery process as well as to test the ac- muscular atrophies, post polio syndrome and curay of the system with integrated modules. muscular dystrophies. The sytem works with three-dimensional CT- Although knowledge of the gene defect and data. The received data are used for the vir- the coded protein – the dystrophin – to date tual positioning of the implant preoperatively. there is no causal therapy of Duchenne mus- Intraoperatively the navigation system com- cular dystrophy (DMD) – the most common pares the virtual data with the surgical view to neuromuscular disease. The natural history of achieve an exact position of the implant. The this disease includes beside the obligatory re- preoperative CT is then compared with a new strictive respiratory insufficiency and the car- postoperative CT to evaluate the accuracy of diomyopathy contractures of the extremities the implantation. Postoperatively osteointe- and progressive scoliosis in almost all patients. gration of the implant is analysed using CT-os- The results of operative treatment of contrac- teodensitometry. Thus for all steps (planning, tures of lower extremities particularly in early surgery and evaluation) of computer assisted course of the disease are investigated in pro- surgery highly precise measurements are con-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 63 CLINICALClinical THEORETICAL Chairs addi INSTITUTEStionally to the University Hospital

Department of Orthopaedics in the Waldkrankenhaus Division of Orthopaedic Rheumatology

Address Research Rathsberger Strasse 57 91054 Erlangen Cellular and molecular basis of cartilage Phone: +49 9131 8223305 degeneration and regeneration Fax: +49 9131 8223340 Besides clinical and epidemiological studies www.orthop.-rheum.med.uni-erlangen.de on human osteoarthritis, the research work fo- Head of Division cussed on the pathomechanisms of osteoar- Prof. Dr. med. Bernd Swoboda thritis and differentiation patterns of chondrocytes. Based on these biomolecular principles, Contact novel strategies for regeneration and repair of Prof. Dr. med. Bernd Swoboda articular cartilage were investigated. Phone: +49 9131 8223305 1) The role of hypoxia for chondrocyte differ- Fax: +49 9131 8223340 entiation and cartilage metabolism Immunohistochemical detection of cellular hypoxia in [email protected] Project manager: K. Gelse articular cartilage and meniscus of murine knee joints erlangen.de Articular cartilage is an avascular tissue and, thus, characterized by severe hypoxic condi- Research Focus tions. Chondrocytes are well adapted to such • Cellular and molecular basis of cartilage low oxygen levels. In this respect, the transcrip- degeneration and regeneration tion factor Hypoxia inducible factor-1 (HIF- • Endoprostheses for degenerative and inflam- α 1 ) does not only play an important role for the matory joint diseases α metabolic adaption of the cells, but also for the • Arthroscopic synovectomy in rheumatoid differentiation of chondrocytes. We could dem- of these proteins. Using adenoviral and AAV- patients onstrate that HIF-1α is essential for the survival based gene transfer systems, we could achieve and activity of the chondrocytes within the ar- the secretion of biologically relevant amounts ticular cartilage. In an animal model, the chem- of IGF-1 and BMP-2 for a period of sever- Structure of the Institution ical inhibition of this factor resulted in signifi- al weeks. The therapeutical potential of mes- cant apoptosis of the chondrocytes coinciding enchymal stem cells stimulated by such gene The Division of Orthopaedic Rheumatology is with servere degenerative changes of the artic- therapy approaches was investigated in an an- an independent institution of the Friedrich-Al- ular cartilage. Furthermore, it could be shown imal model with large cartilage defects with- exander University which is associated to the that the chondrocyte phenotype is associated in the knee joint. In these experiments, only Department of Orthopaedics. with the activity of HIF-1α. In cartilage repair BMP-2 gene transfer proved to be a sufficient Clinical activities focus on the treatment of tissues, transplanted mesenchymal stem cells stimulus to efficiently induce chondrogenic dif- patients with degenerative and inflammatory differentiated into chondrocytes exclusively in ferentiation of the cells and to support, at least joint diseases. The head of the department is deeper hypoxic tissue layers, while in more su- transiently, the generation of hyaline-like car- also speaker of the Erlangen Arthritis Centre perficial layers with higher oxygen levels, the tilage repair tissue. However, in the long term, which is an interdisciplinary association of phy- cells only adopted a fibroblast-like phenotype. with a decline of transgene expression, a recur- sicians treating these patients. In this respect, we could demonstrate that the ring dedifferentiation of the mesenchymal cells Clinical research activities concentrate on the growth-factor bone morphogenetic protein-2 could be observed which coincided with a de- evaluation of surgical treatments. Of interest efficiently induced chondrogenesis even in terioration of the repair tissue quality. are preventive procedures like synovectomies. areas of the repair tissue with higher oxygen As an alternative for cell stimulation by gene Comparing joint replacements in patients with levels. Interestingly, this was strongly associ- therapeutical methods, a further project in- degenerative and inflammatory joint diseases ated with a striking increase in HIF-1α activity. vestigated the endogenous secretory-para- will help to identify different preoperative find- Current research investigates the role of hypox- crine potential of autologous chondrocytes. ings, different intraoperative challenges as well ia and HIF-1α as a therapeutic tool for the gen- We could show that rib chondrocytes represent as long term patients´ satisfaction. eration of hyaline repair cartilage. an endogenous source for chondrogenic fac- Another focus of basic research are the mecha- 2) Cell- and gene therapy approaches for car- tors (including BMP-2). Chondrocytes, which nisms of induction and progression of osteoar- tilage regeneration were applied in form of cell spheroids into the thritis. Projects are funded by the DFG and the Project manager: K. Gelse subchondral bone plate of cartilage lesions, ex- IZKF. A better understanding of osteoarthritis A number of specific growth- and differentia- erted a positive paracrine chondrogenic effect will help to develop new therapeutic approach- tion factors, such as bone morphogenetic pro- on ingrowing mesenchymal stem cells from the es like tissue engineering. tein-2 (BMP-2) or Insulin-like growth factor-1 bone marrow and supported the formation of The scientific projects are done by two M.D.s (IGF-1) have the capability to induce and sup- secondary repair cartilage. The reservoir of fur- which are also involved in patient care and one port chondrogenic differentiation of mesen- ther endogenous factors, which are of thera- technician. Another scientist and two techni- chymal cells. Gene transfer of these factors may peutic value for cartilage and bone regenera- cians are funded by the DFG and The IZKF. be suited to provide a more prolonged supply tion, is currently intensively investigated.

64 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) duction of inflammatory infiltrates achieved Selected Publications by arthroscopic knee joint synovectomy in pa- Carl HD, Schraml A, Swoboda B, Hohenberger G (2007) tients with adult-onset rheumatoid arthritis Synovectomy of the hip in patients with juvenile rheumatoid with special regard to the removal site, using arthritis. J Bone Joint Surg Am, 89: 1986-92 preoperative and postoperative synovial tis- Grimmer C, Pfander D, Swoboda B, Aigner T, Mueller L, sue samples. Our results confirmed that ar- Hennig FF, Gelse K (2007) Hypoxia-inducible factor 1alpha is involved in the prostaglandin metabolism of osteoarthritic throscopic synovectomy effectively reduces cartilage through up-regulation of microsomal prostaglan- acute and chronic inflammatory infiltrates in din E synthase 1 in articular chondrocytes. Arthritis Rheum, patients with RA who have refractory synovitis 56: 4084-94 of the knee and improves knee function. How- Pullig O, Tagariello A, Schweizer A, Swoboda B, Schaller ever, the reduction of inflammatory infiltrates P, Winterpacht A (2007) MATN3 (matrilin-3) sequence variation (pT303M) is a risk factor for osteoarthritis of the appears to depend on the anatomic region of CMC1 joint of the hand, but not for knee osteoarthritis. the joint, so that additional measures such as Ann Rheum Dis, 66: 279-80 radiation synovectomy may be applied. Gelse K, Mühle C, Knaup K, Swoboda B, Wiesener M, Hen- nig F, Olk A, Schneider H (2008) Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage Degeneration of articular cartilage of femur (F) and repair tissue is associated with increased HIF-1alpha activity. tibia (T) with the formation of osteophytes (*) in the Teaching Osteoarthritis Cartilage, 16: 1457-65 murine knee Gelse K, Pfander D, Obier S, Knaup KX, Wiesener M, Hennig Staff of the Division of Orthopaedic Rheuma- FF, Swoboda B (2008) Role of hypoxia-inducible factor 1 tology is active in the curriculum for general alpha in the integrity of articular cartilage in murine knee orthopaedics. Specialized lectures are on prob- joints. Arthritis Res Ther, 10: R111 Endoprostheses for degenerative and lems of arthritis surgery and the basics of osteo- International Cooperation inflammatory joint diseases arthritis induction and progression. Prof. Dr. T. Kirsch, PhD, Departement of Orthopaedic Sur- Project manager: B. Swoboda Students are welcome to visit us when treating gery, Director of MusculoskeletaL Research Centre, 301 East The aim of this observational study is to identi- ambulant patients or in the OR when doing sur- 17 th Street Suite 1500, New York, NY 1003, USA fy differences in the treatment of patients with gery on rheumatoid patients. Meetings and International Training degenerative and inflammatory joint diseases Courses undergoing joint replacement surgery. Preop- 23.06.2007: Frueharthritis, Kollegienhaus Friedrich-Alexan- erative findings, intraoperative differences as der University Erlangen-Nürnberg well as the patients’ satisfaction will be docu- 19.04.2008: Der entzuendliche Rueckenschmerz, Kollegien- mented. Since joint replacements in rheuma- haus, Friedrich-Alexander University Erlangen-Nürnberg toid patients are frequently done at an early age, a focus will be long-term results after joint replacement, especially of the knee.

Arthroscopic synovectomy in rheumatoid patients Project manager: H.-D. Carl We investigated the results following synovectomy in studies comprising patients with juvenile and adult-onset rheumatoid arthritis. A study on open hip joint synovectomy in JIA patients was performed in collaboration with the Orthopaedic accident clinic Rummelsberg. Evaluating a series of sixty-seven open hip-joint synovectomies carried out in fifty-six patients with juvenile rheumatoid arthritis, we showed that open hip synovectomy in patients with juvenile rheumatoid arthritis is a safe procedure that can improve hip-joint function for up to five years. A histologic and immunohistochemical study was carried out in collaboration with Prof. R. Kinne, Experimental Rheumatology Unit, Uni- versity of Jena, to assess the intraoperative re-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 65 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 1 – Gastroenterology, Lung Diseases and Endocrinology Chair of Internal Medicine I

Address drome) were characteristic for metabolic and search topic. Here, model of inudec arousals Ulmenweg 18 psychologic factors and intervention strategies by nCAPA is under development. 91054 Erlangen compared to alimentary adipositas. The knowl- Phone: +49 9131 8535000 edge status of patients with primary or second- Drug safety and pharma- Fax: +49 9131 8535209 ary adrenal insufficiency regarding hormone covigilance www.medizin1.uk-erlangen.de substitution was evaluated and teaching con- Project manager: H. Dormann Head of Department cepts were established. We investigated meta- A database of unwanted side effects was es- Prof. Dr. med. Markus F. Neurath bolic and inflammatory parameters in patients tablished. Aspects of epidemiology, risk pro- witgh OSAS. files and predictors of side effects were ana- Contact lysed with a special focus on malnutritioned Ulrike Uhlich Experimental hepatology & oncology patients. The KLASSE system was established Phone: +49 9131 8535204 Project manager: M. Ocker on collaboration with the department of phar- Fax: +49 9131 8535209 The group investigates translational approach- macology, the Department of Medicine 1 and [email protected] es for therapy and pathogenesis of gastroen- the Pharmacy of the University Regensburg terologic and hepatologic diseases. The expres- and the Hadassah University in Jerusalem, Isra- Research Focus sion of embryonic genes as a prognostic factor el. The system was introduced in various hos- • Endocrinology in pancreatic cancer was investigated. Mecha- pitals. A further system for optimised prescrip- • Experimental hepatology & oncology nisms of epigenetic tumor therapy and iden- tion of antiinfective drugs was established on • Intensive Care, Infectious Diseases, Tropical tification of alternative pathways of apoptosis the basis of medical logic modules and a strat- and Travel Diseases by HDAC inhibitors are a focus in hepatocellu- ified drug safety database. The GaID system • Clinical and experimental pneumology lar carcinoma. This project was continued to a generates individuale risk profiles and contra- • Drug safety and pharmacovigilance phase I clinical trial. In an animal model of he- indications. In cooperation with BfArM, PEI, • Gastroenterologic oncology patocellular carcinoma (HCC), the technique the national drug safety commission and the • Ultrasound of transarterial chemoembolisation was estab- department of psychiatry, hepatic side effects • Inflammatory bowel diseases lished. We also established a model of liver fi- of drugs were analysed. • Meetings and continuing education brosis in cannabinoid receptor knockout mice. • International cooperations Gastroenterologic oncology Intensive care, infectious diseases, tropical Project manager: A. Wein and travel diseases The IVOPAK project was performed together Structure of the Institution Project manager: R. Strauß with the department of surgery and gives evi- Incidence and extensity of posttraumatic stress dence on the treatment of patients with met- The Department of Medicine 1 covers research syndrome were investigated in intensive care astatic colorectal cancer in Northern Bavaria. in the fields of gastroenterology, hepatolo- patients. A multicenter study on the influence The multicenter phase II trial on Irinotecan and gy, metabolism and nutrition, endocrinology, of dornase alpha on lung function and venti- 5-FU after progression of platinum-based first- pneumology, intensive care medicine, infec- lation time was closed. Dosage of pharmaceu- line treatment in patients with colorectal can- tious diseases, endoscopy and ultrasound. ticals, esp. antiinfective drugs, are difficult to cer was continued. A prospective multicenter Several research groups investigate these fields calculate in intensive care patients. In a pilot phase II trial (InTACT II-GeMicAn) investigates in clinical and experimental approaches. Re- project, we obtained data on therapeutic drug gene expression profiles in primary colorectal cently, projects in the area of medical teaching monitoring in intensive care patients. A Ger- cancers to investigate if risk patterns predicting were established. man-Arabic alumni network was established a disease recurrence could be identified. together with the German Academic Exchange A new project on the influence of a palliative Service (DAAD). second line treatment on life quality in patients Research with metastatic colorectal cancer was estab- Clinical and experimental lished. A phase II trial on palliative care in pa- Endocrinology pneumology tients with gastric cancer was prepared. Project manager: I. Harsch Project manager: F. Fuchs Metabolic characteristics and coincidence with Metabolic effects of sleep related breathing dis- Ultrasound obstructive sleep apnea sydrome (OSAS) as orders are the research focus of the group. Pre- Project manager: D. Strobel well as effects of appetite regulating hormones vious results showing an amelirotation of insu- Ultrasound contrast enhancers allow to differ- were investigated in patients with diabetes lince resistance under therapy were confirmed. entiate solid liver tumors. In collaboration with mellitus. In an experimental setting, we inves- Currently, the effects of continuous positive air- the German society for ultrasound in medi- tigated wound healing in diabetic pigs. Psy- way pressure (CPAP) therapy on plasma levels cine, the following multicenter trials were er- chological factors and expression of adenosin of obestatin, apelin and visfatin are investigat- stablished: 1) characterisation of liver tumors, deaminase were investigated in patients with ed. We also examined the influence of an opti- 2) detection of liver metastases in colorectal autoimmune thyroiditis. Patients with multiple mized diabetes therapy on OSAS. Mechanisms cancer, 3) detection of liver metastaes in pan- symmetric lipomatosis (Launois Bensaude syn- of arousal reactions in OSAS are a further re- creatic cancer.

66 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) View to the Departments of Medicine 1 and Medicine 2 Source: University Hospital Erlangen

Tumor differentiation by ultrasound contrast medicine, physical examination course, inter- colon tumor cell invasion and inhibits tumor growth in enhancers was investigated in patients with nal medicine) and with models and simulators. murine colon cancer models. J Cell Mol Med, 12: 330-42 solid pancreas and kidney tumors. A pilot trial Several lectures deal with general internal med- International Cooperation on computer assisted quantification of contrast icine and the different foci of the clinic. The international collaborations of the department are listed enhancement in liver tumors was performed. at http://www.medizin1.klinikum.uni-erlangen.de The value of high resolution ultrasound in com- Selected Publications parison to MR-Sellink was analysed. Meetings and International Training Courses The application of ultrasound-guided percuta- Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, Meier-Hellmann A, Insel neous high frequency thermotherapy was in- Please visit our internet page to find an overview on the various R, Radke J, Schuettler J, Gaertner R (2007) Selenium in meetings and continuing education topics at the department: vestigated in hepatocellular carcinoma. In ad- Intensive Care (SIC): results of a prospective randomized, http://www.medizin1.uk-erlangen.de/e114/index_ger.html dition to local effects on tumor integrity, im- placebo-controlled, multiple-center study in patients with munostimulatory effects were obserevd in an severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med, 35: 118-26 animal model and in patients. The spectrum Okamoto K, Ocker M, Neureiter D, Dietze O, Zopf S, of side effects after ultrasound guided interven- Hahn EG, Herold C (2007) bcl-2-specific siRNAs restore tions in the abdomen was investigated. gemcitabine sensitivity in human pancreatic cancer cells. J Cell Mol Med, 11: 349-61 Inflammatory bowel diseases Wagner AD, Buechner-Steudel P, Wein A, Schmalenberg H, Project manager: M. Raithel Lindig U, Moehler M, Behrens R, Kleber G, Kuss O, Fleig WE (2007) Gemcitabine, oxaliplatin and weekly high-dose 5-FU The following projects were investigated: 1) as 24-h infusion in chemonaive patients with advanced or Differentiation of IgE- and non-IgE-mediated metastatic pancreatic adenocarcinoma: a multicenter phase allergies in the gastrointestinal tract. 2) Deter- II trial of the Arbeitsgemeinschaft Internistische Onkologie mination of luminal TNFalpha and of plasma (AIO). Ann Oncol, 18: 82-7 levels of TNF and histamine in IBD. 3) Levels of Boeck S, Hoehler T, Seipelt G, Mahlberg R, Wein A, Hoch- haus A, Boeck HP, Schmid B, Kettner E, Stauch M, Lordick leukotriene in urine (LTB4, LTC4, D4 and E4) in F, Ko Y, Geissler M, Schoppmeyer K, Kojouharoff G, Golf patients with IBD and mastocytosis. 4) Activ- A, Neugebauer S, Heinemann V (2008) Capecitabine plus ity of diaminoxidase in small intestine in cor- oxaliplatin (CapOx) versus capecitabine plus gemcitabine relation with plasma-DAO. 5) Mediator diag- (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in nostics from urine and plasma after histamine advanced pancreatic cancer. Ann Oncol, 19: 340-7 provocation tests Gali-Muhtasib H, Kuester D, Mawrin C, Bajbouj K, Diestel A, Ocker M, Habold C, Foltzer-Jourdainne C, Schoenfeld P, Peters B, Diab-Assaf M, Pommrich U, Itani W, Lippert Teaching H, Roessner A, Schneider-Stock R (2008) Thymoquinone triggers inactivation of the stress response pathway sensor CHEK1 and contributes to apoptosis in colorectal cancer The Department of Medicine 1 contributes to cells. Cancer Res, 68: 5609-18 curricular teaching for medical students from Gali-Muhtasib H, Ocker M, Kuester D, Krueger S, El-Hajj Z, 2nd to final year.T he necessary skills are tought Diestel A, Evert M, El-Najjar N, Peters B, Jurjus A, Roessner in practical courses in (introduction to clinical A, Schneider-Stock R (2008) Thymoquinone reduces mouse

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 67 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 2 – Cardiology and Angiology Chair of Internal Medicine II

Address Research Magnetic Resonance Tomography Ulmenweg 18 Project manager: M. Schmid, S. Achenbach 91054 Erlangen Cardiac computed tomography In collaboration with the the Institute of Radi- Phone: +49 9131 8535301 Project manager: S. Achenbach ology (Head Prof. Uder) and Siemens Medical Fax: +49 9131 8535303 A major focus of the internationally renowned Solutions, Erlangen, the research group focuses www.med2.med.uni-erlangen.de research group “Cardiac Computed Tomog- on the development and validation of new car- Head of Department raphy (CT)” is the development and valida- diac magnetic resonance techniques in clinical Prof. Dr. med. Werner G. Daniel tion of new techniques for coronary artery vi- studies. One field is prognostic importance of sualization by contrast-enhanced CT, as well T2 weighted and contrast-enhanced imaging Contact as the analysis of the accuracy for detection of after myocardial infarction and the determina- Prof. Dr. med. Werner G. Daniel coronary artery stenoses in various clinical sit- tion of infarct size as an surrogate endpoint for Phone: +49 9131 8535301 uations (Fig. 1). Similarly, the use of CT tech- research studies. Studies of myocardial perfu- Fax: +49 9131 8535303 niques to detect, quantify and characterize cor- sion with adenosine stress using new high-res- [email protected] onary atherosclerotic plaque especially in the olution sequences are another focus of interest. context of acute coronary syndromes is a main Furthermore, in suspected peri-myocarditis, Research Focus area of research. Further topics are efforts to reso-called edema-sensitive sequences are evalu- • Cardiac computed tomography duce radiation exposure in cardiac CT, analysis ated to detect the acute inflammatory process. • Echocardiography of post-processing tools for coronary CT angi- Additional research topics are the non-invasive • Magnetic Resonance Tomography ography and analysis of myocardial perfusion quantitation of valvular heart disease, in partic- • Interventional cardiology by contrast-enhanced CT. Researchers and cli- ular aortic stenosis, with comparison to estab- • Electrophysiology nicians of the Department of Cardiology col- lished standards (echo, catheterization), mor- • Molecular and experimental cardiology laborate closely with colleagues from the De- phologic and functional MRI imaging in stress partment of Radiology as well as the Institute cardiomyopathy (tako-tsubo) and characteriza- of Medical Physics (Prof. Dr. med. W. Kalender). tion and localization of myocardial fibrosis in di- Structure of the Institution Further national and international cooperations lated cardiomyopathy. exist for example with the German Heart Cen- The department is the internal medicine de- tre, Munich, the University Hospital in Zurich partment focussing on cardiology and angiol- and the Massachusetts General Hospital, Bos- ogy. Together with the Department of Cardiac ton, MA, USA. Surgery, the Division of Pediatric Cardiology and the Division of Pediatric Cardiac Surgery, Echocardiography the Department of Medicine 2 forms the Uni- Project manager: F. A. Flachskampf versity Heart Centre of Erlangen. The depart- The echocardiography research group focuses ment is a tertiary referral centre offering the on tissue Doppler and deformation (“strain”, full array of in-patient and out-patient diag- “2D strain”) imaging, especially in the field nostic and therapeutic options for cardiovas- of ischemia detection, the identification of cular diseases, including advanced techniques heart failure patients who benefit from car- like ablation therapy of atrial fibrillation or diac resynchronization therapy, and myocar- interventional aortic valve replacement. The dial deformation characteristiscs in patients department employs 37 physicians, eight of with aortic valve disease before and after valve them have permanent teaching positions at replacement. Further topics are the techni- the Medical Faculty (Habilitation), a biologist, cal foundations for ultrasound thrombolysis, and 109 non-physician nursing or supporting echocardiography (including contrast echo- staff. It possesses two large normal care wards, cardiography) in small-animal models of myo- Fig. 1: Cardiac computed tomography. 3D visualization an coronary care unit, three cath lab suites, and cardial infarction (together with the Institute of coronary morphology by “dual source” computed to- an out-patient department with several special- for Clinical Pharmacology and Toxicology) and mography. The arrow indicates a severe narrowing of the ized clinics for heart failure, congenital heart in the application of engineered heart tissue left anterior descending artery. disease, arrhythmias and pacemakers/defibril- as a therapeutic option in experimental heart lators. Furthermore, the department disposes failure. Several members of the internationally of a large basic-science laboratory. renowned group were voted members of the Interventional cardiology board of the European Association of Echocar- Project manager: J. Ludwig diography. The group holds a yearly workshop The main fields of interest of this research on new echocardiographic techniques. group are the interventional treatment of coronary artery disease and interventional aortic valve replacement in the elderly. In the first field, advanced techniques for treatment of cor-

68 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) onary bifurcation are being developed using cently, C-reactive protein and its receptor Teaching on-line 3D quantification of coronary anatomy. (FcγR) moved into the focus of atheroscle- A further focus lies on treatment of the acute rosis research. Collecting a large patient da- The department provides 25 teaching activities coronary syndrome by improving coronary mi- tabank enabled us to examine the role of C- (from lecture to practical exercise) per semes- crocirculation through pharmacologic modula- reactive protein (CRP) and FcγR in the ini- ter. Members of the department repeatedly tion of free radicals to ultimately minimize in- tiation, progression, and destabilization of won the prize for good teaching of the Medi- farct size and thus improve patient prognosis. coronary plaques. In parallel with clinical in- cal Faculty. Interdisciplinary teaching events are Together with the department of heart surgery, vestigations, the pro-inflammatory effects of organized together together with other depart- transapical and percutaneous aortic valve re- CRP and its receptor on human endothelial ments. The department is also involved in the placement is evaluated, with special attention cells has been characterized. planning, development, and implementation to post-interventional arrhythmias and cere- b) CRP has a damaging effect on vessels and of the newly created curriculum of “medical bral ischemia. myocardium. In the rat model of myocar- process management”. The cardiac computed dial infarction (MI) we investigate the ef- tomography group holds regular international Electrophysiology fect of human CRP on myocardial necrosis. courses in this method, and the echocardiog- Project manager: M. Wilhelm We will determine the possibility of limiting raphy group organizes a yearly workshop on The electrophysiology research group partic- the deleterious effect of CRP on myocardi- new techniques. Hospitations for guest physi- ipates in several multicenter studies of new um by using the specific neutralizing anti- cians can be arranged in all laboratories of the technology implemented in implantable de- CRP antibodies. department. fibrillators (ICD). In the ACTION study, heart c) DC (dendritic cells) play an important role in failure patients undergo home monitoring dur- atherosclerosis. Our previous studies showed Selected Publications ing an individualized physical exercise training that DC participate in plaque destabilization Flachskampf FA, Gallasch J, Gefeller O, Gan J, Mao J, Pfahl- program. Another study examines the clini- and MI, and that their functions can be mod- berg AB, Wortmann A, Klinghammer L, Pflederer W, Daniel cal value of a lung water sensor in heart fail- ulated by statins. The present studies focus WG (2007) Randomized trial of acupuncture to lower blood pressure. Circulation, 115: 3121-9 ure patients for monitoring therapy (Biotronik on the role of DC in coronary artery disease, Lumax 540 HF-T). All ICD patients are included restenosis and stroke, the long-term aim Ropers U, Ropers D, Pflederer T, Anders K, Kuettner A, Stilianakis NI, Komatsu S, Kalender W, Bautz W, Daniel WG, in a structured, prospective follow-up program. being establishing DC as potential canditates Achenbach S (2007) Influence of heart rate on the diagnos- In a further project, candidates for cardiac re- for therapeutic interventions. tic accuracy of dual-source computed tomography coronary synchronization therapy are pre-operatively d) Calcification and stenosis of aortic valves angiography. J Am Coll Cardiol, 50: 2393-8 analyzed by cardiac computed tomography bears important similarity to atherosclero- Yilmaz A, Lipfert B, Cicha I, Schubert K, Klein M, Raithel D, with regard to their asynchrony. sis. Our micro-array analyses of stenosed Daniel WG, Garlichs CD (2007) Accumulation of immune cells and high expression of chemokines/chemokine recep- In patients undergoing ablation therapy of valves detected a number of differential- tors in the upstream shoulder of atherosclerotic carotid atrialfibrillation by cryo-balloon, 3-dimension- ly expressed pro-inflammatory genes. The plaques. Exp Mol Pathol, 82: 245-55 al fusion imaging based on electro-anatomical role of these genes in development of aor- Cicha I, Goppelt-Struebe M, Muehlich S, Yilmaz A, Raaz D, mapping and cardiac computed tomography is tic valve stenosis is currently under investi- Daniel WG, Garlichs CD (2008) Pharmacological inhibition being developed and refined (Fig. 2). gation. of RhoA signaling prevents connective tissue growth factor induction in endothelial cells exposed to non-uniform shear Finally, professional football players are system- e) Using bifurcating flow-through cell culture stress. Atherosclerosis, 196: 136-45 atically evaluated by ECG and other non-inva- slides which mimic in vivo shear stress pat- Schmid M, Pflederer T, Jang IK, Ropers D, Sei K, Daniel sive techniques. terns, we investigate the impact of laminar WG, Achenbach S (2008) Relationship between degree and disturbed flow on important atherogen- of remodeling and CT attenuation of plaque in coronary esis-related endothelial functions, such as atherosclerotic lesions: an in-vivo analysis by multi-detector computed tomography. Atherosclerosis, 197: 457-64 recruitment of leukocytes and platelets, expression of inflammatory proteins, and re- Stumpf C, Lehner C, Raaz D, Yilmaz A, Anger T, Daniel WG, Garlichs CD (2008) Platelets contribute to enhanced MCP-1 lease of cytokines. levels in patients with chronic heart failure. Heart, 94: 65-9 f) C-kit+/CD34-/CD45- adult cardiac progenitor cells were found to be part of the physio- International Cooperation logical regeneration process of the myocar- Thomas J.Brady, Massachusetts General Hospital, Harvard dium in animal studies. We analyze exper- University, Boston, USA imentally the presence and distribution of Research Equipment adult cardiac progenitor cells in hearts from Siemens Healthcare Herzkatheter-Angiographieanlage (3 terminal heart failure cases. Labore) g) In patients with arterial hypertension and GE Healthcare Vivid 7 (2 Geraete) chronic heart failure, the association of in- Siemens Healthcare Dual Source Computertomograph flammatory biomarkers with the extent of Philips Echokardiographiegeraet ie33 Fig. 2: Fusion imaging of cardiac computed tomography diseseas has been investigated. and electro-anatomical mapping to enable detection and h) Analyses of differential expression of cyto- Biosense Webster (Johnson & Johnson) Carto Biosense percutaneous catheter ablation of tachycardias (arrhyth- kines and chemokines in order to predict Webster Electroanatomical Mapping System mias with rapid heart beat). coronary calcifications and coronary stenoses in patients undergoing cardiac CT.

Molecular and experimental cardiology Project manager: A. Yilmaz, C. Stumpf, C. Gar- lichs Atherosclerosis is a chronic inflammatory disease. The research projects of the group therefore focus on new pathomechanisms of this inflammatory disease in order to identify innovative strategies for its treatment and prevention. a) Inflammatory / immunological mechanisms play an essential role in atherogenesis. Re-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 69 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 3 – Rheumatology and Immunology Chair of Internal Medicine III

Address Research - Analysis of inflammatory mechanisms in adult Krankenhaussstrasse 12 onset Still´s disease 91054 Erlangen Clinical Immunology and Rheumatology Project manager: J. Rech, B. Manger Phone: +49 9131 8533363 - Pathomechanisms of bone destruction in Inflammatory mechanisms and cytokine pro- Fax: +49 9131 8534770 rheumatoid arthritis files in Patients with adult onset Still´s disease www.med3.med.uni-erlangen.de Project manager: G. Schett, J. Zwerina are analyzed with respect to clinical presenta- Head of Department RA is one of the most common inflammato- tion and outcome to identify therapeutic strat- Prof. Dr. med. Georg Schett ry rheumatic joint diseases with an estimated egies for this rare disease. prevalence of 1%. Chronic arthritis, if poorly - Mechanisms for the activation of fibroblasts Contact controlled, typically provokes extensive joint in systemic sclerosis (SSc) Prof. Dr. med. Georg Schett damage with the emergence of bone destruc- Project manager: J. Distler Phone: +49 9131 8539133 tion associated with significantly decreased Ssc is characterized by a progressive accumu- Fax: +49 9131 8534770 functional capacities. Hence, the project group lation of extracellular matrix components with [email protected] focuses on the pathophysiology of bone de- progressive fibrosis of the involved organs. struction by the use of experimental arthritis The fibrosis is mediated by an excessive, un- Research Focus models. They investigate the mechanisms lead- controlled production of extracellular matrix • Clinical Immunology and Rheumatology ing to increased synovial activation of osteo- by fibroblasts. However, therapies to inhibit • National and International Clinical Trials clasts and decreased ability to repair bone de- selectively the overproduction of extracellu- • Immunodeficiencies and Infectious Diseases struction with the help of osteoblasts. lar matrix and prevent fibrosis are lacking. The • Immunogenetics and Transplant - Immunomodulatory effects of apoptotic and research group investigates novel signaling cas- immunology necrotic cells cades that lead to activation of fibroblasts and Project manager: M. Herrmann, R. Voll studies potential therapeutic approaches to in- During the execution of apoptosis and necro- hibit the overproduction of extracellular matrix Structure of the Institution sis the cellular surfaces get modified. These by SSc fibroblasts. changes are the basis for the clearance of the - Activation of synovial fibroblasts by micropar- Up to September 2007 the Department of dying cells in vivo. In contrast to the pro-in- ticles in rheumatoid arthritis (RA) Medicine 3 covered the fields of Immunology, flammatory clearance of necrotic cells, apop- Project manager: J. Distler Rheumatology, Hematology and Oncology. totic cells are eliminated without inflammation Microparticles, released from cytokine acti- With the appointment of Prof. Mackensen, the and immune response. This fact has important vated and apoptotic leukocytes, accumulate Department got divided into the present De- consequences for both, the etiopathogenesis in high numbers in the involved joints in pa- partment of Medicine 3 (Rheumatology and of autoimmunity and for the development of tients with RA. The group could demonstrate Immunology) under the administration of Prof. tumor vaccines. that microparticles represent a novel mecha- Dr. med. Georg Schett and the new instituted - Regulation of NF-κB nism for inter-cellular communication. Mic- Department of Medicine 5 under the adminis- Project manager: R. Voll, M. Herrmann roparticles might thus play an important role tration of Prof. Dr. med. Andreas Mackensen. This transcription factor serves a major role in in the pathogenesis of RA by triggering a vi- Different research groups are investigating the the transcriptional regulation of many genes cious circle of inflammation and bone-erosion. inflammatory joint diseases: pathogenesis and which are involved in inflammation and im- The mechanisms, by which microparticles ac- development of therapeutic strategies; patho- mune response. Furthermore, NF-κB-activation tivate synovial fibroblasts, are currently a major genesis of autoimmune diseases, systemic vas- induces various anti-apoptotic factors. The lat- focus of the group. culitis, therapeutic strategies for immune defi- ter are able to prevent cell death. Due to the - Pathogenesis of RPGN in ANCA-associated ciencies, infectious immunology, immunoge- central role of NF-κB for inflammation and im- systemic vasculitides netic, diagnosis and treatment of allergic dis- mune response a targeted inhibition of NF-κB Project manager: J. Zwerina eases, clearance of apoptotic cells and pursue is supposed to be a very efficient new princi- The group investigates the mechanisms of the clinical trials. ple for the therapy of inflammatory diseases. activation of intrinsic renal cells and infiltrating The Department of Medicine 3 got awarded as - Analysis of risk factors and long-term outcome immune cells that lead to an massive up-regu- “EULAR Centre of Excellence”, with the DVO in patients with systemic lupus erythematosus lation of pro-inflammatory cytokines and pro- Research Unit Award and Dr. Joerg Distler was Project manager: B. Manger liferation leading to the crescent formation in awarded with the Career Promotion Award. In a cohort of 410 SLE patients genetic, sero- affected glomeruli. Potential candidate mole- logical and clinical predictors for long-term cules responsible for this deregulation are in- outcome are analyzed in retrospective and vestigated in kidney biopsies of patients with prospective studies. One focus is the investi- a RPGN as well as experimental RPGN models. gation of premature atherosclerosis and ovar- - The role of 12/15-lipoxygenase (12/15-LO) in ian failure in SLE. the regulation of innate and adaptive Immunity Project manager: G. Kroenke 12/15-LO is a central arachidonic acid-metabolizing enzyme. The aim of this project is to

70 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) elucidate the molecular role of 12/15-LO and and clinical research on development and eval- Selected Publications its metabolites in macrophages and dendritic uation of new therapeutic and diagnostic pro- Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkon- cells. Moreover, a potential involvement of this cedures. The clinic is working on the develop- taite I (1997) Immunosuppressive effects of apoptotic cells. enzyme in the phagocytosis of apoptotic cells ment of immunotherapies such as therapeutic Nature, 390: 350-1 and during the interaction between DCs and vaccines and immunomodulators. The clinic Bondanza A, Zimmermann VS, Rovere-Querini P, Turnay T-lymphocytes will be investigated. In addi- participated in national and international clini- J, Dumitriu IE, Stach CM, Voll RE, Gaipl US, Bertling W, Pöschl E, Kalden JR, Manfredi AA, Herrmann M (2004) tion, Dr. G. Kroenke studies the role of 12/15- cal studies including studies for the evaluation Inhibition of phosphatidylserine recognition heightens the LO during chronic inflammatory diseasesin vivo of new innovative therapeutics of HIV-infection immunogenicity of irradiated lymphoma cells in vivo. J Exp using 12/15-LO deficient mice and various dis- such as preventive and therapeutic vaccines Med, 200: 1157-65 ease models (TNF-transgenic mice, collagen- with recombinant MVA-Nef vectors. In addi- Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dw- induced arthritis). tion other projects are investigating further yer D, Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G - Allergology infectious and immunologic diseases such as (2007) Dickkopf-1 is a master regulator of joint remodeling. Project manager: G. Eger Borrelia burgdorferi infections, chronic fatigue Nat Med, 13: 156-63 The group of Internistic Allergology is work- syndrome and humoral immunodeficiencies. McInnes IB, Schett G (2007) Cytokines in the pathogenesis ing on the diagnosis and the development of of rheumatoid arthritis. Nat Rev Immunol, 7: 429-42 new treatment principles for allergological dis- Immunogenetics and Transplant Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann ease entities. These disease entities include immunology K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE (2008) bronchitic asthma, chronic sinusitis, food and Project manager: B. Spriewald The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. drug allergies/hypersensitivities, contact aller- The laboratory provides service for the Nat Med, 14: 748-55 gies and pollinosis as well as allergies against Eurotransplant area Northern Bavaria with the Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as animal hair and house dust. The group has suc- transplant centres Erlangen-Nürnberg, Würz regulators of immune responses. Nat Rev Immunol, 8: 34-47 cessfully developed a test procedure to differ- burg and Regensburg. The laboratory is accred- entiate so called Pseudoallergies within the re- ited by the European Federation of Immun- International Cooperation spiratory tract being induced by different med- genetics. One research area in collaboration Prof. G. Firestein, University of California, San Diego, USA ications, from allergological disorders i.e. pol- with the experimental cardiac surgery unit is Prof. E. Wagner, Prof J Penninger, Prof K Redlich, Prof J Smo- linosis or allergic asthma. the induction of transplantation tolerance and len, Institut fuer Molekulare Biotechnologie, Vienna, Austria the modulation of transplant arteriosclerosis Prof. S. Kiechl, Prof L Wildt, Univ.-Klinik Innsbruck, Austria National and International Clinical Trials through the application of donor alloantigen Prof. L. Joosten, Radboud University, Nijmegen, Netherlands Project manager: M. Baeuerle, M. Ronneberg- and co-stimulation blockade. An important Prof. J. B. Imboden, University of California, San Francisco, er, J. Wacker, C. Stach contribution to clinical research is the detection USA Various national and international studies were and differentiation of anti-HLA alloantibodies. Prof. J. Savill, Prof I Dransfield, The University of Edin- conducted, primarily to investigate new treat- Imunogenetic studies analyse polymorphisms burgh, GB ment approaches in rheumatic diseases. The of several cytokines and T cell regulatory genes Prof. D. S Pisetzky, Durham University, Durham, USA major focus of the therapeutic trials is on treat- and their association with rheumatic, malig- Prof. T. Swaak, Erasmus Universiteit Rotterdam, Netherlands ment with “biologicals” e.g. therapeutic prin- nant and endocrinological disorders. Prof. J. van de Winkel, University Medical Centre Utrecht, ciples which block the proinflammatory cyto- Netherlands kine tumornecrosis factor . Another focus is α Prof. A. Tincani, Hospital and University of Brescia, Italy the initiation and conduction of a multicenter Teaching Prof. D. Isenberg, Centre for Rheumatology Research, trial with the TNF-inhibitor infliximab in pa- London, GB tients with psoriatic arthritis. In the course of The education offered by the Department of Prof. O. P. Rekvig, University of Tromso, Norway international multicenter trials we are conduct- Medicine 3 is bound with lectures, courses and ing standardization seminars for examination internships into the master plan of teaching in Prof. S. Muller, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strassbourg, France techniques in patients with RA. the internal medicine. Prof. Y. Shoenfeld, Sheba Medical Centre, Tel-Hashomer, Graduate School Israel Immunodeficiencies and Infectious The graduate school is integrated in the Collab- Prof. A. Manfredi, Immunologia Clinica, Milano, Italy Diseases orative Research Centre (SFB) 643 and engaged Project manager: T. Harrer with strategies pf cellular immune intervention. Prof. B. Walker, Boston Medical Centre, Boston, USA The Department of Medicine 3 is an important Speaker: Prof M Herrmann. Prof. B. Autran, Hôpital Pitié-Salpêtrière, Paris, France treatment centre for patients with primary and Prof. A. Vandamme, Katholieke Universiteit Leuven, secondary immunodeficiencies, with HIV-infec- Netherlands tion and with a variety of other infectious dis- Research Equipment eases such as borrelia infections, chronic viral Scanco Medical AG XtremeCT in vivo MicroCT Scanner infections and patients with chronic fatigue syndrome. The major interest of research of the group are various aspects of HIV-infection such as immunology of HIV-infection and basic

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 71 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 3 – Rheumatology and Immunology Division of Molecular Immunology

Address and transcription factors. Subsequently, new marrow and differentiate via transitional stages Glueckstrasse 6 mouse models are being established by ho- into mature antigen-responsive B cells. 91054 Erlangen mologous recombination in ES cells and blas- Phone: +49 9131 8535913 tocysts as well as by pronucleus injections. The Nonsense-codon mediated decay (NMD) Fax: +49 9131 8539343 Division of Molecular Immunology is well inte- of non-functional mRNA (mRNA surveil- www.molim.uni-erlangen.de grated into the Erlangen research environment lance) Head of Division through its central location in the Nikolaus- Project manager: H.-M. Jaeck, J. Wittmann Prof. Dr. rer. nat. Hans-Martin Jaeck Fiebiger-Centre and through its leading role in Another major focus of research is the molec- research groups and training grants (e.g., Re- ular control of recognition and decay of non Contact search Unit (FOR832) and post graduate pro- functional Ig-mRNAs, a pathway that is termed Prof. Dr. rer. nat. Hans-Martin Jaeck gramme (GK592)). Nationally, the Division of nonsense-codon mediated decay (NMD) of Phone: +49 9131 8535912 Molecular Immunology is an important part non-functional mRNA (mRNA surveillance). Fax: +49 9131 8539343 of the study group (Arbeitskreis) Biology of B Nonsense Ig mRNA is encoded from non-pro- [email protected] lymphocytes within the DGfI (Deutsche Gesell- ductively rearranged Ig genes during B cell de- schaft fuer Immunologie.) velopment as a consequence of a defective VDJ Research Focus The overall research activities of the Division of recombination. As faulty mRNAs can be trans- • Nonsense-codon mediated decay (NMD) of Molecular Immunology focus on molecular as- lated into potentially toxic proteins, the eluci- non-functional mRNA (mRNA surveillance) pects of maturation and activation of antibody- dation of control mechanisms and factors in- • The role of small, non coding RNAs producing B cells, as well as the pathogenesis volved in mRNA decay is of particular interest (miRNAs) in the control of B cell maturation of B cell leukemia and autoimmune diseases. for B and T cell maturation. The role of NMD and antigen-induced B cell activation B-Lymphocytes express immunoglobulin (Ig) in central B cell maturation is currently ana- • Molecular control of early B cell receptors on their surface, which allows them lyzed in a mouse line, in which a specific NMD differentiation to recognize foreign antigens and pathogens. factor, which was discovered in our lab, can • Signaltransduction in B cells Ig receptors consist of two covalently associ- be conditionally deleted in developing B cell ated identical immunoglobulin heavy (IgH) progenitors. Structure of the Institution and two identical immunoglobulin light (IgL) chains, which differ from cell to cell in their The role of small, non coding RNAs The Division of Molecular Immunology was variable regions. When B cells are activated by (miRNAs) in the control of B cell founded as an independent section within the contact to pathogen, they develop into either maturation and antigen-induced Department of Internal Medicine 3 in 1997. The memory B cells or so-called plasma cells, the B cell activation laboratories reside in the Nikolaus-Fiebiger- latter of which then produce huge amounts of Project manager: H.-M. Jaeck, J. Wittmann Centre and the division is headed by Prof. Dr. soluble antibody molecules. These antibodies Another research focus is the role of microR- Hans-Martin Jaeck together with three senior then bind to the pathogen, leading to its elimi- NAs during central and peripheral develop- postdoctoral scientists, who supervise currently nation and/or destruction (Fig. 1). ment of B cells, the antigen-induced differenti- eight PhD students, five technicians and various B cells emerge from hematopoietic stem cells ation of mature B cells, as well as the pathogen- rotation students. The main scientific focus of in the bone marrow. During their maturation esis of diseases, such as multiple myeloma or the division concentrates on the humoral im- process, B cells pass different developmental EBV (Epstein-Barr virus) infection. miRNAs are mune response with a special emphasis on B stages characterized by the rearrangement small, 22-nt long, non coding RNAs that con- cell biology. In addition, members of the divi- of Ig gene segments, which starts at the IgH trol the expression of specific target genes at sion participate in teaching at the undergradu- locus and later at the IgL locus. Each of these the post-transcriptional level (Fig. 2). miRNAs ate, graduate and doctoral levels, which is re- processes needs to be carefully and tightly con- bind to the 3’-untranslated region of mRNAs, flected by a broad offer of lectures, seminars trolled to avoid the generation of self-reactive which results either in a block of translation or and lab courses. or leukemic B cells. One part of the first criti- an acceleration in the degradation of the target cal checkpoint in early B cell development is mRNA. miRNAs play a central role in the reg- the expression of the pre-B cell receptor (pre- ulation of cell fate and cell differentiation pro- Research BCR) in early progenitor B cells. Only cells that cesses in animals and plants. Dysregulation of express a functional IgH chain can assemble a miRNA expression was detected in various tu- Several research groups within the division ex- pre-BCR and subsequently receive signals for mors. Therefore, we are currently investigating amine molecular mechanisms of development, survival, proliferation and differentiation. Dur- the function of miRNAs during development activation and differentiation of B cells in cell ing the next developmental stage, rearrange- of normal B cells as well as the pathogenesis culture systems and transgenic mouse lines. ment takes place at the IgL locus, leading to the of Multiple Myeloma and B cell autoimmune Methods include state of the art molecular biol- synthesis of an IgL chain that is then assembled diseases. Currently, we are analyzing miRNA ogy, cultivation of primary B cells, flow cytom- with the IgH chain to form the B cell receptor expression profiles in different B cell stages etry and cell sorting, and mouse immunology. (BCR). The BCR is then controlled for binding and myeloma as well as lymphoma cells by Cell culture systems are being used to identify to self structures in the bone marrow environ- high-throughput-sequencing of miRNA librar- new, for instance miRNAs, adaptor proteins ment. B cells with a non-self BCR leave the bone ies, which will serve as a platform for further

72 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) tors. Therefore, the main goal of this project is to identify new signal elements in B cells. So far, three new adaptor proteins have been identified.T he function of these proteins in the proximal and distal signalling pathways of the BCR Fig. 1: Overview – humoral immunity and CD40 is currently being investigated in cell culture systems and transgenic mouse lines.

Teaching

The division participates in undergraduate and graduate education within the bachelor and master programs in biology and molecular medicine. Students have the opportunity to work on their bachelor and master theses embedded in the research focus of the division. Furthermore, the Division engages in educat- ing and training of doctoral students from the DFG training group GK 592 and the research group FOR 832 by offering numerous workshops and seminars, like journal clubs or scientific writing and presentation workshops.

Selected Publications Wittmann J, Hol EM, Jaeck HM (2006) hUPF2 silencing identifies physiologic substrates of mammalian nonsense- Fig. 2: RNA interference by endogenous microRNA mediated mRNA decay. Mol Cell Biol, 26: 1272-87 Avramidou A, Kroczek C, Lang C, Schuh W, Jaeck HM, Mielenz D (2007) The novel adaptor protein Swiprosin-1 enhances BCR signals and contributes to BCR-induced apoptosis. Cell Death Differ, 14: 1936-47 Morris C, Wittmann J, Jaeck HM, Jalinot P (2007) Human functional analysis of specific miRNAs involved Signaltransduction in B cells INT6/eIF3e is required for nonsense-mediated mRNA decay. in the B cell maturation and the generation of Project manager: D. Mielenz EMBO Rep, 8: 596-602 multiple myeloma or B cell lymphoma. The unique passport of each single B cell is the Schuh W, Meister S, Herrmann K, Bradl H, Jaeck HM (2008) B cell receptor (BCR). The BCR allows a specific Transcriptome analysis in primary B lymphoid precursors Molecular control of early B cell antigen to select its cognate B cells via binding following induction of the pre-B cell receptor. Mol Im- munol, 45: 362-75 differentiation to the BCR from a pool of billions of B cells. On Vettermann C, Herrmann K, Albert C, Roth E, Boesl MR, Project manager: H.-M. Jaeck, W. Schuh one hand, this permits an effective and specif- Jaeck HM (2008) A unique role for the lambda5 nonim- One major focus is the analysis of mechanisms ic immune response; on the other hand, it pre- munoglobulin tail in early B lymphocyte development. J that control early B cell development and sig- vents the activation of potentially dangerous B Immunol, 181: 3232-42 nalling of the pre-B cell receptor. For example, cells with self-antigens. The specificity of a BCR Wittmann J, Jaeck HM (2008) Chapter 13. Identifying substrates of mRNA decay factors by a combined RNA the interaction of the pre-BCR with structures may furthermore decide which anatomic niche interference and DNA microarray approach. Methods and ligands in the bone marrow microenviron- will be populated by a given B cell. Since ex- Enzymol, 449: 263-94 ment and its impact on survival and prolifera- pression of the BCR per se controls B cell sur- tion of progenitor B cells is studied using dif- vival, newly formed B cells are positively select- International Cooperation ferent mouse models. Using transcriptome- ed for proper surface expression of the BCR and Prof. Dr. Matthias Wabl, University of California, San and proteome analyses, we identified various negatively for self-reactivity. The selected B cell Francisco, USA cellular components of the pre-BCR signalling pool, however, should recognize any kind of Prof. Dr. Heinz Jacobs, University of Amsterdam, Neth- erlands cascade, for example the transcription factor antigen presented in the blood or on antigen- Krueppel-like factor 2 (KLF2) and a number of presenting cell. The diverse requirements that Meetings and International Training small non-coding microRNAs (miRNAs). We are imposed upon the BCR require thus a fine- Courses currently investigate the function of KLF2 in tuned intracellular signal transduction machin- 15.09.2007: International Symposium 10 Years ´Molecular B cell maturation and activation as well as the ery whose elements are not fully characterized Immunology, Erlangen function of pre-BCR-controlled miRNAs in con- yet and that are also employed by other recep- 15.10.-17.10.2008: 2nd International GK Symposium, ditional B cell-specific knockout mouse lines. tors on B cells, such as CD40 or toll-like recep- Regulators of Adaptive Immunity, Erlangen

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 73 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 4 – Nephrology and Hypertensiology Chair of Internal Medicine IV

Address sepsis and multiorgan failure. The transplant In parallel, the potential long term consequenc- Krankenhausstrasse 12 centre Erlangen-Nürnberg and the Northba- es of hypoxia on renal structure are being anal- 91054 Erlangen varian regional centre of the German Sepsis ysed, in particular fibrogenesis, epithelial mes- Phone: +49 9131 8539002 Network are associated with the Department enchial transition and the growth of renal cysts. Fax: +49 9131 8539209 of Medicine 4. A junior research group at the Nikolaus-Fiebig- www.medizin4.uk-erlangen.de er-Centre deals with the role of HIF in kidney Head of Department cancer (PD Dr. M. Wiesener). Prof. Dr. med Kai-Uwe Eckardt Research Mechanisms of hypoxia inducible gene expression are of particular relevance also for the reg- Contact Development and progression of chronic ulation of erythropoiesis through the synthe- Prof. Dr. med. Kai-Uwe Eckardt kidney disease sis of erythropoietin (EPO). In addition to ani- Phone: +49 9131 8539002 Projects in this research area aim to determine mal experiments investigating this regulation, Fax: +49 9131 8539209 changes of specialized renal cells in conjunc- it could be shown for the first time in a Phase [email protected] tion with the initiation of kidney injury and to I/II study in dialysis patients that therapy with identify the mechanisms, which result in re- an inhibitor of HIF degradation induces en- Research Focus generation or progressive loss of function. To dogenous EPO production within and outside • Development and progression of chronic this end, analyses are being performed in iso- the kidneys. kidney disease lated glomerular, endothelial or tubular cells, • Pathophysiologic relevance of hypoxia- human kidney tissue and animals. One focus Pathogenesis of arterial inducible gene expression in this area includes the growth and migration hypertension and hypertensive • Pathogenesis of arterial hypertension and pattern of glomerular cells and the influence endorgan damage hypertensive endorgan damage of cytokines, cell cycle regulators and their re- A further important research area relates to • Acute and chronic renal allograft failure spective inhibitors, as well as the role of integ- studies of arterial hypertension. A specific focus • Systemic consequences of kidney disease rin receptors. Another focus comprises studies in this area lies on target organ damage in- and renal replacement therapy determining the influence of renal autonomous duced by hypertension in kidneys, heart, eye innervation on inflammatory processes in the and vasculature. In addition, the aetiology and kidney. Projects primarily related to the renal pathogenesis of arterial hypertension are being Structure of the Institution vasculature include studies of the role of oxida- investigated. tive stress in diabetic nephropathy. This research includes studies on sodium ho- The Department of Internal Medicine 4 com- In parallel to the experimental studies, clinical meostasis which test the hypothesis that stores prises the Department of Medicine 4 (Nephrol- studies are performed, which aim to retard the of non-osmotically active sodium exist in the ogy and Hypertension) at the University Hos- progression of specific kidney disease, includ- body, and that their capacity has an important pital Erlangen and the Community Hospital in ing certain types of glomerular diseases and impact on blood pressure regulation. Of par- Nürnberg. Together they represent the largest adult polycystic kidney disease. ticular relevance in this context appear to be research and treatment centre for kidney dis- mechanisms in the skin, where alterations in ease and hypertension in Germany. Pathophysiologic relevance of hypoxia- sodium supply influence lymph-angiogenesis. More than 90 physicians and basic scientists inducible gene expression Additional projects deal with the role of the work in the Department of Medicine 4. One pathomechanism, which is intensively in- renin-angiotensin system and the sympathet- Patient related and experimental research aims vestigated, concerns hypoxia and its relevance ic nervous system for the pathogenesis of hy- to better understand the pathogenesis of kid- for kidney disease. Focus of these studies is the pertension and kidney injury. These studies ney disease and hypertension and their pro- regulation and functional relevance of the hy- include electrophysiological investigations of gression and adverse consequences, to identi- poxia inducible transcription factors HIF-1 and ganglion cells, chemical measurements of tis- fy novel therapeutic strategies and to evaluate HIF-2. sue hormones and studies in transgenic mice, therapeutic options. Research projects at this Based on studies of the physiological expres- as well as tissue analyses. Electrophysiological institution play a major role in research net- sion of these factors and their regulating en- measurements of sympathetic nerve activity works, such as the Clinical Research Unit 106 zymes, the activity of the HIF system is being are not only being conducted in animal models (End organ damage in arterial hypertension) investigated in different types of kidney dis- but using microneurography also in humans. In and the Collaborative Research Centre 423 ease. In addition, experiments are performed addition, symphathetic outflow to the kidney (Kidney injury: pathogenesis and regenerative to test if kidney disease can be influenced by and endothelial function of renal vessels are mechanisms) and contribute significantly to modulation of the HIF system. It could be indirectly measured through determination of the research focus “Kidney and circulation re- shown that inhibitors of HIF degradation result renal perfusion and sodium excretion. Addi- search” of the Medical Faculty. in a marked nephroprotection. This approach tional studies in patients are dealing with the The main clinical areas comprise diagnosis is potentially transferable into the clinic in order regulation of endothelial function and in par- and therapy of kidney diseases, renal trans- to avoid acute kidney injury and reduce isch- ticular the influence of lipids and hormones. In plantation, diagnosis and therapy of essential emia reperfusion injury in the context of kidney cooperation with the Department of Ophtal- and secondary hypertension and treatment of transplantation. mology, perfusion, structure and endothelial

74 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) function of retinal vessels in patients with hy- causes of an increased cardiovascular risk and Selected Publications pertension are being analysed. the optimization of renal replacement therapy. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, The Clinical Research Unit “Target organ dam- Partly in collaboration with the Department Gürkan A, Margreiter R, Hugo C, Grinyó JM, Frei U, Vanren- age in arterial hypertension” (KFO 106), co- of Medicine 2 mechanisms of atherogenesis terghem Y, Daloze P, Halloran PF, ELITE-Symphony Study (2007) Reduced exposure to calcineurin inhibitors in renal ordinated by Prof. Schmieder, uses a clinical are being investigated and the specific conse- transplantation. N Engl J Med, 357: 2562-75 research unit for its investigations, which has quences of impaired renal function on vascu- Boutin AT, Weidemann A, Fu Z, Mesropian L, Gradin K, been established at the Medical Clinic 4. lar pathology. This includes e.g. experimental Jamora C, Wiesener M, Eckardt KU, Koch CJ, Ellies LG, studies of the role of asymmetric Dimethylar- Haddad G, Haase VH, Simon MC, Poellinger L, Powell FL, Acute and chronic renal allograft failure ginin (ADMA) and of impaired angiogenesis in Johnson RS (2008) Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell, 133: 223-34 In cooperation with the Departments of Urolo- kidney disease. gy and Surgery, approximately 80 – 100 kidney The characteristic systemic consequences of Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, – and combined kidney-pancreas transplanta- chronic kidney disease include also anemia and Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer tions are performed per year, including living disturbances in bone and mineral metabolism, M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, donor transplantations. which have both been identified as cardiovas- Loeffler M, Reinhart K, German Competence NetworkS epsis (SepNet) (2008) Intensive insulin therapy and pentastarch The research program in this field aims at op- cular risk factors. The clinic participates in sev- resuscitation in severe sepsis. N Engl J Med, 358: 125-39 timizing long term graft function with particu- eral multicenter trials aiming to optimize man- Weidemann A, Bernhardt WM, Klanke B, Daniel C, Buch- lar emphasis on grafts from marginal donors. agement of these complications. holz B, Câmpean V, Amann K, Warnecke C, Wiesener MS, To this end, the clinic participated in several A rare complication of anemia management Eckardt KU, Willam C (2008) HIF activation protects from multicenter trials evaluating novel immuno- with recombinant human EPO is the develop- acute kidney injury. J Am Soc Nephrol, 19: 486-94 suppressive drugs or their combination and has ment of neutralizing antibodies leading to pure Fellström BC, Jardine AG, Schmieder RE, Holdaas H, played an important role in the so called Elite red cell aplasia. A therapeutic trial with a novel Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon Symphony Study. EPO-mimetic that does not cross react with the AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci An additional aim of this research area is to antibodies has been initiated. D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, better characterize donor kidneys. In cooper- The AURORA trial has been conducted to ad- Wüthrich RP, Gottlow M, Johnsson E, Zannad F, AURORA Study Group (2009) Rosuvastatin and cardiovascular events ation with the Deutsche Stiftung Organtrans- dress the question as to where statins improve in patients undergoing hemodialysis. N Engl J Med, 360: plantation, kidney function of brain dead kid- the poor cardiovascular prognosis of patients 1395-407 ney donors in Bavaria has been systematical- on dialysis. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela ly investigated to identify parameters, which Additional clinical research deals with acute T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss allow to predict the subsequent success of kidney injury, in particular in the context of J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze organ transplantation and will thus be help- sepsis and multiorgan failure. The North Ba- J (2009) Macrophages regulate salt-dependent volume and ful for future decision making about donor ac- varian SepNet Regional Centre, located at the blood pressure by a vascular endothelial growth factor-C- ceptance. In addition, during the first month Department of Medicine 4 in Erlangen and dependent buffering mechanism. Nat Med, 15: 545-52 after the transplantation, marker proteins are Nürnberg has participated in observational and International Cooperation searched for in serum and urine, which indi- treatment trials and has played an important cate rejection episodes at an early stage. A fur- role in the so called “VISEP” study. Please find further informations on our website: www.medizin4.uk-erlangen.de ther prospective trial deals with the influence of kidney transplantation on the course of vas- Meetings and International Training cular calcifications. In parallel to the clinical tri- Teaching Courses als, experimental studies are being performed 03.03.2007: Sepsis und Multiorganversagen, Nürnberg in a rat transplant model in order to identify The Department of Medicine 4 with its clinical 22.–23.02.2008: Target Organ Damage in Arterial Hyper- novel strategies for the improvement of organ units in Erlangen and Nürnberg contributes to tension, Erlangen function. the entire spectrum of curricular teaching in 17.–19.10.2008: Molecular Targets in Renal Disease, internal medicine, including main lectures, dif- Bamberg Systemic consequences of ferent courses and training of final year medical kidney disease and renal replacement students. In addition, several specialized semi- therapy nars are being offered and optional courses in Approximately 10% of the population suffer Intensive care medicine, transplantation, kid- from chronic kidney disease, as measured by ney and vascular system. reduced kidney function and/or increased uri- There is also the opportunity for clerkships nary protein excretion. Kidney disease is asso- and short term visits. To demonstrate the link ciated with the risk of progressive loss of renal between experimental research and clinical function, as well as a marked increase in car- pathophysiology, a lecture series has been of- diovascular risk. fered for the first time for advanced medical Research projects at the Department of Medi- students. cine 4 in this context deal with epidemiological questions, aspects of public health care, the

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 75 CLINICALUNIVER THEORETICALSITY HOS INSTITUTESPITAL

Department of Medicine 5 – Haematology and Oncology Chair of Haematology and Oncology

Address class I and class II typing and chimerism anal- long-term goal is to develop a clinical strate- Krankenhausstrasse 12 ysis after allogeneic stem cell transplantation. gy for using DN T cells as a cellular therapy for 91054 Erlangen Since 1999, this laboratory has been accredited treatment of graft-versus-host disease after al- Phone: +49 9131 8535955 by the European Federation of Immunogenet- logeneic stem cell transplantation. Fax: +49 9131 8535958 ics (EFI) and provides as one of twelve labora- www.medizin5.uk-erlangen.de tories of the German Transplantation Founda- Tumor immune escape Head of Department tion (Deutsche Stiftung Organtransplantation, Project manager: A. Mackensen, M. Aigner, K. Prof. Dr. med. Andreas Mackensen DSO) immunogenetic diagnostics for the area Singer, R. Gary of Northern Bavaria. Tumors can evade the recognition by the im- Contact The clinical focus is on hematologic and lym- mune system. One well-known immune escape Prof. Dr. med. Andreas Mackensen phatic malignancies, including but not limited mechanism is the dysregulation of the antigen Phone: +49 9131 8535955 to acute and chronic leukemias, myelodyspla- processing machinery (APM) in tumors, which Fax: +49 9131 8535958 sias, myeloproliferative disorders, malignant consists of all proteins and complexes involved [email protected] lymphoma and multiple myeloma. In addi- in the processing of antigens either produced tion, solid tumors are being treated, including intra-cellular or taken up externally. In a proj- Research Focus osteosarcoma, gastrointestinal tumors, head ect funded by the German José Carreras Leu- • T cell based immunotherapy and neck cancer, lung cancer, and urological kemia Foundation we try to determine the im- • Tumor immune escape tumors. The full range of treatment modalities, portance of this particular mechanism for the • Natural killer (NK) cells including allogeneic stem cell transplantation, pathogenesis of acute myeloid leukaemia. • Antibodies is available at the department. Furthermore, in In the last years the study of tumor metabolites • HLA-laboratory 2008, the interdisciplinary outpatient urologic- and their effects on the adaptive immune sys- oncologic centre “AURONTE” was established tem moved into the center of interest of tumor together with the Chair of Urology, realizing an immunology. By modulation of their metabo- Structure of the Institution important step towards interdisciplinairy treat- lism, tumors are able to generate advantages ment of urogenital tumors. for growth and proliferation for themselves. On October 1st 2007, the Chair of Hematolo- The influence of metabolites produced by tu- gy and Oncology at the University Hospital of mors on the activation, proliferation and vari- the Friedrich-Alexander-University Erlangen- Research ous effector functions of cytotoxic CD8+ T-cells Nürnberg was created. Professor Dr. Andreas is studied by the group of Prof. Mackensen/ Mackensen holds the first Chair of Hematol- T cell based immunotherapy Dipl. Biol. K. Singer in a project funded by the ogy and Oncology and serves as the chairman Project manager: A. Mackensen, M. Aigner, interdisciplinary clinical research centre (IZKF). of the Department of Medicine 5 – Hematology S. Voelkl T-cell dependent immune responses are initi- and Oncology, which was newly established in The Collaborative Research Centre (SFB) 643 ated via antigen recognition of peptide-MHC the internal medicine of the University Hospi- focuses on new approaches for cellular immune complexes by specific T-cell receptors. During tal Erlangen. The department has a total of 61 intervention. In project C8 the group of Prof. this interaction, T-cells acquire membrane frag- employees (15 on extra-departmental fund- Mackensen / Dr. Aigner develops new strate- ments and surface molecules from their target ing). The scientific section counts 10 post- gies for the in vitro generation of tumor-anti- cells in a process called trogocytosis. The im- doctoral fellows, 12 graduate students and 9 gen-specificT -cells for adoptive T-cell therapy. portance of this phenomenon for the formation technicians. In a clinical research group (leader Prof. Mack- of a strong antitumor immune response is to be The scientific section is constituted of various ensen) supported by the Bavarian immune characterized by Prof. Mackensen/Dipl. Biol. R. research subgroups with a common focus on therapy network (BayImmuNet), the isolation Gary in a project funded by the DFG. the development of new treatment strategies and subsequent expansion of patient-derived for cellular and humoral immunotherapy of tumor-specific T-cells under “Good Manufac- Natural killer (NK) cells malignant diseases. In addition, core research turing Practice” (GMP) conditions is being es- Project manager: E. Ullrich projects include studies on tumor immune- tablished as prerequisite for the application of The research group of Prof. Dr. E. Ullrich, Dipl. escape mechanisms and allogeneic bone mar- these cellular products in the context of clini- Biol. K. Meinhardt and A. Abendroth mainly row transplantation with a special emphasis cal studies for treatment of malignant diseases. focus on the role of natural killer (NK) cells in on the use of regulatory cells (T lymphocytes The population of human TCRα/β+ CD4- CD8- cellular immunoregulation, especially in anti- and NK cells) to modulate the graft-versus- double-negative (DN) T-cells plays a critical tumor responses and bone marrow transplan- host immune response after allogeneic stem role in the regulation of immune responses. In tation for treatment of malignant hematolog- cell transplantation. The Chair of Hematolo- a project funded by the DFG Prof. Mackensen ic diseases. gy and Oncology jointly operates the labora- and Dr. Voelkl investigate the immunoregulato- Bone marrow transplantation (BMT) and stem tory for immunogenetics and transplantation ry function of human DN T cells. Furthermore, cell transplantation (SCT) have gained wide (HLA-laboratory, head PD Dr. B. Spriewald) the role of DN T cells under pathologic con- acceptance in the treatment of hematological together with the Chair of Medicine III. The ditions such as autoimmunity and transplan- malignancies. Although BMT provides curative main activities of this laboratory include HLA tation rejection is currently investigated. The graft-versus-leukemia (GVL) effects, the graft-

76 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) versus-host disease (GVHD) is an often lethal Antibodies by qualified faculty in an integrated and inter- complication of allogeneic BMT. A great chal- Project manager: B. Stockmeyer disciplinairy fashion. In the summer semester lenge of current research on allogeneic BMT The team of PD Dr. Bernhard Stockmeyer, of 2008, a new internal medicine program in attempts to separate the undesirable GVHD Dipl. Biol. Heike Horner and Dipl. Biol. Yvonne hematology and oncology was introduced. In complications from the desirable GVL effects. Guettinger focuses on the development of re- this comprehensive program small groups of Recently, clinical studies exploiting the impact combinant monoclonal antibodies and deriv- medical students learn the basics of hematol- of innate effector cells such as NK cells have atives for targeted tumor therapy. Therefore ogy and oncology in a patient-oriented setting. provided promising results, especially in killer we characterize tumor cell antigens, which are inhibitory receptor-ligand-mismatched trans- suitable for polymorphonuclear granulocyte plantation. It has been observed that alloge- (PMN)-mediated antibody-dependent cyto- Selected Publications neic donor NK cells mediate GVL effects and toxicity (ADCC). We are particularly interest- Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, ed in the interaction between the intracellular Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner parts of target antigens with the cytoskeleton K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor or signal transduction molecules like phospho- cell-derived lactic acid on human T cells. Blood, 109: 3812-9 kinases to define motives that induce target Gottfried E, Kreutz M, Mackensen A (2008) Tumor-induced cell death. modulation of dendritic cell function. Cytokine Growth We have identified the receptor for the con- Factor Rev, 19: 65-77 stant part of immunoglobulin A (FcaRI) as trig- Spriewald BM, Ensminger SM, Bushell A, Wood KJ (2008) ger molecule for PMN mediated ADCC. In co- Neutralizing interleukin-4 prevents transplant arteriosclero- operation with Prof. G. Fey, Department of Ge- sis mediated by indirect pathway T cells under CD40-CD154 costimulation blockade. Transplantation, 86: 1615-21 netics, Faculty of Natural Science, we are cur- Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L rently generating multispecific recombinant (2008) Natural killer cell-directed therapies: moving from antibody constructs triggering FcaRl mediat- unexpected results to successful strategies. Nat Immunol, ed ADCC. Due to the specific requirements of 9: 486-94 PMN for suitable target antigens we will com- International Cooperation bine different specifities for tumor antigens (e. g. HLA-class II and CD19) in a single recombi- Michael I. Nishimura, Department of Surgery, Medical University of South Carolina, Charleston, USA nant antibody derived small modular immuno- J. van de Winkel, University of Utrecht, Netherlands Confocal microscopy of activated NK cells showing per- pharmaceutical. Thereby we expect to increase forin expression (green fluorescence). Prof. Ullrich 2008. tumor selectivity and cytotoxicity in the treat- Laurence Zitvogel, Institut Gustave Roussy, Paris – Villejuif, France ment for B-cell malignancies. This project is funded by the Wilhelm Sander-Stiftung. Research Equipment Becton Dickinson FACS Canto II HLA-laboratory Applied Biosystems Sequencer AB Genetic Analyser 3130 Project manager: B. Spriewald support immune reconstitution, while prevent- In recent years the laboratory was interested in ing GVHD. new methods for the detection of various sub- It has now been shown that NK cells represent classes of anti-HLA antibodies in solid organ a highly heterogeneous population of pheno- transplantation. Our immunogenetic studies typically and functionally different subsets. Our look into polymorphisms of several cytokines own previous work focused on the character- and T-cell regulatory genes and their associa- ization of different subpopulations of murine tion with rheumatic and malignant disorders. NK cells, Dendritic Cells (DC) and Killer Den- Another focus is experimental studies for the in- dritic Cells (KDC). Our recent projects aim to duction of transplantation tolerance and reduc- analyse the immunoregulatory functions of dif- tion of chronic rejection. These studies are per- ferent NK- and DC-subsets in different tumor formed in close collaboration with the group models and in a murine GVHD model upon al- of experimental heart surgery. This project is logeneic BMT. funded by the Interdisciplinary Centre of Clini- Understanding the role of NK and DC immune cal Research (IZKF). cell subsets in GVL and GVHD will improve the implementation of cellular therapies in the treatment of human malignancies. An inter- Teaching national collaboration with the laboratory of Prof. L. Zitvogel, Paris-Villejuif, France, is fund- A traditional teaching program (lectures, semi- ed by INCa and German Academic Exchange nars, practica) covering all subjects in the field Service (DAAD). of hematology and oncology is being offered

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 77 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Nuclear Medicine Chair of Clinical Nuclear Medicine University Hospital

Address Research In 2007 and 2008, this research was support- Krankenhausstrasse 12 ed by the German Research Foundation (DFG) 91054 Erlangen Molecular imaging and the Federal Ministry of Education and Re- Phone: +49 9131 8533411 Molecular medicine interprets disease as dis- search (BMBF). Fax: +49 9131 8539262 turbed expression or activity of proteins such www.nuklear.med.uni-erlangen.de as enzymes or receptors. Diagnostic nuclear Correlative imaging Head of Department medicine images the distribution of radioac- The tremendous progress of technology has Prof. Dr. med. Torsten Kuwert tively labelled substances within the body of created a wide array of new ways to image patients. This distribution is a consequence of the human body and considerably improved Contact the interaction of the radiopharmaceuticals already existing methodology. However, the Prof. Dr. med. Torsten Kuwert with functionally relevant proteins; therefore, complexity of the diagnostic process has cor- Phone: +49 9131 8533411 by visualizing this interaction and thus the ex- respondingly also increased. Therefore, the in- Fax: +49 9131 8539262 pression and activity of proteins, nuclear medi- tegration of information from different imaging [email protected] cine can bridge the gap between molecular bi- modalities has become an important issue. Ide- ology and clinical imaging. an important con- ally, image datasets from two different modali- Research Focus dition to capitalize on this potential of nucle- ties are registered to one common coordinate • Molecular imaging ar medicine as an also clinically useful tool of system to allow for true correlative imaging. • Correlative imaging molecular imaging is a scientific infrastructure The manufacturers of medical imaging devices that unifies elements of chemical, cell biologi- have developed two different solutions to this cal and molecular biological techniques. there- problem: on the one hand, devices have been Structure of the Institution fore, recently, a laboratory of molecular imag- designed that unify two cameras of different ing has been established within the Depart- modalities, the socalled hybrid systems. In par- The Department of Nuclear Medicine covers a ment of Nuclear Medicine. One main research ticular, hybrid systems combining emission to- broad range of the diagnostic and therapeutic area of the laboratory of molecular imaging is mographic cameras with X-ray computerized procedures of this specialty. It is equipped by a the investigation of the metabolism and uptake tomographs (CTs) are currently commercially therapeutic ward, three planar γ cameras, two of radiopharmaceuticals in cell cultures aimed available. On the other hand, user platforms multidetector SPECT cameras, and one SPECT/ at elucidating the regulation of the accumula- and data structures have been homogenized so spiral-CT hybrid system. In cooperation with tion of F-18-deoxyglucose and radiolabelled that the exchange of image data between dif- the Institute of Radiology, a PET/CT hybrid amino acids within endothelia, inflammatory ferent modalities and also the registration of in- camera is operated in the Imaging Sciences cells, and thyrocytes. The evidence thus gath- dependently acquired images have been much Institute, a joint venture between Siemens ered is relevant to the interpretation of clinical facilitated. In cooperation with the Chair of Pat- Medical Solutions and the Department. The PET. In 2007, one of the publications from this tern Recognition of the University of Erlangen- radiochemical laboratory of the Department is scientific focus was honoured with the Brahms- Nürnberg (Director: Prof. Hornegger) and Sie- equipped by synthesis modules for synthesis- Prize of the German Society for Nuclear Med- mens Medical Solutions the Clinic of Nuclear ing radiotherapeutics and by a further module icine. The development of new radiopharma- Medicine develops new methodology of correl- for producing PET tracers, which is operated ceuticals is the second research focus of the ative imaging and investigates its clinical value. under GMP conditions in cooperation with the Laboratory of Molecular Imaging: In coopera- PETNET GmbH. In the laboratory of molecular tion with Prof. Gmeiner from the Chair of Phar- imaging of the Department new radiopharma- maceutical Chemistry of the University of Er- Teaching ceuticals are being developed and evaluated. langen-Nürnberg radioligands for the D3- and The for this purpose implemented methodol- D4-subtype of the dopamine receptor have The Chair teaches nuclear medicine to students ogy includes chemical, radiochemical, and cell been synthesized and validated in vitro. As yet, of medicine. Furthermore, the Chair organizes biological facilities. In addition, the laboratory radiopharmaceuticals suited to study these re- the course on radioprotection for students of operates a highly resolving autoradiographic ceptor subtypes supposed to be implicated in molecular medicine. He also participates in detector system and a micro-PET. the pathogenesis of several neuropsychiatric teaching physiology, pharmacology and com- disorders are lacking so that this project may puter sciences. In abroad fashion, the Chair be considered to be truly innovative. In 2007 performs postgraduate teaching for physicians and 2008, this project was supported by the in Middle and Upper Franconia. German Research Foundation (DFG). In 2008, a part of this project was awarded the pharmaceutical science prize “Phoenix”. Further- more, new radiotracers for the imaging of angiogenesis and peptides are being developed.

78 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Prante O, Einsiedel J, Haubner R, Gmeiner P, Wester HJ, Kuwert T, Maschauer S (2007) 3,4,6-Tri-O-acetyl-2- deoxy-2-[(18)F]fluoroglucopyranosyl Phenylthiosulfonate: A Thiol-Reactive Agent for the Chemoselective (18)F- Glycosylation of Peptides. Bioconjug Chem, 18: 254-262 Salama I, Hocke C, Utz W, Prante O, Boeckler F, Hübner H, Kuwert T, Gmeiner P (2007) Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands. J Med Chem, 50: 489-500 Han J, Köstler H, Bennewitz C, Kuwert T, Hornegger J (2008) Computer-aided evaluation of anatomical accuracy of image fusion between X-ray CT and SPECT. Comput Med Imaging Graph, 32: 388-95 Kollorz EK, Hahn DA, Linke R, Goecke TW, Hornegger J, Kuwert T (2008) Quantification of thyroid volume using 3-d Ex vivo autoradiography of rat brain slices after i.v. injection of [18F]FAUC F41 (10 MBq, 30 ultrasound imaging. IEEE Trans Med Imaging, 27: 457-66 min p.i. coronal, 20 µm; left column). Co-injection of the D4 selective neutral antagonist FAUC Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, 213 (1mg/kg; right column) inhibited the binding of [18F]FAUC F41 in hippocampus (HC; gd: Gmeiner P (2008) Synthesis, Radiofluorination, and In Vitro dentate gyrus) and hypothalamus (HT), cortical regions and septum. The striatum (ST; lower Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 row) is known as a brain region with low D4 receptor expression Receptor Ligands: Discovery of an Inverse Agonist Radioli- gand for PET. J Med Chem, 51: 1800-1810 Stadlbauer A, Prante O, Nimsky C, Salomonowitz E, Buchfelder M, Kuwert T, Linke R, Ganslandt O (2008) Metabolic Imaging of Cerebral Gliomas: Spatial Correla- tion of Changes in O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Proton Magnetic Resonance Spectroscopic Imaging. J Nucl Med, 49: 721-729

International Cooperation Dr A.H. Vija, Molecular Imaging, Siemens Medical Solutions, Hoffman Estates, Chicago, USA Dr. rer.nat. R. Haubner, Klinik fuer Nuklearmedizin, Med- izinische Universitaet Innsbruck, Austria

Research Equipment Siemens Tier PET “Inveon” Patient with iodine arid pulmonal metastases of thyroid carcinoma. The SPECT / CT allows a Siemens SPECT/CT Symbia T6 precise anatomical mapping of metastasis once in the lung and once in the left hilus. This information is crucial for further therapeutic management (surgery, irradiation) Siemens PET/CT Biograph 64

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 79 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Institute of Radiology Chair of Diagnostic Radiology

Address Research purpose the inflowing (arterial) spins become Maximiliansplatz 1 labelled and their concentration in the organ 91054 Erlangen Non-invasive diagnostic of of interest can be measured as signal strength. Phone: +49 9131 8536065 cardiovascular disease Our focus of interest is the kidney. In vivo exper- Fax: +49 9131 8536068 Project manager: K. Anders, A. Kuettner, R. iments of the physiologic change of the kidney www.idr.med.uni-erlangen.de Janka, A. Schmid, M. Lell perfusion after drug therapy or after contrast Head of Institute Due to the technical progress of computed to- media applications become possible. Prof. Dr. med. Michael Uder mography and magnetic resonance imaging both methods offer new possibilities in the di- Biological assessment of DNA damage due Contact agnostic assessment of cardiovascular disease to diagnostic irradiation Dr. med. Siegfried Schwab which are explored in vitro and clinically in co- Project manager: M. Uder, M. Kuefner, S. Phone: +49 9131 8536065 operation with the Departments of Cardiolo- Schwab, M. Heckmann, C. Engert Fax: +49 9131 8536068 gy (Prof. Daniel), Otorhinolaryngology (Prof. The established dose parameters in radiolog- [email protected] Iro), Vascular Surgery (Prof. Lang), Maxillofa- ic procedures can determine exposition, but cial Surgery (Prof. Neukam), Department of they do not adequately evaluate the dose de- Research Focus Computer Science – Pattern Recognition (Prof. position and the biological x-ray interactions • Non-invasive diagnostic of cardiovascular Dr. Ing. J. Hornegger), as well as the Institute in the patient. The determination of DNA dou- disease for Medical Physics (Prof. Kalender), Siemens ble-strand breaks using an immunofluores- • Functional and metabolic magnetic reso- Healthcare and the Department of Radiology, cence microscopic technique, which was estab- nance imaging (MRI) UCLA, David Geffen School of Medicine (Prof. lished in collaboration with Prof. Dr. Loebrich • Biological assessment of DNA damage due Dr. D. Enzmann). (TU Darmstadt), provides an accurate and sen- to diagnostic irradiation New CT angiography examination protocols sitive estimate of biological radiation effects. • Imaging of the head and neck are developed to assess adult and pediatric car- The method is based on the phosphorylation of • Breast imaging diovascular disease (coronaries, carotids, aorta the histone variant H2AX after DSB formation, • Contrast media induced nephropathy and peripheral vasculature). A special aspect is which can be stained with a specific antibody. the minimization of radiation exposure as well Recent studies have shown a strong correla- Structure of the Institution as establishing suitable measurement models. tion between DSB levels and dose length prod- Another focus is the optimization of contrast uct in patients undergoing CT scans and with- The Department of Radiology of the University media injection protocols. Novel CT techniques in 24 hours after exposure the number of DNA of Erlangen-Nürnberg has six subsections (in- such as dual spectral analysis are used for vessel lesions returned to the baseline levels. In angi- ternal medicine, surgery, otorhinolaryngology, visualization. After testing in models the clini- ography DNA damages were dependent on the pediatric radiology, gynecology, and neurora- cal potential is explored. Focus point is the au- dose deposed, the anatomic region exposed, diology). The staff of the department consists tomated vessel segmentation and analysis of and the duration/fractionation of the exposure. of 4 professors, 4 assistant professors, 31 med- atherosclerotic plaque. In current studies the influence of new CT tech- ical doctors, 2 experimental scientists, 69 ra- MRI allows for precise functional assessment of nologies (e.g. dual-source CT, Flash-CT) on the diographers and assistant medical technicians cardiac chambers as well as valves. Focuses of biological dose is investigated in patients and and 21 employees in the office and controlling. research are the functional analysis of the entire in biological phantom models as well. Further- The Department of Radiology provides the full heart in patients with impaired cardiac function more the potential protective effect of radical range of radiologic imaging modalities. Fur- and the evaluation of novel therapies. binding substances should be assessed. thermore a variety of interventional procedures as imaging guided biopsies or angiographic Functional and metabolic magnetic Imaging of the head therapies are performed. resonance imaging (MRI) and neck In cooperation with Siemens Medical Solu- Project manager: M. Uder, R. Janka, S. Alibek Project manager: M. Lell, S. Alibek, F. Hink- tions the Imaging Science Institute integrates Diffusion weighted imaging (DWI) visualiz- mann, M. Kramer, S. Schwab new developments in diagnostic imaging and es the diffusion of free water molecules in tis- Methodological and clinical studies evaluat- novel IT-solutions into the clinical routine and sue. The use of this technique in other body re- ing the use of CT und MRI in morphological into the academic research. gions than the brain is a new field of research. and functional imaging of head and neck tu- Different study groups and projects evaluate Improvements of the MR hardware and soft- mors. Cooperation with the Department of the clinical impact of various imaging proce- ware enable DWI measurements in a reason- Ear, Nose and Throat - Head and Neck Surgery dures or go for new developments. Focuses able time, even in free breathing. We use this (Prof. Iro), Department of Maxillofacial Surgery of research are the imaging of the head and technique to differentiate malignant from be- (Prof. Neukam) and the Department of Radia- neck, breast, heart, vessels and the evaluation nign tissue and inflammatory from tumour tis- tion Therapy (Prof. Fietkau). of functional MRI respectively. Furthermore ex- sue in selected patient groups. Methodological and clinical studies evaluating perimental laboratory studies play a well-estab- In MRI perfusion measurements without the the use of CT and MRI in the preparation and lished role in our scientific activities. use of contrast material are possible. For that planning of reconstructive surgery in coopera-

80 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Alibek S, Zenk J, Bozzato A, Lell M, Grunewald M, Anders Double strand breaks in blood lymphocytes are visualized using fluorescence micros- K, Rabe C, Iro H, Bautz W, Greess H (2007) The value of dynamic MRI studies in parotid tumors. Acad Radiol, 14: copy after staining against the phosphorylated histone variant γ-H2AX. The bright 701-10 spots are called foci, each focus represents one double strand break. Heinrich MC, Kuhlmann MK, Kohlbacher S, Scheer M, Grgic A, Heckmann MB, Uder M (2007) Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: in vitro study. Radiology, 242: 425-34 tion with the Department of Oral and Maxillo- and gadolinium based contrast agents. In ad- Lell MM, Ditt H, Panknin C, Sayre JW, Klotz E, Ruehm SG, facial Surgery (Prof. Neukam). dition, the Institute of Radiology is involved in Villablanca JP (2008) Cervical CT angiography comparing routine noncontrast and a late venous scan as masks for Methodological and clinical studies in dose re- multicenter studies comparing the incidence of automated bone subtraction: feasibility study and examina- duction techniques in CT in cooperation with CIN in high-risk patients with different types of tion of the influence of patient motion on image quality. the Institute of Medical Physics (Prof. Kalender). contrast media. Invest Radiol, 43: 27-32 Lell MM, Gmelin C, Panknin C, Eckel KT, Schmid M, Bautz Breast imaging WA, Greess H (2008) Thin-slice MDCT of the neck: impact on cancer staging. AJR Am J Roentgenol, 190: 785-9 Project manager: R. Schulz-Wendtland, E. Wen- Teaching kel, S. Schwab, R. Janka, B. Adamietz Schwab SA, Uder M, Schulz-Wendtland R, Bautz WA, Janka R, Wenkel E (2008) Direct MR galactography: feasibility Breast imaging is an important research do- Besides the university standard lectures and study. Radiology, 249: 54-61 main of the Institute of Radiology. Professor practical courses, innovative clinically orien- Kuefner MA, Grudzenski S, Schwab SA, Azoulay S, Heck- Schulz-Wendltand and his research team ad- tated courses as interactive discussions of clini- mann M, Heinrich MC, Lobrich M, Uder M (2009) X-ray- dress questions in the field of new develop- cal cases are offered regularly. In these courses induced DNA double-strand breaks after angiographic ex- ments in digital mammography in cooperation the students are taught a much more analytic aminations of different anatomic regions. Rofo, 181: 374-80 with different medical systems manufacturers. and clinical than systematic approach towards International Cooperation On the basis of substantial experimental and the interpretation of radiologic images. Special Prof. Dr. D. Enzmann, Department of Radiology, UCLA, clinical studies, their work includes develop- radiological “crash-courses” help the students Los Angeles, USA ment, implementation and comparison of dif- to prepare effectively for the state examination. Dr. J. Petersen, Department Radiologie, Medizinische Uni- ferent digital mammography systems includ- Furthermore we always offer the possibility to versitaet Innsbruck, Austria ing tomosynthesis (Hybridsystems). In coop- perform clinical electives or internships in our eration with the Fraunhofer Institut, Erlangen department. Students who want to do a doc- Meetings and International Training Courses and the Definiens AG (Prof. Binnig) a CAD sys- tor’s degree are supervised for writing their ex- tem is being developed. Furthermore, a new perimental or clinical thesis. Fortbildungskurs Mammadiagnostik 03.2007, Erlangen MRI-based method for diagnosting ductal dis- MR-Compact 06.2007, Bamberg ease was implemented. Another main focus Mammasonokurs 09.2007, Erlangen in breast MRI lies in the development of new Forum interventionelle Neuroradiologie 11.2007, Erlangen MRI sequences for better differentiation be- Fortbildungskurs Mammadiagnostik 04.2008, Erlangen tween malignant and benign breast disease Mamma-MRT Kurs 05.2008, Erlangen and the development of an automated breast ultrasound. Angiographiekurs 06.2008, Erlangen MR-Compact 06.2008, Bamberg Contrast media induced nephropathy Kinderradiologie-Symposium 09.2008, Erlangen Project manager: M. Uder, M. Heinrich Mammasonokurs 09.2008, Erlangen Contrast media induced nephropathy (CIN) Herz-MRT Kurs 10.2008, Erlangen is a common cause of hospital-acquired acute Mamma-MRT Kurs 12.2008, Erlangen renal failure and is associated with increased rates of mortality and morbidity as well as lon- Research Equipment ger hospital stays and poor long-term progno- Siemens Magnetom Trio sis. A working group from the Institute of Ra- Siemens Magnetom Avanto diology is investigating in vitro mechanisms in- Siemens Sensation Definiton AS+ volved in the pathogenesis of contrast media induced nephropathy. Tubulotoxic effects are Siemens Sensation 64 being investigated in renal tubular cell cultures. Siemens Axiom Artis with flat panel detector Important features of these experiments are the comparisons between isoosmolar and low osmolar contrast media and between iodinated

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 81 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Institute of Radiology Division of Neuroradiology University Hospital

Address Research Quantitative and qualitative assessment Schwabachanlage 6 of optical fiber tracts in glaucoma patients 91054 Erlangen Clinical and experimental validation of using diffusion tensor imaging and Phone: +49 9131 8539388 flat-panel volume CT high-field MRI Fax: +49 9131 8536179 In cooperation with the Institute of Medical In cooperation with the Department of Oph- www.neuroradiologie.med.uni-erlangen.de Physics, Siemens Medical Solutions and the De- thalmology (Prof. Michelson) we evaluate dif- Head of Division partment of Computer Science/Institute of Pat- fusion tensor imaging (DTI) using 3 Tesla MRI Prof. Dr. med. Arnd Dörfler tern Recognition we evaluate and further de- to assess quantitative and qualitative changes velop flat-panel volume CT and angiograph- within the optical fiber tracts in glaucoma pa- Contact ic techniques and postprocessing algorithms tients at a very early stage. Disorders in optical Prof. Dr. med. Arnd Dörfler in cerebrovascular disease. Hereby, a focus is fiber tracts result in reduced fractional anisot- Tel.: +49 9131 8534326 set on the optimized visualization of cerebral ropy (FA) and atrophy of the tracts which can Fax: +49 9131 8536179 microimplants, such as stents, coils and new be used for staging and to evaluate therapeu- [email protected] perfusion techniques and 3D visualizations in tical strategies in glaucoma. stroke patients. Research Focus Simulation of hemodynamics and fluid • Clinical and experimental validation of Multimodal CT and MR imaging in of dynamics in cerebral aneurysms flat-panel volume CT cerebrovascular disease In cooperation with the Department of Com- • Multimodal CT and MR imaging in of In cooperation with the Department of Neurol- puter Science/Institute of Pattern Recognition, cerebrovascular disease ogy we participate in several acute stroke stud- Siemens Medical Solutions and the Depart- • Preoperative comprehensive imaging ies. Using multimodal imaging algorithms in- ment of Chemical Engeneering/Fluid Mechan- of epilepsy cluding perfusion-, diffusion- and angiograph- ics we evaluate the hemodynamic and fluid • Quantitative and qualitative assessment ic imaging by CT and mainly MRI we evaluate dynamics in cerebral aneurysms and malfor- of optical fiber tracts in glaucoma patients the individual indication for acute stroke ther- mations. A special focus is put on the effects of using diffusion tensor imaging and apies such as thrombolysis and/or other neuro- different endovascular therapies using differ- high-field MRI protective therapies. For the follow-up of pa- ent endovascular microimplants such as stents • Simulation of hemodynamics and fluid tients with intracranial microstents we evaluate and coils. dynamics in cerebral aneurysms the potential of flat-panel DynaCT (intravenous • Experimental research on multimodal contrast media application and rotational angi- Experimental research on multimodal imaging in a glioma model and validation ography) to replace conventional angiography. imaging in a glioma model and validation and development of new interventional An additional focus is set on the improvement and development of new interventional therapies in an aneurysm model of non-invasive imaging in the work-up of cere- therapies in an aneurysm model brovascular disease using different MRA tech- Funded by the DFG (KFO 661) we evaluate mul- Structure of the Institution niques and various contrast agents. timodal imaging strategies to assess brain gliomas using micro-CT, high-field MRI and mi- In the Division of Neuroradiology a total of 32 Preoperative comprehensive imaging of cro-PET. We closely cooperate with the Institute stuff members are employed. Research is per- epilepsy of Medical Physics, the Institute of Experimen- formed by 11 medical doctors, 5 postgradu- In cooperation with the Epilepsy Centre/De- tal and Clinical Pharmacology and Toxicology, ates, and externally funded by one biologist, partment of Neurology and the Department of Core Unit small animal imaging, and the De- one computer scientist and one veterinarian, Nuclear Medicine we evaluate different multi- partment of Nuclear Medicine. Additionally, respectively. modal imaging strategies in the preoperative using an elastase-induced aneurysm model, The Division of Neuroradiology performs the work-up of patients with focal seizures refrac- we evaluate different imaging techniques and neuroradiological work-up for patients of the tory to best medical treatment. A major focus new materials and techniques for endovascu- University Hospital of Erlangen and for many is here put on high-resolution morphologic and lar treatment. patients referred from external hospitals. A functional MR imaging, i.e. MR spectroscopy, special focus lies on the endovascular therapy DTI, functional MRI, perfusion- and diffusion- of neurovascular diseases such as aneurysms, weighted MRI and MR volumetry. Additional- stenoses of neck and brain vessels and arterio- ly, a dedicated GABA-specific MR spectroscopy venous malformations (AVMs) and the mini- sequence is used to evaluate different antiepi- mal-invasive therapy of spinal pain syndromes. leptic therapies.

82 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) The Division of Neuroradiology focuses mainly on visualisation and cerebrovascular therapy

Teaching Selected Publications Institut fuer Neuroradiologie, Klinikgruppe Hirslanden, Zuerich, Switzerland Doelken MT, Richter G, Stefan H, Doerfler A, Noemayr A, The Division of Neuroradiology is involved in Kuwert T, Ganslandt O, Nimsky CH, Hammen T (2007) Meetings and International Training training medical students. We offer a large va- Multimodal coregistration in patients with temporal lobe epilepsy--results of different imaging modalities in lateraliza- Courses riety of lectures and practical courses partly in tion of the affected hemisphere in MR imaging positive and 07.–08.02.2008: Workshop “Hands-on Angiography”, ECR cooperation with the neurological and neuro- negative subgroups. AJNR Am J Neuroradiol, 28: 449-54 Wien, Austria surgical department, ophthalmology, psychia- Richter G, Engelhorn T, Struffert T, Doelken M, Ganslandt 07.–08.02.2008: Workshop “Hands-on MRI”, ECR Wien, try and radiology. In addition, we train resi- O, Hornegger J, Kalender WA, Doerfler A (2007) Flat panel Austria dents in Neurororadiology and general radiol- detector angiographic CT for stent-assisted coil embolization of broad-based cerebral aneurysms. AJNR Am J Neu- 23.02.2008: Workshop “Neuroradiologie fuer die Praxis”, ogy and radiological technicians. roradiol, 28: 1902-8 Leipzig, Germany Engelhorn T, Hufnagel A, Weise J, Baehr M, Doerfler A (2007) 14.06.2008: Workshop “Hands-on Stroke MRI”, Erlangen Monitoring of acute generalized status epilepticus using 17.–19.10.2008: Refresherkurs: Neuroradiologie. 61. multilocal diffusion MR imaging: early prediction of regional Jahrestagung der Bayerischen Roentgengesellschaft Bad neuronal damage. AJNR Am J Neuroradiol, 28: 321-7 Windsheim Doelken M, Struffert T, Richter G, Engelhorn T, Nimsky 24.–25.10.2008: Workshop “Interventionelle Neuroangio C, Ganslandt O, Hammen T, Doerfler A (2008) Flat-panel graphie”, Erlangen and Forchheim detector volumetric CT for visualization of subarachnoid hemorrhage and ventricles: preliminary results compared 22.11.2008: Workshop “Hands-on Stroke MRI”, Erlangen to conventional CT. Neuroradiology, 50: 517-23 13.12.2008: Workshop “Hands-on Stroke-MRT”, Linz, Savaskan NE, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Austria Ganslandt O, Nimsky C, Buchfelder M, Eyuepoglu IY (2008) Small interfering RNA-mediated xCT silencing in gliomas Research Equipment inhibits neurodegeneration and alleviates brain edema. Nat Siemens Axiom Artis dBA; Biplanare Flachdetektor-Angiog- Med, 14: 629-32 raphieanlage mit integrierter CT-Option Engelhorn T, Struffert T, Richter G, Doelken M, Ganslandt Siemens Somatom Sensation 64; 64-Zeilen-CT O, Kalender W, Doerfler A (2008) Flat panel detector angiographic CT in the management of aneurysmal rupture dur- Siemens 1.5 Tesla Magnetom Sonata MRT ing coil embolization. AJNR Am J Neuroradiol, 29: 1581-4 Siemens 3 Tesla Magnetom TimTrio MRT International Cooperation Dr. A. Bose, Department of Radiology and Neurology, Lenox Hill Hospital New York, USA Department of Neuroscience/Neuroimaging, Ospedale San Raffaele, Mailand, Italy Institut fuer Radiologie und Neuroradiologie, Landesner- venklinik Linz, Austria

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 83 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Surgery Chair of Surgery

Address awards from the University Hospital Erlangen lines. The specific diagnostics and the multi- Krankenhausstrasse 12 for equal opportunity for women. This depart- modal therapeutical strategies administered in 91054 Erlangen ment takes part in subprojects of the DFG with many patients result from an interdisciplinary Phone: +49 9131 8533296 focus on “Infection of the endothelium” (1130) cooperation of clinicians and scientists of nu- Fax: +49 9131 8536595 and Graduiertenkolleg 1071 “Viruses of the merous medical departments. www.chirurgie.med.uni-erlangen.de immune system”. During the reported period Head of Department two patents have been developed. Results of Anorectal dysfunction the research were transformed into economics Project manager: K. Matzel Prof. Dr. med. Dr. h. c. W. Hohenberger by issuing a licence for an ELISA by two com- In 1994, the world’s first sacral nerve stimu- Contact panies in the USA (Genway Biotech, Quest Di- lation per pace maker combined with gracilis Prof. Dr. med. Dr. h. c. W. Hohenberger agnostics). plastic for therapy of faecal incontinency has Phone: +49 9131 8533201 been implanted at this clinic. Since then the Fax: +49 9131 8536595 method has been continuously improved. The [email protected] Research patients are participating in an extensive post operational review program, which allows doc- Research Focus Clinical trials office umenting sustainable therapeutic effects for • Clinical trials office Project manager: H. Golcher the first time. Repeated workshops on a na- • Clinical cancer registry Gastrointestinal tumors: Based on earlier find- tional and international scale, which are dedi- • Anorectal dysfunction ings, the study “Neoadjuvant chemo radiother- cated to convey innovative therapeutic meth- • Molecular mechanisms of inflammatory apy and adjuvant chemotherapy with 5-fluoro- ods, initiate international cooperation. Vari- related angiogenesis uracil (5-FU) and oxaliplatin versus 5-FU alone ous international studies for the development • Molecular mechanisms of infection related in locally progressed rectal cancer of UICC and evaluation of new treatment procedures angiogenesis stages II and III” (CAO/ARO/AIO – 04) was for anorectal dysfunction, e.g. the NASHA/Dx • Clinical-experimental research launched in 2006 in close collaboration with study have been developed and conducted in the Department of Radiation Therapy where- cooperation. as a total of 63 patients haven been included Structure of the Institution until 2/2009 (Prof. Hohenberger, Prof. Goehl). Molecular mechanisms of inflammatory A prospective-randomised, multi-center phase related angiogenesis Research activities are structured into clinical III trial investigates if preoperative chemo ra- Project manager: M. Stuerzl research (clinical trials, clinical diagnosis and diation of a resectable tumor of the pancreatic In studies conducted beforehand, the study therapy research) and fundamental molecular head leads towards better median overall sur- group managed to identify the great GTP research (molecular mechanisms of angiogen- vival (ISRCTN78805636) (Prof. Hohenberger, ase guanylate binding protein 1 (GBP-1) as esis and tumor diagnostic). Dr. Golcher). the main regulator of the inflammatory relat- The clinical trials of the Department of Surgery Further multi-center trials investigate malig- ed angiogenesis inhibitor. New studies on the are largely supervised by the Clinical Trials Of- nant melanoma, gastrointestinal stroma tu- mechanism of the effects of GBP-1 have shown fice, founded in 2003, with its principle task mors and colon carcinoma. There are also other that GBP-1 is definitely reducing the migra- being the efficient initiation and monitoring diseases evaluated by clinical trials like anorec- tion and invasion capability of endothelial cells of the clinical trials. From the very beginning tal dysfunction, acute cholecystitis, prevention through Integrin mediated signal processes numerous trials targeting the improvement of of incisional hernias and resection of deviating (Weinlaender et al., 2008). cancer therapy, optimization of presently avail- ileostomies (Prof. Hohenberger, Prof. Matzel, First available indications are suggesting that able surgical techniques and to establish new Dr. Golcher). this mechanism could result in an improved surgical techniques have been supervised. survival of colorectal carcinoma with inflam- The fundamental molecular research has been Clinical cancer registry matory stroma reactions. In order to study the conducted at the Division of Molecular and Project manager: W. Hohenberger, S. Merkel epigenetic effects of inflammatory stroma re- Experimental Surgery (AMEC), also founded Since 1978 a Clinical Cancer Registry is kept actions on the angiogenic behaviour of tumor in 2003. for prospective, structured and organ specific vascular endothelial cells, it was managed for Main focus of the research of the AMEC is documentation of cancer. At present more than the first time to cultivate vital microvascular en- molecular oncology with focus on new mark- 20.000 patients are registered. The main focus dothelial cells of more than 20 various colorec- ers for prognosis and molecular regulation is the colorectal cancer with nearly 9 000 doc- tal carcinomas. This included taking compara- of inflammation associated angiogenesis in umented cases. Patients are tracked live-long ble cell samples of not affected healthy colorec- tumor and infectious diseases. In the report- and the rate of `lost cases` is 0.5%. tal tissue from the very same patients. At comed period the department consisted of eleven The main target of the science based evalua- parable examinations, significant differences scientific researchers (three post-docs, eight tion of these data are an improvement of clas- were detected between the two groups of cell postgraduates). In over 80% funding came sification of tumors, identification of prognostic samples (Schellerer et al., 2007). This suggests from grants from German Research Foundation markers, definition of indicators for quality and that at tumor endothelial cells, an epigenetic (DFG), Deutsche Krebshilfe, IZKF and ELAN- the implementation of the German S3-guide- imprinting is in effect on the micro milieu in

84 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) the tumor. Hopefully, new starting points can Selected Publications be developed for a more specific anti-angio- Schellerer VS, Croner RS, Weinlaender K, Hohenberger W, genic therapy through the detected differences Stuerzl M, Naschberger E (2007) Endothelial cells of human colorectal cancer and healthy colon reveal phenotypic differences in culture. Lab Invest, 87: 1159-70 Molecular mechanisms of infection related angiogenesis Croner RS, Foertsch T, Brueckl WM, Roedel F, Roedel C, Papadopoulos T, Brabletz T, Kirchner T, Sachs M, Behrens J, Project manager: M. Stuerzl Klein-Hitpass L, Stuerzl M, Hohenberger W, Lausen B (2008) For the examination of the infection associated Molecular signature for lymphatic metastasis in colorectal angiogenesis, analysis for the development of carcinomas. Ann Surg, 247: 803-10 the AIDS associated Kaposi‘s sarcoma (KS) is at Golcher H, Brunner T, Grabenbauer G, Merkel S, Papado- the centre of attention. This sarcoma is an en- poulos T, Hohenberger W, Meyer T (2008) Preoperative chemoradiation in adenocarcinoma of the pancreas. A single dothelial tumor which is initiated through the centre experience advocating a new treatment strategy. Eur human herpes virus-8 (HHV-8). The target of J Surg Oncol, 34: 756-64 the study is to determine which of the 86 genes Groundbreaking for a new building at the Department of Naschberger E, Croner RS, Merkel S, Dimmler A, Tripal that comprise HHV-8 is playing a part in the an- Surgery. Source: University Hospital Erlangen P, Amann KU, Kremmer E, Brueckl WM, Papadopoulos T, giogenic activation of KS and whether several Hohenadl C, Hohenberger W, Stuerzl M (2008) Angiostatic immune reaction in colorectal carcinoma: Impact on survival of these genes concur in the context of the de- and perspectives for antiangiogenic therapy. Int J Cancer, velopment of KS. For these studies new system- 123: 2120-9 ized biologic approaches were introduced at Weinlaender K, Naschberger E, Lehmann MH, Tripal P, Paster the clinic for the first time in order to allow con- W, Stockinger H, Hohenadl C, Stuerzl M (2008) Guanyl- ducting a great number of genetic functional ate binding protein-1 inhibits spreading and migration of endothelial cells through induction of integrin alpha4 analyses simultaneously. With this approach it Teaching expression. FASEB J, 22: 4168-78 was possible as a first step to map out the in- Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel tracellular localization of all HHV-8 coded pro- In the context of the main course, live broad- S. (2009) Standardized surgery for colonic cancer: complete teins (Sander et al., 2008). Knowledge of the casts of operations into the lecture hall are ar- mesocolic excision and central ligation--technical notes and intracellular localization of herpes viral proteins ranged for visualization. Moreover a bed side outcome. Colorectal Dis. 11: 354-64 constitutes an important starting point for the teaching is included in the internships. To fur- determination of pathogenic functions. Fur- ther deepen the acquired knowledge from International Cooperation ther studies enhance this systemized biologi- the main course, intensive prep classes are of- Prof. JX . Chen, Shanghai Renji Krankenhaus der Shanghai cal application for the high-throughput analy- fered alongside other measures. In order to Jiaotong Universitaet, China sis of viral proteins to cellular signal transduc- gain a realistic perspective of the clinical rou- Prof. T. Holm, Karolinska Institutet, Colorectal Surgical Unit, tion. Comparing proteomic analysis for genetic tine, smaller, supervised groups are allowed to Solna, Stockholm, Schweden effects complements this approach. visit the operation room and the intensive care Prof. S. Laurberg, Universitaet Aarhus, Department of unit. During the winter term 2007/2008 Prof. I. Surgery, Denmark Clinical-experimental research Schneider was granted the Lecturer’s Award of Prof. Dr. Christine Hohenadl, Austrianova Biomanufacturing Project manager: R. Croner the Medical Faculty. The Division of Molecular AG, Wien, Austria The objective of this study group is the indi- and Experimental Surgery conducts a practical Univ.-Prof. Dr. Hannes Stockinger, Abteilung Molekulare vidualization of the multi modal therapy for course in high-throughput methods for compa- Immunologie, Medizinische Universitaet, Wien, Austria gastrointestinal tumours based on molecular rable proteomic and genomic functional anal- Dr. Terry Robins, Quest Diagnostics, Madison, USA predictors and factors for prognosis. In coop- ysis for students of molecular medicine over a eration with partners, high-throughput meth- 3-week period. Alternating exchange of basic ods (e.g. genetic expressional analysis, pro- researchers and medical scientists should im- teomic analysis) for the identification of mo- prove translational research. lecular predictors are applied. With the help of microarray analysis it was possible to identify a group of 50 predicting genes for the metastasis of lymph nodes from primary tumors of colorectal carcinoma (Croner et al., 2008). After patent registration by the university, the identified markers are currently being validated prospectively in clinical studies and in cooperation with the industry. The functional characterization of the genes identified is currently conducted through cooperation projects (PD Croner, Prof. Stuerzl).

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 85 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Surgery Division of Pediatric Surgery

Address Research data were recorded for 12 hours. Gene expres- Krankenhausstrasse 12 sion of IL-1β and IL-8 in lung tissue was quan- 91054 Erlangen Prospective, psychological evaluation of tified by TaqMan real-time polymerase chain Phone: +49 9131 32923 dysmorphic disease pattern (thoracic wall reaction (PCR). A lung injury score was calcu- Fax: +49 9131 34432 deformities) in the course of surgical cor- lated based on the results of histological ex- www.chirurgie.med.uni-erlangen.de and rection amination. www.trichterbrust.com Project manager: P. G. Weber, A. Mueller, B. IL-1Ra given as aerosol or intravenously signif- Head of Division Reingruber icantly reduced mean pulmonary artery pres- Prof. Dr. med. Hans Peter Huemmer Since 1956, more than 3,000 procedures on sure (MPAP) and did not influence mean sys- chest wall deformities had been performed in temic arterial pressure (MAP) compared with Contact the Erlangen Division of Pediatric Surgery The the control group. IL-1β and IL-8 mRNA expres- Prof. Dr. med. Roman Carbon experiences obtained include not only the op- sions normalized to β-actin and hypoxanthine- Phone: +49 9131 33296 erative features but also psychological situation guanine-phosphoribosyl transferase were sig- Fax: +49 9131 34432 in those patients. Body shape and contouring nificantly reduced in the IL-1Ra-Aerosol group [email protected] mark major impact to the patients and normal- but not in IL-1Ra-i.v. group compared to the ly result in a critical, ambiguous and psycholog- control group. The lung injury score were not Research Focus ically striking behaviour. It‘s a fact that psycho- significantly different between IL-1Ra groups • Prospective, psychological evaluation of logical strain does not correlate rationally with and the control group. Application of aerosol- dysmorphic disease pattern (thoracic wall the grade of chest deformity. Sometimes, the ized IL-1Ra reduced MPAP without affecting deformities) in the course of surgical cor- patients are seriously affected caused by their MAP in a piglet model of surfactant depletion rection body shape even in the time after surgical cor- with pulmonary hypertension. Furthermore, • Reduction of pulmonary hypertension and rection. This study aims on those patients who there is evidence for reduction of early pro- expression of pro-inflammatory interleukins are not satisfied with their body shape even inflammatory pulmonary reaction following 1 /8. β though the objective result seems to be. Such treatment with topical admission of IL-1Ra as • Palliative Chemotherapy in patients with patients should be found out by preoperative aerosol that might become a therapeutic op- advanced colorectal cancer evaluation in order to provide an individual- tion to reduce induction of lung fibrosis and the • Constitution and implementation of an ly performed path of treatment, e.g. to dog subsequent risk of bronchopulmonary dyspla- interdisciplinary VACTERL consultation-hour. them with psychotherapy before, during and sia (BPD) after lung injury. • Sealing in pediatric surgery: Innovative after surgery. Perhaps, with the help of corre- surgical management of NEC sponding psychological tests, one can be dis- Palliative Chemotherapy in patients with • Sealing in pediatric surgery: Fast-track sur- couraged from the operation. advanced colorectal cancer gery of recurrent pneumothorax A collective of male patients with pectus exca- Project manager: N. Spychalski vatus is prospectively searched in a standard- Prolonged infusion with 5-fluorouracil/folinic Structure of the Institution ized comprehensive questionaire at given times acid protcols with view on the toxicity profile of (pre-operatively, 3 vs 6 months post-operative- sodium folinic acid versus calcium folinic acid. Locations: Department of Surgery and De- ly, 1 year post-operatively). In the study palliative high dose chemothera- partment of Pediatrics. Closest relation to the py was inspected by 5-fluorouracil (NaF) re- Department of Pediatrics (Prof. Rascher) and Reduction of pulmonary hypertension and spectively calciumfolinat (CaF) for 100 consec- its specific departments. Envolvement into expression of pro-inflammatory interleu- utive non selected patients with an advanced the expert network of the franconian perina- kins 1β/8. Large animal model for neonatal colorectal cancer. 5-FU and NaF were infused tal centre (Prof. Schild, Prof. Doetsch). In the respiratory distress syndrom simultaneously for 24 h. The incompatibility of frame of the Erlangen University Pediatric Op- Project manager: A. Rueckel CaF and 5-FU by simultaneous infusion effect- erative Centre (KIOZ) close cooperation with In neonatal respiratory distress syndrome ed a sequential application of CaF as 2h quick the pediatric institutions of anaesthesiology (IRDS) with pulmonary hypertension, interleu- infusion and 5-FU as 24h-infusion (acc. AIO/Ar- (Prof. Schuettler), urology (Prof. Schott), car- kins (IL-1ß, IL-8) are involved in the pulmonary dalan-scheme). Among NaF there was no case diac surgery (Prof. Cesnjevar), traumatology inflammatory reaction. The purpose of this of catheter occlusion caused by salt sedimenta- (Prof. Hennig), orthopedics (Prof. Forst), and study was to determine whether systemic or tion as described by CaF. So it is assumed that neurosurgery (Prof. Buchfelder). Close connec- aerosolized administered IL-1 receptor antag- NaF and 5-FU are compatible for simultaneous tions and cooperations to university associated onist (IL-1Ra) Anakinra (Kineret™) affects lung application. Regarding the application of NaF teaching academic pediatric hospitals in Bam- mechanics and pulmonary artery pressure in it was observed a saw similar frequency and se- berg (Prof. Deeg), Bayreuth (Prof. Rupprecht) surfactant depleted newborn piglets. After in- verity of toxicity as for CaF, also as equieffective and Fuerth/B. (Prof. Klinge). duction of severe lung injury by bronchoalve- data of progress in the intern comparison of the olar lavage, neonatal piglets received repeti- therapy groups as conventional studies. A sig- tive treatment of either aerosolized IL-1Ra (IL- nificant benefit of NaF was shown by the econ- 1Ra-Aerosol) or intravenous IL-1Ra (IL-1Ra-i.v.), omy of time. Out of this it results an increase or saline solution as control. Cardiopulmonary of quality of life and a decrease in costs. Con-

86 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) sequently the application of NaF in the high- surgery topics, e.g. “emergency in pediatric dose therapy with 5-FU in colorectal cancer is surgery”, in the context of cycles of lectures/ a matter for further approval. tutorials). 3. specific (contents consists of questions/problems out of pediatric surgery in the- Constitution and implementation of an in- ory and practical experience which might be terdisciplinary VACTERL consultation-hour. worked out systematically and/or innovative. Project manager: N. Spychalski Therefore seminars for doctoral researchers/ In long-term support of patients with multiple graduates are organized. Practical experience extensive malformations such as VACTERL, dif- to promote specialization occurs in phantom ferent departments were involved. By logistic courses/tutorials for minimally invasive pediat- management it is possible to offer an optimal ric surgery (“Skills-lab“, “Hands-on courses”). support to those patients. Ambition is a pro-

spective registration for recording patient‘s Selected Publications development and standardization of follow-up Carbon R, Carbon R, Reingruber B, Weber P, Baar S, care. The VACTERL consultation-hour is well- Zebra maneuver. Patch sealing of small bowel anasto- Kriegelstein S (2007) Innovative surgical management of established since December 2006. It takes moses in an earlyborn (1220 g, 33rd GW) NEC – Results of 52 consecutive cases. Inflamm Res, 56 place twice a month with a high patients com- Suppl.: S203-S203 pliance, a significant quality of care and collect- Henrich K, Huemmer HP, Reingruber B, Weber PG (2008) ing scientific relevant data. Gastroschisis and omphalocele: treatments and long-term outcomes. Pediatr Surg Int, 24: 167-73

Sealing in pediatric surgery: Innovative dure must meet minimal invasion criteria. Tis- International Cooperation surgical management of NEC sue management must be effective and effi- G. Berci, Cedars-Sinai Medical Centre, Endoscopic Research, Project manager: R.T. Carbon cient so as to minimize and prevent complica- Los Angeles, USA Necrotizing enterocolitis (NEC) is a severe tions. Such an appropriate concept has been septic disease of preterm infants and new- developed for patients with cystic fibrosis and borns and is characterized by mortality rates recurrent pneumothorax, consisting of thora- of 40%. Around 50% of the children survive coscopy in connection with minimally invasive the invasion with conservative measures (par- tissue management (ATSS: AMISA-TachoSil®- enteral nutrition, antibiotics). There is no bind- System, ready-to-use sealing). Evidence-based ing concept for operative treatment, with the results for fast-track parameters were obtained spectrum of therapy ranging from pure drain- for 131 patients (1993-2006) and compared to age insertion to extensive resection measures. a patient collective that had been treated with After experimental evaluation, (DDS, tensile conventional surgery (284, 1985-1996): Drain- strength, elasticity, adhesive strength), an in- age requirements: 38.5 vs. 100.0 %, drainage novative, antimicrobially effective gluing sys- time: 0.5 vs. 17.2 d, time in ICU: 1.2 vs. 4.7 d, tem (manual application of gentamicin-im- time on ward: 4.8 vs. 34.3 d, complications: 1.8 pregnated Tacho-Sil®) was introduced into the vs. 34.9 %, recurrence: 9.9 vs. 45.1 %. regimen, with this system supporting atraumatic, reconstructive and augmenting entero- plasties. A total of 52 preterm infants (1998- Teaching 2005, Ø 1183 g, Ø week 31, 41 patients Bell II, 11 patients Bell III) underwent a total of 84 op- The presentation of pediatric surgery as a sub- erations, 252 gluings, 122 intestinal re-sections ject occurs in three segments: 1. curricular and 83 ostomies. Gluing saved Ø 17.8 cm of in- (contents are composed of general and spe- testine (range: 1.8-38 cm)/patient, and short- cial topics from pediatric surgery in theory bowel syndrome was prevented in three pa- and practical experience. The knowledge is tients (5.8%). There were no septic complica- deliverd in single lectures/events, partly inte- tions and the mortality rate was 13.5%. grated in the main lecture of general surgery, according to IMPP-regulations. The presenta- Sealing in pediatric surgery: Fast-track tion is characterized by a problem-orientated surgery of recurrent pneumothorax method (POL) of instruction/teaching and/ Project manager: R. T. Carbon or interactive features. The whole package is Fast-track surgery involves an interdisciplin- completed by teaching units in cooperation ary concept of accelerating the rehabilitation with the technical schools (pediatric nursing, of patients who have undergone surgery. To physiotherapy, medical massage)). 2. interdis- better advance this aim, the surgical proce- ciplinary (contents are assorted from pediatric

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 87 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Surgery Division of Trauma Surgery

Address Besides the clinical and experimental research risk for the patient. So far, no extensive biome- Krankenhausstrasse 12 projects, the Division of Trauma Surgery is chanical studies on the stability and reliabili- 91054 Erlangen closely integrated in the recently founded ty of this implant for this approach have been Phone: +49 9131 8533272 “Trauma-Network” and is actively involved in published. Therefore, this internal fixateur sys- Fax: +49 9131 8533300 its further development. The aim of this net- tem was evaluated for its resistance and fixa- www.unfallchirurgie.uni-erlangen.de work is the improvement of the nationwide tion stability in the pelvis in experimental set- Head of Division quality of medical care of severely injured pa- tings and compared with the current golden tients by improved communication, better co- standard of conventional plate osteosynthesis. Prof. Dr. med. F. F. Hennig ordinated standards of medical care and qual- Preliminary results demonstrate that, with re- Contact ity-based cooperation. spect to biomechanical properties, the mini- Prof. Dr. med. F. F. Hennig mal-invasive internal fixateur system is compa- Phone: +49 9131 8533272 rable to the more invasive plate osteosynthesis. Fax: +49 9131 8533300 Research [email protected] Factors and molecular mechanisms of Development of a ceramic knee chondrocyte differentiation and cartilage Research Focus endoprothesis repair • Development of a ceramic knee endopro- Project manager: F. F. Hennig Project manager: K. Gelse thesis This project, which is based on a research cor- Chondrocytes are physiologically well adapt- • Biomechanical studies of a minimal-invasive poration with Rotec medical technology, Peter ed to the severe hypoxic conditions within ar- internal fixation method Brehm surgery mechanics and the Department ticular cartilage. We could show that hypoxia • Factors and molecular mechanisms of chon- of Glass & Ceramics of the University Erlan- is even essential for the induction and mainte- drocyte differentiation and cartilage repair gen, focuses on the development of an inno- nance of the chondrocyte phenotype. For ex- • “Molecular” magnetic resonance imaging vative ceramic knee endoprothesis. This project ample, in cartilage repair tissue, spontaneous • Early diagnosis and monitoring of osteoar- is supported by the “Bavarian Research Fund”. chondrogenic differentiation of transplanted thritis Compared with conventional metal-implants mesenchymal stem cells was only present in • Bone physiology and its pharmacokinetics of CoCr-alloy, the fundamental advantages of deeper hypoxic layers of the tissue. The forma- ceramic materials are an even further reduced tion of cartilaginous repair tissue of high qual- wear of friction and the completely non-allergic ity in superficial, less hypoxic tissue layers could Structure of the Institution properties. The main criteria for the acceptance only be induced by additional stimulation of of ceramic implants are based on the reliability transplanted cells by gene transfer of certain The Division of Trauma Surgery of the Univer- of their fixation into bone following cementa- growth factors (e.g. BMP-2). We could demon- sity Hospital Erlangen employs 14 physicians. tion in comparison to conventional metal-im- strate that BMP-2 induces similar effects as hy- Besides patient care, clinical and experimental plants. The technical specifications including poxia, including the increase in the activity of research work is performed together with 10 the reliability of fixation and the functional re- the transcription factor HIF-1α which is crucial doctoral candidates, 1 post-doctoral scientist quirements of a specific implantation equip- for chondrocyte metabolism. and 1 technician. ment were defined and monitored through- Further experiments showed that rib chon- The different research groups work on the out development and prototype construction drocyte spheroids represent an endogenous evaluation and development of novel innova- including the evaluation and verification in ca- source of growth factors and, thus, exert ther- tive surgical methods and implants for joint daver surgical approaches. First preliminary re- apeutically useful paracrine effects on mesen- replacement and fracture treatment. Further- sults were promising with respect to function- chymal stem cells. The role of hypoxia and the more, the research focuses on basic mecha- ality and operability. reservoir of endogenous therapeutically useful nisms of cartilage and bone biology, which factors for cartilage and bone regeneration re- provides the basis for the development of re- Biomechanical studies of a minimal-inva- mains the main focus of the current projects generative strategies for the musculoskeletal sive internal fixation method supported by the German Research Founda- system. This also includes imaging and func- Project manager: A. Olk, M. Blanke tion (DFG) and the Interdisciplinary Centre for tional non-invasive methods for the analysis of Injuries of the pelvis are often associated with Clinical Research (IZKF). cartilage repair tissue. Another research focus a disrupture of the symphysis. Such injuries are investigates methods for the early diagnosis often considered instable and need surgical sta- “Molecular” magnetic resonance imaging and characterization of osteoarthritis by mag- bilisation. Such lesions can be treated by vari- Project manager: G. Welsch netic resonance imaging. ous surgical approaches which often coincide The research project of musculoskeletal mag- The central research projects are supported by with considerable trauma by the surgical ap- netic resonance imaging are performed in co- approved fundings including the German Re- proach. However, the surgical stabilisation can operation with the MR Centre of the Depart- search Foundation (DFG)“, “Bavarian Research also be performed using an internal fixateur ment of Radiology of the Medical University of Fund”, IZKF, German Society for Orthopaedics system, which can be applied by minimally in- Vienna and particularly focuses on the evalu- and Orthopaedic Surgery (DGOOC), and ELAN vasive principles. The duration of surgery can ation of cartilage repair tissues. Multi-mod- (fund of the university hospital). be significantly reduced with a lower surgical al-/ multi-parametrical approaches were estab-

88 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) lished for diagnosis, therapy and follow-up of Selected Publications focal cartilage defects under consideration of Brem MH, Pauser J, Yoshioka H, Brenning A, Stratmann J, orthopaedic-traumatological and radiological Hennig FF, Kikinis R, Duryea J, Winalski CS, Lang P (2007) aspects of cartilage repair. The aim is to non- Longitudinal in vivo reproducibility of cartilage volume and surface in osteoarthritis of the knee. Skeletal Radiol, invasively attain detailed information on the 36: 315-20 composition of articular cartilage, that closely Brem MH, Schlechtweg PM, Bhagwat J, Genovese M, Dill- correlate with histological examination. Thus, ingham MF, Yoshioka H, Lang P (2008) Longitudinal evalu- modern MR imaging is supposed to acquire a ation of the occurrence of MRI-detectable bone marrow high diagnostic predictive value for the analy- edema in osteoarthritis of the knee. Acta Radiol, 49: 1031-7 sis of cartilage tissue. Gelse K, Mühle C, Franke O, Park J, Jehle M, Durst K, Göken So far, “molecular” MR imaging allowed ade- M, Hennig F, Mark KV, Schneider H (2008) Cell-based re- surfacing of large cartilage defects: Long-term evaluation quate characterization of the ultrastructure of of grafts from autologous transgene-activated periosteal cartilage and cartilaginous repair tissue. The cells in a porcine model of osteoarthritis. Arthritis Rheum, content of proteoglycans, the alignment of col- Development of a ceramic knee endoprothesis 58: 475-488 lagen fibres, the hydration status of cartilage as Gelse K, Mühle C, Knaup K, Swoboda B, Wiesener M, Hen- well as remodelling processes of repair tissues nig F, Olk A, Schneider H (2008) Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage could be visualized and quantified leading to repair tissue is associated with increased HIF-1alpha activity. important additional information on the prop- Osteoarthritis Cartilage, 16: 1457-65 erties of cartilage. Welsch GH, Mamisch TC, Hughes T, Domayer S, Marlovits S, Bone physiology and its pharmacokinetics Trattnig S (2008) Advanced morphological and biochemical Early diagnosis and monitoring of Project manager: J. Gusinde magnetic resonance imaging of cartilage repair procedures in the knee joint at 3 Tesla. Semin Musculoskelet Radiol, osteoarthritis This project investigates the bone affinity of 12: 196-211 Project manager: M. Brem various drugs and their pharmacokinetics in Welsch GH, Trattnig S, Scheffler K,S zomonanyi P, Quirbach Risk factors for the development of osteoar- osseous tissue. From a therapeutical point of S, Marlovits S, Domayer S, Bieri O, Mamisch TC (2008) thritis and their monitoring were evaluated by view, the accumulation of drugs in bone tissue Magnetization transfer contrast and T2 mapping in the MR imaging methods in cooperation with the can either be desired or inadvertant. For exam- evaluation of cartilage repair tissue with 3T MRI. J Magn Reson Imaging, 28: 979-86 Department of Radiology of the Harvard Med- ple, bone infections are a dreaded complication ical School. A novel method for quantitative which requires efficient antibiotic therapy. In International Cooperation determination of cartilage morphology could this study, Moxifloxacin proved to be an antibi- Prof. Dr. S. Trattnig, Exzellenzzentrum Hochfeld MRT, Klinik be developed. The project investigated longi- otic drug with a high bone affinity resulting in fuer Radiodiagnostik, Medizinische Universitaet Wien, tudinal changes in surface characteristics and effective drug levels within osseous tissue. This Wien, Austria volume of articular cartilage in early stages of study also investigates other drugs that may Prof. Dr. P. Lang, Prof. Dr. Duryea, Brigham and Women`s osteoarthritis. accumulate within bone and which may nega- Hospital, Harvard Medical School, Boston, USA Furthermore, the role of bone marrow edema tively affect bone metabolism. With respect to for the process of osteoarthritis was investigat- hematogenic distribution, additional animal ed by MR imaging. It could be shown that the studies are performed to further characterize bone marrow edema is not a mandatory phe- microvascularization of bone tissue. nomenon in early stages of knee osteoarthritis. Its localization and extent is rather variable and does not closely correlate with the process Teaching of osteoarthritis. Bone marrow edema rather seems to be associated with physical activity The comprehensive education comprises the and local inflammatory processes. traditional main lecture and the curricular practical courses and additional integrated practical seminars, such as sewing courses and implant workshops, as well as colloquia focussing on interdisciplinary subjects. Interactive courses are also provided as an intensive training for final exams. Furthermore, the divison offers the opportunity to participate in clinical rounds and attend in emergency wards and operation rooms.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 89 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Surgery Division of Transfusion Medicine and Haemostaseology University Hospital

Address dard by the German Accrediation System for cellular blood components. Additionally, the Krankenhausstrasse 12 Testing (DAP). influence of different blood bags and of com- 91054 Erlangen ponent volumes on the quality of stored plate- Phone: +49 9131 8536972 lets is examined. Fax: +49 9131 8536973 Research www.transfusionsmedizin.uk-erlangen.de Preparation of dry platelet concentrates Head of Division Separation of progenitor cells from and platelet storage in additive solutions peripheral blood or cord blood Project manager: J. Ringwald Prof. Dr. med. Reinhold Eckstein Project manager: J. Zingsem The preparation of platelet concentrates in ad- Contact Haematopoietic progenitor and stem cells can ditive solutions attracts growing attention since Prof. Dr. med. Robert Zimmermann be identified among bone marrow cells and there is the possibility to inactivate pathogens Phone: +49 9131 8542110 circulating white blood cells. Another interest- that contaminate cellular blood components. Fax: +49 9131 8536973 ing source of progenitor cells is cord blood. Ag- Such inactivation procedures presuppose the [email protected] gressive novel strategies for therapy of malig- reduction of the plasma portion in platelet con- nant diseases require the isolation and storage centrates. Additionally, the portion of plasma Research Focus of these cells. The infusion of concentrates of that may be used otherwise is higher if “dry • Separation of progenitor cells from periph- progenitor and stem cells following high-dose platelets” are produced. Clinically, the reduc- eral blood or cord blood chemo- and radiotherapy enables the reconsti- tion of the plasma portion in platelet compo- • Preparation and characterization of white tution of haematopoiesis. A major focus of re- nents may reduce the frequency of adverse re- cell-poor platelet concentrates by apheresis search is the isolation of haematopoietic pro- actions, e.g. of allergic reactions. The resuspen- • Preparation of dry platelet concentrates and genitor cells in children. Main research interests sion of platelets in additive solutions requires platelet storage in additive solutions are the adaptation of apheresis procedures to the production of “dry platelets” – concen- • Platelet-derived growth factors for wound clinical problems of the isolation of progenitor trates containing more than 3000 x 10e+3 per healing and angiogenesis cells in pediatric patients with small total blood µl. For this purpose, we performed several se- • Autologous blood donation and haemato- volume and flow cytometry as method of qual- ries of platelet preparations using the TRIMA poiesis ity control and improvement. In the recently separator by Gam-broBCT. Platelet concen- • Collection of monocytes for the generation opened cord blood bank, research is focused trates in the additive solutions PAS II, PAS III of dendritic cells to cord blood derived-hematopoietic progeni- and PAS III M were compared with each other • Clinical research related to hemotherapy tor cells in cooperation with the departments and with platelets in plasma by analyses of the • Clinical research related to haemostaseology of pediatrics, gynecology and obstetrics and in vitro quality of fresh and stored platelet con- other departments of the hospital. centrates.

Structure of the Institution Preparation and characterization of Platelet-derived growth factors for wound white cell-poor platelet concentrates by healing and angiogenesis The Division of Transfusion Medicine and Hae- apheresis Project manager: R. Zimmermann mostaseology is located at the Department of Project manager: J. Zingsem, J. Ringwald Platelets contain growth factors which stimu- Surgery of the University Hospital Erlangen. Platelet apheresis processing large blood vol- late wound healing, angiogenesis, and possi- The head of the Division is Extraordinarius for umes to produce platelet-rich plasma has be- bly bone repair. Thereby these cells do not only Transfusion Medicine and Haemostaseology. come a standard procedure. In the past, plate- initiate coagulation at sites of injury but induce The department produces pharmaceutical let concentrates collected by apheresis were the processes of healing, too. Possible clinical products from blood and has a widespread contaminated by large amounts of white cells. application of these findings is the local appli- manufacturing permit by the local and the fed- Contamination of platelet concentrates with cation of concentrated platelets as a source of eral authorities. white cells may cause typical secondary effects growth factors for wound healing and bone re- The division offers all laboratory methods for associated with blood transfusion as cytomega- pair. Additionally, the phenomenon of growth diagnostics in the fields of immunohematolo- lovirus transmission, immunization to HLA class factor release from activated platelets to plas- gy and haemostaseology, organizes the depots I antigens and other antigens of white cells and ma during procedures with extracorporeal cir- of blood preservations and plasma derivates secretion of cytokines during storage. There- culation is a focus of research. for the treatment of coagulation disorders and fore, a major research focus is the preparation the cord blood and stem cell bank of the uni- of extremely white cell-poor platelet concen- Autologous blood donation and versity hospital. trates making additional filtration unnecessary. haematopoiesis The quality managment system of the depart- Apheresis procedures were developed for pro- Project manager: V. Weisbach ment has been certified according to the DIN ducing concentrates with standardized plate- The preoperative donation of autologous blood EN ISO 9001:2000 standard. Laboratories of let content but containing almost no residu- is a procedure with a substantial, albeit not yet the department have been accredited by the al white cells. Another research interest is the quantifiable risk for the patient.T he risks of ho- European Federation for Immunogenetics (EFI) evaluation of quality control-procedures de- mologous transfusion, which shall be avoided and according to the DIN EN ISO 15189 stan- tecting very low white cell-contaminations of by autologous blood, have been permanently

90 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) decreasing during the past several years. Thus, Selected Publications if preoperative autologous blood donation is Ringwald J, Schroth M, Faschingbauer F, Strobel J, Strasser performed at all, it has to be performed in an E, Schild RL, Goecke TW (2007) Intrauterine use of hyper- optimal way to improve the overall transfusion concentrated platelet concentrates collected with Trima Accel in a case of neonatal alloimmune thrombocytopenia. risk for an individual patient considering the Transfusion, 47: 1488-93 very low risks nowadays associated with ho- Strasser EF, Keller B, Hendelmeier M, Ringwald J, Zingsem mologous blood transfusion. The compensa- J, Eckstein R (2007) Short-term liquid storage of CD14+ tory erythropoiesis after repeated autologous monocytes, CD11c+, and CD123+ precursor dendritic cells blood donation shows marked interindividual produced by leukocytapheresis. Transfusion, 47: 1241-9 variability. Patients with a weak erythropoiet- Weisbach V, Strobel J, Hahn B, Roedel F, Lotter M, Zingsem ic response have an elevated risk to need ho- J, Ringwald J, Eckstein R (2007) Effect of gamma irradiation with 30 Gy on the coagulation system in leukoreduced mologous blood. It is a main focus of this work fresh-frozen plasma. Transfusion, 47: 1658-65 group to explore the mechanims underlying Zingsem J, Strasser E, Ringwald J, Zimmermann R, Weisbach this variability and to investigate measures to V, Eckstein R (2007) Evaluation of a new apheresis system enhance the power of compensatory erythro- for the collection of leukoreduced single-donor platelets. Transfusion, 47: 987-94 poiesis after autologous blood donation. High-resolution imaging of von-Willebrand-factor (vWF) multimers; Line 3: von-Willebrand syndrome type 3 Weiss DR, Thiel C, Strasser EF, Zimmermann R, Eckstein Collection of monocytes for the generation R (2008) An optimized electrophoresis method for high- resolution imaging of von-Willebrand multimers. Thromb of dendritic cells Haemost, 100: 949-51 Project manager: E. Strasser Zimmermann R, Wintzheimer S, Weisbach V, Strobel J, Circulating monocytes are precursors of den- Teaching Zingsem J, Eckstein R (2009) Influence of prestorage leuko- dritic cells which play a key role in the immune reduction and subsequent irradiation on in vitro red blood systems function by presenting antigens to The department offers lectures, seminars and cell (RBC) storage variables of RBCs in additive solution saline-adenine-glucose-mannitol. Transfusion, 49: 75-80 specific lymphocytes.T he collection and culti- practical hands-on training for students: vation of these cells enables the development • Participation in the principal subject “Labo- International Cooperation of new strategies in the treatment of malignant ratory diagnostics” of the German regulation BEST group der ISBT, International Society of Blood Transfu- diseases. Members of the Department of Trans- on education in medicine sion (ISBT), Amsterdam, Netherlands fusion Medicine cooperate with collegues from • Participation in the practical training course Meetings and International Training the Department of Dermatology to adjust the in surgery Courses collection procedures optimally to the specific • Further lectures, seminars and practical train- 16.–17.11.2007: Fortbildungsveranstaltung 2007 der clinical and experimental demands of proce- ings according to the university calendar Bayerischen Landesaerztekammer “Qualifikation alsT ransfu- dures aimed at the cultivation, expansion and • Regular seminars for the Bavarian Medical sionsverantwortlicher/ Transfusionsbeauftragter”, Erlangen priming of dendritic cells. Council 21.–22.11.2008: Fortbildungsveranstaltung 2008 der • Teaching at the school for assistant medical Bayerischen Landesaerztekammer “Qualifikation alsT ransfu- Clinical research related to hemotherapy technicians sionsverantwortlicher/ Transfusionsbeauftragter”, Erlangen, Bayerische Landesaerztekammer Other research interests regard to the exami- • Teaching for assistant medical technicians nation of antibodies against red cell antigens and for nurses (Prof. Weisbach), the characterization of factors influencing the quality of stored red cell concentrates (Prof. Weisbach, Prof. Zimmermann) and complex dysfunctions of the coagulation system (PD Dr. Ringwald, PD Dr. Strasser).

Clinical research related to haemostaseology Project manager: J. Ringwald, E. Strasser Other research interests regard to thrombo- philia, traveller´s thrombosis and haemostasis dysfunctions resulting in bleeding disorders. A study on traveller´s thrombosis (“traveller´s thrombosis – a state of practice in Germany”) was awarded in 2003 by the der ISTM (Interna- tional society for travel medicine) (PD Dr. Ring- wald). Other current study objectives are pre- analytical determinants of fibrinolysis tests, he- mostasis tests in systemic lupus erythematodes and other currently relevant topics.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 91 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Plastic and Hand Surgery

Address Research following application of osteoinductive fac- Krankenhausstrasse 12 tors. In the second phase vascularisation and 91054 Erlangen Gene expression profiles and intracellular bone formation following application of vital Phone: +49 9131 8533277 signal pathways in acute wounds under autologous osteoblasts into optimized matri- Fax: +49 9131 8539327 vacuum therapy ces are investigated in the arteriovenous loop www.plastische-chirurgie.uk-erlangen.de Project manager: M. Leffler model (rat). At the end the axially vascularised Head of Department Vacuum therapy leads to a significant improve- constructs will be implanted into critical-sized ment in the treatment of problematic wounds, bone defects. Prof. Dr. med. Raymund E. Horch but the underlying biological mechanisms are Contact still not fully understood. The aim of this proj- Vascularisation of bioartificial tissue via Prof. Dr. med. Raymund E. Horch ect is to examine gene expression profiles of embryonic endothelial progenitor cells Phone: +49 9131 8533277 tissue biopsies before and after vacuum ther- Project manager: O. Bleiziffer Fax: +49 9131 8539327 apy. Tissue samples were analysed using mi- Endothelial progenitor cells (EPC) may sup- [email protected] croarray technology and molecular biology port vascularisation of bioartificial tissues due methods (PCR, Western Blot). Differences in to their angiogenic potential. In the present Research Focus gene expression profiles and in the activity project EPC are transplanted in a fibrin matrix • Gene expression profiles and intracellular of single genes will be analysed. Besides this in vivo inside an arteriovenous loop and their signal pathways in acute wounds under corresponding signal pathways will be exam- impact on construct vascularisation is investi- vacuum therapy ined. The aim is to find a distinct gene expres- gated. Transgenic EPC expressing pro-or an- • Histological and molecular biological sion profile which correlates with an improved ti-angiogenic mediators, respectively, will be analyses of the pathologies of the discus wound healing under vacuum therapy. employed to modulate neoangiogenesis. EPC ulnocarpalis localization and construct vascularisation are • Engineering of axially vascularised bone tis- Histological and molecular biological investigated by morphometric analysis, immu- sue using biomorph ceramics analyses of the pathologies of the discus nohistochemistry and micro CT scan. The re- • Vascularisation of bioartificial tissue via em- ulnocarpalis sults may support creation of functional blood bryonic endothelial progenitor cells Project manager: F. Unglaub vessel networks in bioartificial constructs or • Imaging tools and molecular biological The working group concentrates on experi- support antiangiogenetic cancer therapy. analyses of ischemia and reperfusion in hu- mental investigations regarding the patholo- man free flaps gies of the discus ulnocarpalis of the wrist. De- Imaging tools and molecular biological • Generation of axially vascularised neo-tissue generative lesions and traumatic lesions are in- analyses of ischemia and reperfusion in in the large animal model of the sheep cluded in the investigative studies. The studies’ human free flaps • Tissue engineering of skeletal muscle with aim is to uncover degeneration and regenera- Project manager: A. Dragu nanofibers tion mechanisms occurring in the fibrocarti- The use of free flaps in plastic and reconstruc- lage of the wrist. For these purposes, biopsies, tive surgery represents an established micro- which are retrieved during arthroscopic wrist surgical procedure, for the successful closure of Structure of the Institution procedures, are examined regarding their mo- defects of the human body. However, the post- lecular biological properties: apoptotic path- operative monitoring of viability and perfusion Under the auspices of the head of the depart- ways are immuno-histochemically analyzed, of the transplanted tissue represents a clinical ment, Prof. Horch and 4 attending plastic sur- and the role of inflammation in the develop- problem (e.g. buried flaps). The limited time geons, 8 residents, 2 lab technicians, 2 vet- ment of fibrocartilage degeneration is inves- of free flap ischemia also represents a clinical erinarian doctors, 2 scientists and 16 medical tigated. Other main focuses of the investiga- problem. Innovative imaging tools in nuclear student are working in a number of different tions are the vascularization of the fibrocarti- medicine are used on an interdisciplinary basis teams on various topics of basic and clinical / lage, and its regeneration potential. to evaluate viability and perfusion of the free applied science. Besides clinical studies and re- flap. Additionally, gene expression analyses are search based on in vitro investigations of clinical Engineering of axially vascularised bone performed in order to understand more about samples, different large and small animal mod- tissue using biomorph ceramics ischemia and reperfusion in free flaps. els are established. With these in vivo studies Project manager: U. Kneser, A. Arkudas, E. many issues are addressed in the field of plas- Polykandriotis tic and reconstructive surgery, especially con- Aim of this project in cooperation with Prof. cerning angiogenesis and tissue engineering. Greil, Material Research Centre, Department of Glass and Ceramics, is to generate axially vascularised bone tissues based on biomorph calcium phosphate scaffolds. In the first phase matrices are evaluated in the subcutaneous screening model (rat) with regard to vascularisation, biocompatibility and bone generation

92 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Arkudas A, Beier JP, Heidner K, Tjiawi J, Polykandriotis E, Srour S, Sturzl M, Horch RE, Kneser U (2007) Axial pre- vascularization of porous matrices using an arteriovenous loop promotes survival and differentiation of transplanted autologous osteoblasts. Tissue Eng, 13: 1549-60 Arkudas A, Tjiawi J, Bleiziffer O, Grabinger L, Polykandriotis E, Beier JP, Stuerzl M, Horch RE, Kneser U (2007) Fibrin Gel-Immobilized VEGF and bFGF Efficiently Stimulate Angiogenesis in the AV Loop Model. Mol Med, 13: 480-7 Bleiziffer O, Eriksson E, Yao F, Horch RE, Kneser U (2007) Gene transfer strategies in tissue engineering. J Cell Mol Med, 11: 206-23 Leffler M, Hrach T, Stuerzl M, Horch RE, Herndon DN, Jeschke MG (2007) Insulin attenuates apoptosis and exerts anti-inflammatory effects in endotoxemic human macrophages. J Surg Res, 143: 398-406 Micro-CT visualisation of axial vascularisation via an arteriovenous loop in the rat Beier JP, Horch RE, Arkudas A, Polykandriotis E, Bleiziffer animal model O, Adamek E, Hess A, Kneser U (2009) De novo generation of axially vascularized tissue in a large animal model. Microsurgery, 29: 42-51 Unglaub F, Kroeber MW, Thomas SB, Wolf MB, Arkudas A, Dragu A, Horch RE (2009) Incidence and distribution of blood vessels in punch biopsies of Palmer 1A disc lesions in the wrist. Arch Orthop Trauma Surg, 129: 631-4

International Cooperation Generation of axially vascularised Teaching neo-tissue in the large animal model of the Prof. Dr. Alois Lammetschwandtner, Lehrstuhl fuer Biologie, Universitaet Salzburg, Austria sheep According to the german “Statutes of the medi- Prof. Dr. Dietmar Hutmacher, Institute of Health and Bio- Project manager: J. Beier, U. Kneser cal act (AeAppO)”, a lecture series of 25 aca- medical Innovation, Queensland University of Technology, In the newly developed arteriovenous loop demic hours per semester (AHS) is held as part Brisbane, Australia model in the sheep, axial vascularisation in of the general surgery lecture series. It covers Prof. Elof Eriksson, M. D., Ph. D., Plastic Surgery Division, neo-tissues is induced in various hard- and soft general principles of Plastic and Hand Surgery. Harvard Medical School, Boston, USA matrices. Besides histomorphometrical and im- Additionally the following teaching courses are Meetings and International Training munohistological analyses, up-to-date intra- conducted regularly by the Department of Plas- Research Equipment vitral, three-dimensional imaging studies are tic and Hand Surgery: Zeiss 2 Zeiss Operationsmikroskope performed in cooperation with the Institute of - Lecture series on “Specific issues in plastic and Pharmacology (PD Dr. A. Hess, PhD) to assess hand surgery” Leica 1 Leica-Operationsmikroskop vascularisation. In the future we will investigate - Tutorial “Tissue engineering” the potential role of osteogenic growth factors - Clinical ward round of Department of Plastic in this large animal model as well as the trans- and Hand Surgery plantation of mesenchymal stem cells. - Surgical anatomy of the hand and techniques of hand examination Tissue engineering of skeletal muscle with - Interdisciplinary consultation hour in “Breast nanofibers reconstruction” Project manager: J. Beier - Teaching ward round and advanced course in In this research project the generation of neo- plastic surgery muscle tissue is aimed for by in vitro and in - Microsurgical suture techniques vivo application of novel electrospun nanofi- - Teaching ward round and advanced course in bers. Primary myoblasts as well as mesenchy- reconstructive microsurgery mal stem cells are used as cell source. Besides - Postbariactric plastic surgery consultation FACS- and molecular biology analysis in vitro, hour the implantation of these cell-containing con- - Course on examination of the bracial plexus structs in the rat AV-loop model is a promising and peripheral nerves of the upper extremity step towards cultivation of axially vascularized skeletal muscle tissue in vivo.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 93 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Cardiac Surgery Chair of Cardiac Surgery

Address tent that the patients need to be stabilised plant arteriosclerosis using chemokine- and co- Krankenhausstrasse 12 (‘bridged’) with a left ventricular assist device stimulatory-receptor modulating IgG-Fusion 91054 Erlangen (LVAD) or in case of additional right heart fail- proteins” which is part of the post graduate Phone: +49 9131 8533319 ure with a biventricular assist device (BIVAD) programme 750 “Vaskulaere Schaeden an Herz Fax: +49 9131 8532768 until the day of transplantation. und Niere” of the German Research Founda- www.herzchirurgie.med.uni-erlangen.de tion (DFG). The aim of this project is to de- Head of Department Chronic rejection of allografts (transplant velop fusion proteins to costimulatory mol- arteriosclerosis) ecules such as CTLA4-Ig, ICOS-Ig and PDL1- Prof. Dr. med. Michael Weyand Project manager: S. Ensminger Ig to modify and influence T-cell activation. Contact Our group is a collaboration between the De- In addition, a joint project with Dr. Lechmann Prof. Dr. med. Michael Weyand partment of Cardiac Surgery (Prof. Ensminger) and Prof. Steinkasserer from the Department Phone: +49 9131 8533319 and the Department of Medicine 3 and Medi- of Dermatology regarding the effect of CD83 Fax: +49 9131 8532768 cine 5 (PD Dr. Spriewald, M. Poehner, pharma- modulation on the development of transplant [email protected] cist) and is interested in the underlying path- arteriosclerosis just started in November 2003. ological mechanisms leading to the devel- Recent findings implicate an important role Research Focus opment of transplant arteriosclerosis. Today of human cytomegalovirus infection (HCMV) • Therapy of end-stage heart failure: heart transplant arteriosclerosis represents the major for the development of inflammatory-prolif- transplantation or support with a left- or obstacle for indefinite graft survival and has erative vascular lesions in transplanted vas- right ventricular assist device become the leading cause of death in cardiac cularised allografts. Therefore, the major aim • Chronic rejection of allografts (transplant transplant recipients who survive beyond the of this project is to develop a human periph- arteriosclerosis) third year after transplantation. Pharmacologi- eral blood lymphocyte (hu-PBL)/severe com- • Tissue engineering of cardiovascular im- cal agents that effectively prevent acute graft bined immunodeficiency S( CID) mouse Xeno- plants rejection have proven inadequate for averting graft-model to investigate the immunological • Neuropeptide release of the heart late graft loss caused by transplant arterioscle- and pathological mechanisms of HCMV in the • Hospital-economics and management rosis. Currently the only definite treatment of modulation and progression of transplant arte- transplant arteriosclerosis is re-transplantation, riosclerosis. This project called “Investigations which is associated with a significantly poorer into the role of cytomegalovirus in the devel- Structure of the Institution survival rate and an increased overall complica- opment of transplant arteriosclerosis using a tion rate. Transplant arteriosclerosis is the main Hu-PBL/SCID mouse model” is funded for 3 20 medical doctors work in the departement reason for late graft failure and develops in all years by the IZKF of the University of Erlan- of orthopaedic surgery. The research is accom- other vascularised organ transplants such as liv- gen-Nürnberg. plished by all medical doctors, 7 graduate stu- ers and kidneys. dents and 2 technical assistants. In order to develop effective therapeutical Tissue engineering of cardiovascular strategies and translate them into clinical suc- implants cess, a detailed understanding of the mecha- Project manager: M. Weyand, O. Roerick Research nisms responsible for the development of trans- Background for these studies is the develop- plant arteriosclerosis is essential. We have rement of an ingrowth matrix within the tissue Therapy of end-stage heart failure: heart cently established and characterised the ab- engineering of cardiovascular grafts. The pur- transplantation or support with a left- or dominal aortic allograft model as a suitable pose of these investigations is to show, wheth- right ventricular assist device tool to study the development of transplant er it is possible to influence the mobility of en- Project manager: M. Weyand, R. Tandler, M. arteriosclerosis. dothelial cells, smooth muscle cells and fibro- Kondruweit Ongoing projects involve the role and impor- blasts within a fully synthetic matrix by incor- The survival rate of patients with end stage tance of chemokines and chemokine-receptors porating bioactive peptides. The purpose is to heart failure (prevalence approx. 0.1%) with in particular CCR7 and CXCR5 in the develop- define a matrix which provides optimal mo- optimised medical therapy is 0.4 to 0.8 for 1 ment of transplant arteriosclerosis. CCR7, the bility for those cells neededd for a functional year and 0.1 to 0.5 for 5 years. Orthotopic car- major homing receptor for trafficking ofT - and cardiovascular implant. Such a matrix could diac transplantation is the therapy of choice for B cells plays a crucial role in leukocyte homing. be integrated into a cardiovascular prosthesis these patients. Due to an increasing shortage Experiments using CCR7-/- mice (kindly proin order to facilitate and direct the ingrowth of donor organs, a considerable number of pa- vided by Professor Foerster, Hannover) as re- of the patient’s own tissue. A single cell mi- tients die on the waiting list. If necessary, these cipients of aortic allografts showed increased gration model was used to compare the influ- patients can be bridged with an implantable amounts of transplant arteriosclerosis during ence of different cell interactive peptides on ventricular assist device until a suitable donor the absence of this receptor and suggest an in- the mobility of vascular cell lines as microvas- organ is available. In our heart-failure clinic pa- teresting role of this receptor in this disease. cular endothelial cells (MVEC) and aortic vas- tients are evaluated if they are suitable candi- Since Mai 2003 Prof. Ensminger and Dr. Spri- cular smooth muscle cells (SMC). In previous dates for transplantation. In some cases heart ewald supervise a graduate student (M. Poeh- studies it could already be shown that selec- disease has already progressed to such an ex- ner) working on the project “Preventing trans- tively MVEC but not SMC accelerate on a PEG

94 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) matrix derivatised with RGD (fibronectin) and ment since the introduction of the DRGs. Other Selected Publications YIGSR (laminin) in comparison to a matrix de- current projects involve the development of Arnold ML, Ensminger SM, Doxiadis II, Spriewald BM (2008) rivatised with only RGD. These experiments the so called ‘clinical pathways’ in order to im- Effect of Donor Cell Type on Complement-Dependent were extended to the peptide sequences SIK- prove cost unit calculations and enable us to Cytotoxicity Crossmatch Outcome for Patients Immunized Against HLA Class-II Antigens. Exp Clin Transplant, 6: 1-6 VAV, RYVVLPR (both laminin) and DGEA (colla- create computer-simulated scenarios of com- gen) also known from the literature as vascular plex problems of hospital cost management. In Ensminger SM, Helm SN, Ohl L, Spriewald BM, Abele S, Wollin M, Wood KJ, Weyand M, Foerster R (2008) Increased cell interactive. For sufficient cellular adhesion cooperation with the Department of Anaesthe- transplant arteriosclerosis in the absence of CCR7 is associ- RGD was added to the matrix again. At an av- siology we perform a study analysing the costs ated with reduced expression of Foxp3. Transplantation, erage migration speed of 21.1 µm/h for MVEC involving intensive care patients and togeth- 86: 590-600 and 26.9 µm/h for SMC on RGD-PEG hydro- er with the German Heart Centre in Berlin we Schmid C, Jurmann M, Birnbaum D, Colombo T, Falk V, gels both cell lines showed a reduced cell speed are trying to set up a database regarding long- Feltrin G, Garatti A, Genoni M, Gerosa G, Goettel P, Gum- mert J, Halfmann R, Hammel D, Hennig E, Kaufmann F, on RGD plus RYVVLPR and RGD plus DGEA term costs of patients on cardiac assist devices. Lanfranconi M, Meyns B, Mohr F, Mueller J, Nikolov D, (MVEC: – 22% on RYVVLPR+RGD, – 21% on Rucinskas K, Scheld HH, Schmid FX, Schneider M, Sirvydis DGEA+RGD; SMC: – 27% on RYVVLPR+RGD, V, Tandler R, Vitali E, Vlasselaers D, Weyand M, Wilhelm M, Hetzer R (2008) Influence of inflow cannula length in axial- – 22% on DGEA+RGD). For the combination Teaching flow pumps on neurologic adverse event rate: results from of SIKVAV and RGD only MVEC showed a small a multi-center analysis. J Heart Lung Transplant, 27: 253-60 but not significant increase in mobility, where- Beside the traditional teaching forms (main by SMC did not show any difference. lecture and practical courses) hospitations and International Cooperation fellowships can be undertaken anytime. Mon- Prof. Kathryn J. Wood, Nuffield Department ofS urgery, John Radcliffe Hospital, University of Oxford, U.K. Neuropeptide release of the heart day’s seminars to actual clinical and experimen- Project manager: Th. Strecker tal topics take place in our hospital. Prof. Marlene Rose, National Heart and Lung Institute, Im- perial College, Harefield Hospital,S chool of Medicine, U.K. Calcitonin-gene related peptide (CGRP) is a neuropeptide consisting of 37 amino acids and its biological action results in a strong vasodi- latation. CGRP is mainly produced by the sen- soric Aδ- and C-fibres. Recent data suggested that it may play an important role in myocardial ischemia. Neural fibres with a high CGRP content are found in both atria, the pericardi- um and within the adventitia of coronary arteries. Changes in CGRP production correlate with increased activity within cardiac afferent fibres. It was shown in vitro that elevated CGRP concentrations were able to increase the coronary blood flow and reduce the coronary resistance and the mean arterial blood pressure. Further- more, CGRP was demonstrated to be cardio- protective and reduced the infarct size of myocardial infraction. The aim of our project is to develop an experimental mouse model in order to investigate the effects and kinetics of CGRP production in greater detail. In addition analyses of human CGRP production is planned by using tissue from the right ventricle or ascending aortic tissue.

Hospital-economics and management Project manager: R. Feyrer This group is a collaboration between the De- partment of Cardiac Surgery (PD Dr. Feyrer) and the competent office of Healthcare Re- source Groups (DRGs) (U. Kunzmann). One of the main tasks of this group is to face the changes in hospital reimbursement from retrospective payment to a prospective flat rate pay-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 95 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Urology Chair of Urology

Address es of competence in urology. For this purpose Krankenhausstrasse 12 the outpatient centre for uro-oncologic diseas- 91054 Erlangen es (AURONTE) was founded together with the Phone: +49 9131 8533683 Department of Urology and the Department Fax: +49 9131 8534851 of Medicine 5. Any therapeutic decision con- www.urologie.uk-erlangen.de cerning systemic drug therapy, including in- Head of Department dications for neoadjuvant or adjuvant systemic treatment, is based on a common interdisci- Prof. Dr. med. Bernd Wullich plinary conference. Contact Any particular decision on treatment is also dis- Dr. rer. nat. Sven Wach cussed in the context of the current clinical tri- Phone: +49 9131 8523373 als. With this it is assured that all currently ac- Fax: +49 9131 8523374 tivated or planned clinical trails are open to all [email protected] common patients. Since April 2008 the study registry is staffed with our quality managing in- Research Focus tern intern (Dr. Kerscher, K. Jalalian). Currently • Systemic tumor therapy, clinical trials open clinical trials mainly focus on new thera- • Establishment of a clinically annotated peutic options for patients with kidney cancer Fig.1: Real-time analysis of microRNA expression in tumor tissue repository containing urologic or prostate cancer: tumor tissue tumors - Registry for advanced kidney cancer • Tumor genetic research with focus on identi- Epidemiologic registry to provide informa- fication of biomarkers tion on treatment and current regimen of pa- - HAROW-Study • MRT-guided needle biopsy for the diagnosis tients with metastatic or locally advanced kid- Prospective, multicentre german registry trial of prostate carcinoma ney cancer to evaluate the provision of care and treatment - Registry STAR – TOR for newly diagnosed, localized prostate cancer Registry for the assessment of safety, tolerance Further Information: Structure of the Institution and efficacy of Temsirolimus (Torisel®) for the http://www.urologie.uk-erlangen.de/informa- treatment of advanced kidney cancer tionen_fuer_aerzte/studienzentrale/aktuelle_ University hospital: - RCC Switch Study studien/index_ger.html Outpatients’ Clinic and pediatric urology. Randomized phase III first line trial to evaluate Adult renal transplantation unit in coopera- efficacy and safety of sequenced therapy suni- Establishment of a clinically annotated tion with the Department of Medicine 4 (Prof. tinib/sorafenib vs. sorafenib/sunitinib in meta- tumor tissue repository containing uro- Eckardt). static renal cell cancer logic tumors Pediatric renal transplantation unit in coopera- - CRAD001L2401 Project manager: B. Wullich tion with the Department of Pediatrics (Prof. Advanced open-access, multicentre trial of New insights about the occurrence of malig- Rascher). RAD001 (Everolimus), for patients with meta- nant tumors and the identification of new and Uro-oncological outpatients’ unit for systemic static renal cell cancer, following tyrosinkinase- reliable prognostic biomarkers are dependent drug therapy (AURONTE) in cooperation with inhibition failure on the molecular characterization of rather the Department of Medicine 5 (Prof. Mack- - FLARE DOCT/L03323 large cohorts of tissue samples, since the cur- ensen). Evaluation of the use of Taxotere® in hormone- rently used morphologic criteria only poorly re- refractory prostate cancer and the assessment flect the progression behavior of one patient’s Waldkrankenhaus St. Marien: of the PSA FLARE phenomenon specific tumor. To facilitate this research, the Adult urology (inpatients’ department), private - H6Q-MC-SO32 collection of tissue samples originating from insurance patients (outpatients’ department). Randomized double-blind first-line placebo tumors and corresponding non-tumorous tis- Trial documentation centre. controlled phase II trial with or without en- sue as well as blood, serum, and other body flu- zastaurin in combination with docetaxel and ids like urine is crucial for translational research prednisone, followed by enzastaurin mainte- projects. A high quality tissue sample reposi- Research nance therapy in hormone-refractory meta- tory demands a standardized logistics for the static prostate cancer sample transportation from the operating the- Systemic tumor therapy, clinical trials - CA180-227 ater to the Institute of Pathology, as well as the Project manager: P.J. Goebell Randomized double-blind first-line placebo careful and standardized preparation of the The medical care and treatment of patients controlled phase III trial to evaluate the combi- samples carried out by an experienced pathol- with uro-oncologic diseases represent an inte- nation of docetaxel w/o dasatinib for patients ogist. In close cooperation with the local Insti- gral part of the urologic specialty and system- with hormone-refractory prostate cancer tute of Pathology a repository of urologic tissue ic therapy forms besides the provision of sur- samples has been established, in which tissue gical treatment one of the fundamental sourc- samples of all surgically treated malignant uro-

96 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) logic tumors are introduced. For the establish- Using RNA interference or expression vector systemic drug tumor therapy. For acquisition ment of the required SOPs we have established constructs it is possible to modulate the activ- and improvement of specialized surgical tech- a close cooperation with the German Prostate ity of target genes. The functional alterations niques, the urologic clinic uses patient simula- Carcinoma Consortium (DPKK) e.V. and could of tumor cells are then analyzed using prolifer- tors. These include models for practicing sterile furthermore introduce a web-based tissue da- ation, invasion, migration, or apoptosis assays. placement of catheters or laparoscopic meth- tabase system. Additionally, the documenta- ods for minimally invasive surgery. tion of patients’ clinical parameters is carried MRT-guided needle biopsy for the diagno- out with the valuable assistance of the Medical sis of prostate carcinoma Selected Publications information and communication centre (Prof. Project manager: D. Engehausen Kindich R, Florl AR, Jung V, Engers R, Mueller M, Schulz WA, Prokosch) on the basis of a SOARIAN-generat- Magnetic resonance tomography (MRT)-guid- Wullich B (2005) Application of a modified real-time PCR ed clinical database. This database has current- ed biopsy is a novel diagnostic approach in technique for relative gene copy number quantification to the determination of the relationship between NKX3.1 loss ly been optimized for prostate cancer patients cases of suspected prostate cancer. It com- and MYC gain in prostate cancer. Clin Chem, 51: 649-52 Jung V, Kindich R, Kamradt J, Jung M, Mueller M, Schulz WA, Engers R, Unteregger G, Stoeckle M, Zimmermann R, Wullich B (2006) Genomic and expression analysis of the 3q25-q26 amplification unit reveals TLOC1/SEC62 as a probable target gene in prostate cancer. Mol Cancer Res, 4: 169-76 Jung V, Wullich B, Kamradt J, Stoeckle M, Unteregger G (2007) An improved in vitro model to characterize invasive growing cancer cells simultaneously by function and genetic aberrations. Toxicol In Vitro, 21: 183-90 Hugo C, Schott G, Eckardt KU, Wullich B (2008) ABO- incompatible renal transplantation – why and how? Urologe A, 47: 1074-8 Jungwirth N, Haeberle L, Schrott KM, Wullich B, Krause FS (2008) Serotonin used as prognostic marker of urological tumors. World J Urol, 26: 499-504 Fig. 2: Cell culture of the prostata carcinoma cell line DU145 Keck B, Stoehr R, Goebell PJ, Fritsche HM, Wullich B, Hart- mann A (2008) Plasmacytoid carcinoma: Five case reports of a rare variant of urothelial carcinoma. Pathologe, 29: 379-82 and will soon be extended to other urologic tu- bines sophisticated MRT imaging techniques International Cooperation mors. All incorporated procedures are consis- with the guided extraction of prostate biopsy tent with the legal, ethical, technical and orga- samples therefore incorporating the radiolo- OA Dr. Peter J. Goebell, Secretary General, International Bladder Cancer Network (IBCN), Barcelona, Spain nizational regulations of tissue repositories and gist’s (visualization of the target area) and the Prof. Colin Dinney, MD Anderson Comprehensive Cancer databases (patients’ informed consent, data urologist’s (targeting the biopsy needle and Centre, SPORE Bladder Cancer (funded by the National security, standard operating procedures and extraction of the sample) expertise. With the Cancer Institute), Houston, USA quality management) according to the recom- patients lying in a supine position, two biopsy Prof. Pierre Hainaut, IARC, International Consortium of mendations of the BMBF associated telematics samples from every suspect area and one ref- Biological Resource Centres for Cancer, Lyon, France platform for medical research networks. erence sample are extracted, each taken under Peter J. Geary, Marble Arch Working Group on Global visual control of the biopsy needle. The exam- Biorepositories, Montreal, Canada Tumor genetic research with focus on ination takes between 40 and 70 minutes. A Meetings and International Training identification of biomarkers mild sedation as well as local anesthesia are ad- Courses Project manager: S. Wach ministered. This procedure is intended for pa- 10.03.2007: Erlanger Urologie, Waldkrankenhaus The identification and characterization of spe- tients with persistent suspect for prostate can- cific biologic properties of prostate cancer as cer after negative transrectal ultrasound (TRUS) 23.10.2007: Neues vom Prostatakarzinom, Waldkran- kenhaus well as other malignant tumors like bladder or biopsy and shows a high detection rate in this kidney cancer is the main focus of the biolog- cohort with 40%, in a sub cohort with even 28.11.2007: Kinderurologische Gespräche, Waldkranken- haus Erlangen ic research projects. By conducting correlation 60%. This procedure is available in only a few 02.04.2008: Neues vom Nierenzellkarzinom, Waldkran- analyses of certain specific molecular charac- centres worldwide (at this time 4, including Er- kenhaus teristics of tumors with histopathologic crite- langen), requiring the interdisciplinary coop- 17.09.2008: Kinderurologische Gespräche, Waldkran- ria and clinical progression data new biomark- eration between urologists and radiologists kenhaus ers will be identified. These biomarkers are and is constantly improving. Before conduct- 24.10.2008: Erlanger Gesundheitstag Prostatakrebs Ex- thought to provide a more accurate prediction ing this type of examination, the modalities of pertensymposium of the individual patient’s course of the disease payment should be clarified. The total cost of 25.10.2008: Erlanger Gesundheitstag Prostatakrebs (prognostic value) and enable optimized ther- about 1.350 € are at this time not approved by 21.–22.11.2008: dpkk Workshop mit 6. Mitgliederver apy decisions (predictive value). The complete the health insurance Chamber Law for Health sammlung, Vierzehnheiligen Staffelstein spectrum of molecular cytogenetic techniques Care professions. including fluorescence in situ DNA and RNA hybridization and microarray based hybridization techniques (oligonucleotide microarrays Teaching for genomic, expression and microRNA profiling analysis) has been established in the lab- Medical students are taught in the lecture se- oratory. The quantification of microRNA and ries of emergency medicine and specialized gene expression (Fig.1) as well as the determi- urological lectures. Students also conduct a nation of gene copy numbers using real time practical course in the urological clinic or one PCR approaches is a central part of the experi- of the associated teaching hospitals. The clinic mental methods. also allows additional education for achieve- Another important aspect of our tumor biolo- ment of the title medical specialist for urol- gy research are functional studies using short- ogy. Additionally, specialized training cours- and long-term cultures of tumor cells (Fig.2). es are offered for the fields of andrology and

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 97 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Anaesthesiology Chair of Anaesthesiology

Address (Chair and Chairman of the department: Prof. nisms, in which cortical and sub-cortical re- Krankenhausstrasse 12 Dr. Dr. med h. c. Jürgen Schüttler) with extra gions postoperative pain sensitization is rep- 91054 Erlangen Ordinariates for Experimental Anaesthesiol- resented, which genetic factors determine in- Phone: +49 9131 8533676 ogy (Prof. Dr. Dr. rer. nat. Helmut Schwilden) creased postoperative pain and the risk for the Fax: +49 9131 8539191 and Anaesthesiology / Pain Research (Prof. Dr. development of persistent pain, and which psy- www.anaesthesie.uk-erlangen.de med. Carla Nau). An autonomous unit with an chological traits predict postoperative pain. Head of Department Extraordinariate for Molecular Pneumology The team employs basic, disease-, and patient- (Prof. Dr. Dr. Susetta Finotto) was affiliated to related methods of pain research. Prof. Dr. med. Dr. h. c. Jürgen Schüttler the Chair of Anaesthesiology in 2009. The es- Other funded projects investigate hypnotic Contact tablishment of an endowed chair for palliative and analgesic effects of anesthetic and anal- Prof. Dr. med. Carla Nau medicine is nearing completion. The Anaesthe- gesic substances and mechanisms of opioid-in- Phone: +49 9131 8533103 siology Department employs 95 medical doc- duced hyperalgesia by means of psycho-physi- Fax: +49 9131 8539399 tors and 9 scientific members with responsibili- cal methods and functional imaging, the func- [email protected] ties in research and teaching. tion and pharmacology of nociceptor-specific The main research focus is in pain research, ion channels, and single nucleotide polymor- Research Focus which is represented by the interdisciplinary phisms in nociceptor-relevant genes and their • Pain research: determinants and modulators clinical research unit “Determinants and modu- role in acute and chronic pain. of perioperative and palliative pain lators of post-operative pain” (Scientific Head: Pain research in palliative medicine focuses on • Medical technology of diagnostic and Prof. Dr. med. Carla Nau). It is supplemented the improvement of pain therapy of inpatients therapeutic procedures by the group of Prof. Dr. med. Wolfgang Kop- and outpatients with cancer. • Clinical and experimental pharmacology of pert with a focus on pharmacology of analgesic anaesthesia agents in humans. Other focuses are the mon- Medical technology of diagnostic and • Intensive care and emergency medicine: itoring in anesthesia and intensive care medi- therapeutic procedures systemic inflammation, acute lung and cine and the exploration of medical processes To monitor the effect and efficacy of anaes- cardiac failure, resuscitation in the medical care for inpatients and outpa- thetic drugs head related biosignals (spontane- • Research in teaching and learning tients. The latter is accomplished in coopera- ous EEG and auditory evoked potentials) were tion with the Fraunhofer Institute for Integrated examined and mathematically analyzed to ex- Circuits, which holds a medical test and appli- tract therapeutic features and to model their Structure of the Institution cation centre at the Medical Faculty. time course using the pharmacokinetics of the Other groups work on aspects of clinical and drugs. Especially the particularities in pediatric The Department of Anaesthesiology main- experimental pharmacology of anesthesia in- anaesthesia patients were analyzed. Within the tains 50 anesthesia units, 37 of which are run cluding muscle relaxation, and in the context field of vital data monitoring methodologies continuously, to provide anesthesia service to of intensive care and emergency medicine ex- were investigated to measure non-invasive and 15 surgical departments or independent divi- plore generalized inflammation, acute lung and continuously pulse waves and blood pressures sions and several diagnostic and interventional cardiac failure and resuscitation by means of of the arterial systems and to compare it with departments of the University Hospital Erlan- clinical and animal models. the common invasive technique. The research gen. The Department of Anaesthesiology also The working group “Research in Teaching” is grant project “Teletherapy of chronic pain” in- includes an outpatient’s anesthesia division operating at the intersection between teaching vestigated and developed technical options to with an unit for lung function diagnostics and and research and applies simulation of medical improve the location-independent integrated a pain clinic. The Department of Anaesthesiol- processes to optimize teaching and to estab- home care of palliative patients. The analysis ogy is responsible for the management of the lish a scientific foundation for risk and process with respect to medical technology aimed par- interdisciplinary surgical ICU of the University management. ticularly at the telemedical human interaction Hospital with 25 beds and, together with the with infusion pumps for the automated sup- Department of Neurology, holds the Centre for ply with analgesic drugs and documentation Interdisciplinary Pain Therapy. Additionally, the Research via diverse technical signal pathways. Focus of Department of Anaesthesiology is responsible the palliative medicine oriented research was for the management of the ambulance service Pain research: determinants and modula- the analysis of application pattern of the an- for the city of Erlangen, the region of Erlan- tors of perioperative and palliative pain algesic drugs. gen-Hoechstadt and the location of Herzoge- An interdisciplinary clinical research unit (DFG naurach. The department also engages in the KFO 130) focuses on postoperative pain that Clinical and experimental pharmacology of field of air rescue with the air ambulance of the persists beyond the expected healing period. anaesthesia region (Christopher 27) as well as ambulance The interdisciplinary team investigates, which The importance of genotype CYP3A5 for the aircrafts for repatriation of patients. mechanisms in the peripheral and central ner- pharmacokinetics and pharmacodynamics of At the Department of Anaesthesiology is locat- vous system contribute to postoperative pain midazolam for the treatment of intensive care ed the Chair of Anaesthesiology of the Fried- sensitization and in which way anesthetic and patients was investigated in cooperation with rich-Alexander University Erlangen-Nürnberg analgesic substances influence these mecha- the Chair of Clinical Pharmacology with respect

98 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Analysis on research projects of the Clinical Research Unit 130 Source: University Hospital Erlangen

to interindividual variations. For the muscle re- ful. It is investigated, whether a careful intro- Selected Publications laxants mivacurium and rocuronium the im- duction to a stressful situation improves learn- Fromm MF, Schwilden H, Bachmakov I, Koenig J, Bremer F, pact of the mutation of the dystrophin gene ing as compared to an unsparing confronta- Schuettler J (2007) Impact of the CYP3A5 genotype on mid- at locus Xp21 (M. Duchenne) on the pharma- tion with the virtual reality and the consecutive azolam pharmacokinetics and pharmacodynamics during intensive care sedation. Eur J Clin Pharmacol, 63: 1129-1133 cokinetics and pharmacodynamics was mod- “learning from mistakes.” Here, psychological Leffler A, Reiprich A, Mohapatra DP, Nau C (2007) Use- elled and analyzed with respect to its influence conditions play a prominent role that are re- dependent block by lidocaine but not amitriptyline is on the progression of the disease. In animal lated to the respective model of learning. Due more pronounced in tetrodotoxin (TTX)-Resistant Nav1.8 studies (rats) we explored the relationship be- to the scientific relatedness to psychology and than in TTX-sensitive Na+ channels. J Pharmacol Exp Ther, 320: 354-64 tween drug concentrations of desflurane, sevo- pedagogy, a collaboration with the Depart- flurane and isoflurane and its induced EEG -ef ment of Educational Psychology was launched. Palmaers T, Albrecht S, Heuser F, Leuthold C, Schuettler J, Schmitz B (2007) Milrinone combined with vasopressin fects. In contrast to the relationship between improves cardiac index after cardiopulmonary resuscitation drug concentrations and MAC value this is in a pig model of myocardial infarction. Anaesthesiology, rather unknown. These concentration-effect Teaching 106: 100-6 relationships are essential for further investi- Filitz J, Ihmsen H, Guenther W, Troester A, Schwilden H, gations concerning the additivity respectively The cross-sectional area Emergency medicine Schuettler J, Koppert W (2008) Supra-additive effects of tramadol and acetaminophen in a human pain model. non-additivity of these substances in combina- accounts, in addition to the lecture “clinical an- Pain, 136: 262-70 tion with other anaesthetics which in turn are aesthesiology”, for the main part of the teach- Jeleazcov C, Ihmsen H, Schmidt J, Ammon C, Schwilden H, of great importance with respect to the unitary ing curriculum in anaesthesiology. Professional Schuettler J, Fechner J (2008) Pharmacodynamic model- theory of narcosis. lecturers and instructors of the Department of ling of the bispectral index response to propofol-based anaesthesia during general surgery in children. Br J Anaesth, Anaesthesiology organize this cross-section- 100: 509-16 Intensive care and emergency medicine: al area and are firmly committed to applying Leffler A, Fischer MJ, Rehner D, KienelS , Kistner K, Sauer SK, systemic inflammation, acute lung and new concepts of teaching, such as the use of Gavva NR, Reeh PW, Nau C (2008) The vanilloid receptor cardiac failure, resuscitation teaching simulators installed in the simulation TRPV1 is activated and sensitized by local anesthetics in In this research focus, studies about pharma- and training centre of the Department of An- rodent sensory neurons. J Clin Invest, 118: 763-76 cological therapies in cardiopulmonary resus- aesthesiology. The cross-sectional area Q12 re- International Cooperation citation are performed as well as studies about habilitation has a focus in pain therapy at the Prof. K. T. Olkkola, Dept. of Anaesthesiology, Intensive immunomonitoring and options for immuno- Medical Faculty and is organized by the De- Care, Emergency Care and Pain Medicine, University modulation of patients suffering from a system- partment of Anaesthesiology. The classes are Turku, Finland ic inflammatory response syndrome or sepsis. designed as interdisciplinary and interactive Prof. G. Simonnet, Laboratoire Homeostasie-Allostasie- Here, immunological methods as well as ani- lectures. Additionally, the department offers 6 Pathologie, Université Bordeaux, France mal models and clinical studies are exhibited. elective classes and some non-curricular classes Prof. G. K. Wang, Dept. of Anaesthesiology, Perioperative, in the fields of Anaesthesiology, intensive care and Pain Medicine, Brigham and Women‘s Hospital and Research in teaching and learning medicine, emergency medicine, pain therapy, Harvard Medical School, Boston, USA The projects in this area serve both increase and palliative medicine as lectures, internships, Meetings and International Training in scientific knowledge and quality assurance seminars, and exercises. Courses and improvement. The Anaesthesiology De- The Department of Anaesthesiology hosts the 01.–02.06.2007: 1. Erlanger Schmerztage fuer Pflegekraefte partment is involved in the development of oral examination for the European Diploma 30.11.–01.12.2007: 12. Erlanger Notfallmedizinische Tage a national curriculum which is redesigned in in Anaesthesiology and Intensive Care (EDA). “Großschadensereignisse” view of new ways of examination (so-called 07.–08.12.2007: Winter School – Methods in Pain Research, OSCE exams = Objective Structured Clinical Erlangen Examination). 08.–09.02.2008: 8. Erlanger Schmerz- und Palliativtage Research in teaching focuses on learning in a – Schmerztherapie und Palliativmedizin – Forschung und virtual environment. In the field of Anaesthesia Klinik and Emergency Medicine, gain in knowledge 24.–25.10.2008: 38. Bayerische Anaesthesietage BAT, and learning are intertwined with a high de- Erlangen gree of “exposure”, which is perceived as stress- 28.–29.11.2008: 13. Erlanger Notfallmedizinische Tage – Polytrauma Management – Chirurgische Notfaelle

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 99 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Obstetrics and Gynaecology Chair of Obstetrics and Gynaecology University Hospital

Address The department is recognized by the European a member of the international Breast Cancer Universitaetsstrasse 21-23 Board and College of Obstetrics and Gynaeco- Association Consortium (BCAC), which holds 91054 Erlangen logy (EBCOG) as a training hospital for euro- data for more than 30,000 breast cancer pa- Phone: +49 9131 8533553 pean qualification as a physician specializing tients and matched controls. In large-scale ep- Fax: +49 9131 8533552 in obstetrics and gynaecology. idemiological studies, the BCAC is investigat- www.frauen.med.uni-erlangen.de ing genetic risk factors and prognostic factors. Head of Department Research work on ovarian carcinoma (PD Dr. Fasching, Dr. Thiel), in collaboration with the Prof. Dr. med. Matthias W. Beckmann Research international Ovarian Cancer Association Con- Contact Clinical Trial Centre (CTC) and Institute for sortium (OCAC), is also aimed at identifying Prof. Dr. med. Matthias W. Beckmann Women’s Health (IFG®) genetic mutations linked to cancer. In addi- Phone: +49 9131 8533551 More than 100 research projects have been tion, the functional role of five human endog- Fax: +49 9131 8533556 carried out at the IFG® since 2001. These in- enous retroviruses and their significance for in- [email protected] clude clinical phase I–IV studies, as well as invasiveness and for cell–cell fusion has been investigations on new surgical techniques. The vestigated at the molecular level. In close col- Research Focus clinical studies have concerned innovative ap- laboration with the Chair of Biochemistry and • Clinical Trial Centre (CTC) and Institute for proaches to the etiology, diagnosis, and treat- Molecular Medicine (Prof. Becker), it has been Women’s Health (IFG®) ment of breast, ovarian, endometrial, and cer- shown that a neuronal gene (neuron-restrictive • Laboratory for molecular medicine (LMM) vical carcinoma. In addition to modern genet- silencer factor, NRSF) is a susceptibility marker and gynaecological oncology ic studies and chemotherapy protocols, “target in patients with ovarian carcinoma. • Gynaecological endocrinology and therapies” that are of particular current interest In the investigation of endometriotic tissue reproductive medicine are being investigated. samples (Dr. Renner, Dr. Strissel) for DNA from • Specialized obstetrics and perinatal Of particular note currently in connection with herpes simplex virus (HSV) and human papil- medicine genital carcinomas is the AGO Cervix 1 study. lomavirus (HPV), as well as Chlamydia, 13.2% In this randomized phase III study, the chemo- of the samples were found to be HPV-positive. therapy regimens of paclitaxel plus topotecan Further studies are now in progress to examine Structure of the Institution and topotecan plus cisplatin are being com- whether HPV may be linked with endometrio- pared in patients with recurrent or persistent sis-associated malignant diseases. During the reporting period, the Department cervical carcinoma. For women with breast car- In the normal endometrium of patients with of Gynaecology has successfully continued the cinoma, the years 2008 and 2009 are marked breast carcinoma who are treated with or with- structural transformation that was initiated at by the “Evaluate” study program. This is in- out tamoxifen, the LMM researchers found sig- the start of the decade, with the setting up of vestigating therapy management, prospective nificant overexpression of various genes (IGF1 nationally and internationally certified inter- pharmacoeconomics, and the basis for phar- and its receptor, estrogen-receptor alpha and disciplinary centres. The three traditional pil- macogenetic treatment in aromatase inhibi- beta, syncytin-1, PAX2). In addition, it has been lars of the specialty (gynaecology and gyn- tor therapy with letrozole in postmenopaus- shown that tamoxifen enhances the phosphor- aecological oncology, obstetrics and perina- al patients with hormone-sensitive breast car- ylation of proteins such as AKT and mTOR in the tal medicine, along with endocrinology and cinoma. The IFG® coordinates both studies in endometrium, leading to overstimulation of reproductive medicine) are now represented Germany. the estrogen receptor (Dr. Strick, Dr. Strissel). clinically and scientifically by the following or- ganizational units: Laboratory for molecular medicine (LMM) Gynaecological endocrinology and repro- • University Breast Centre for Franconia (UBF) and gynaecological oncology ductive medicine • University Gynaecological Cancer Centre for The basis for research in the LMM (Dr. Strick) is In the field of gynaecological endocrinology, Franconia (GKF) provided by a DNA and tissue bank, which at research has continued successfully on meth- • University Perinatal Centre for Franconia (UPF) the end of 2008 already held more than 11,000 ods of preserving fertility in young women with • University Centre for Reproductive Medicine DNA samples from patients’ blood, as well cancer who need to undergo treatments that for Franconia (UFF) and more than 6000 tissue samples from benign are toxic to the ovaries. At the end of 2008, the • University Endometriosis Centre for Franco- and malignant tumors, in collaboration with department’s tissue bank, where ovarian tis- nia (UEF) the Institute of Pathology at the University of sue that has been removed before treatment Interfaces for scientific work in the department Erlangen (Director: Prof. Hartmann). and cryoconserved for later sterility therapy if are provided by the Laboratory for Molecular Breast cancer research at the LMM (PD Dr. Fas- desired, held samples from over 150 patients. Medicine (LMM) and the associated Clinical ching) is mainly focused on the search for ge- In 2007, the research group achieved the first Trial Centre (CTC, Institute for Women’s Health, netic mutations and their possible correlation successful retransplantation of this type of con- IFG®). In all, some 40 physicians are involved in with the risk of the disease and its prognosis. served ovarian tissue in Germany. The patient, clinical and scientific work in the department. This also includes the effect of mutations on a 28-year-old woman, had undergone com- They are supported by three researchers and enzymes such as CYP2D6 which influences the bined chemoradiotherapy. Five months after four study nurses. metabolic degradation of drugs. The LMM is orthotopic retransplantation of the cryocon-

100 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) served ovarian tissue, there was an increase in Selected Publications estradiol from less than 20 pg/mL to a value of Strick R, Ackermann S, Langbein M, Swiatek J, Schubert 436 pg/mL, and the patient reported her first SW, Hashemolhosseini S, Koscheck T, Fasching PA, Schild spontaneous hormone withdrawal bleeding RL, Beckmann MW, Strissel PL (2007) Proliferation and cell-cell fusion of endometrial carcinoma are induced by the after the cancer treatment (Prof. Dittrich, PD human endogenous retroviral Syncytin-1 and regulated by Dr. Mueller, Prof. Beckmann). Sculpture in front of the perinatology building TGF-beta. J Mol Med, 85: 23-38 of the artist Prof. Stephan Balkenhol Additional studies have focused on metabolic Struwe E, Berzl GM, Schild RL, Beckmann MW, Doerr HG, Source: University Hospital Erlangen risks (hyperinsulinemia and insulin resistance) Rascher W, Doetsch J (2007) Simultaneously reduced gene in women who meet the criteria for polycystic expression of cortisol-activating and cortisol-inactivating enzymes in placentas of small-for-gestational-age neonates. ovary syndrome (PCOS) or who have hyper- Am J Obstet Gynecol, 197: 43.e1-6 androgenemia. It was found that these risks Dittrich R, Mueller A, Hoffmann I, Oppelt PG, Beckmann are most strongly associated with body weight MW (2008) The transplantation of cryo-preserved ovarial (BMI) and with ovarian function. By contrast, tissue as option of the fertility preservation in cancer disease: androgen levels and the extent of clinical an- the birth experience, and the partnership (Dr. Experience from the transplantation of human ovarial tissues on the immune deficient mouse and a 30-year old patient. drogenization phenomena (e.g., hirsutism and Goecke, Dr. Reulbach). Geburtsh Frauenheilk, 68: 538-539 the ultrasound appearance of the polycystic Fasching PA, Loehberg CR, Strissel PL, Lux MP, Bani MR, ovaries) did not have any predictive signifi- Schrauder M, Geiler S, Ringleff K, Oeser S, Weihbrecht S, cance (PD Dr. Mueller, PD Dr. Cupisti, Prof. Teaching Schulz-Wendtland R, Hartmann A, Beckmann MW, Strick R Dittrich). (2008) Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast During the reporting period, teaching work cancer patients. Breast Cancer Res Treat, 112: 89-98 Specialized obstetrics and perinatal was improved and strengthened by the imple- Mueller A, Gooren LJ, Naton-Schoetz S, Cupisti S, Beck- medicine mentation of a special area of responsibility (Dr. mann MW, Dittrich R (2008) Prevalence of polycystic ovary Through collaboration between the LMM and Frobenius, PD Dr. Cupisti). The integration of syndrome and hyperandrogenemia in female-to-male trans- obstetricians (Prof. Schild, Dr. Goecke), it was all teaching duties into the department’s duty sexuals. J Clin Endocrinol Metab, 93: 1408-11 demonstrated in connection with the patho- roster and responsibility rosters made it possi- Strissel PL, Ellmann S, Loprich E, Thiel F, Fasching PA, Stiegler physiology of preeclampsia and the HELLP syn- ble to ensure that there is now adequate staff- E, Hartmann A, Beckmann MW, Strick R (2008) Early aberrant insulin-like growth factor signaling in the progression drome that syncytin-1, which is essential for ing available for all curricular teaching courses to endometrial carcinoma is augmented by tamoxifen. Int human placental development, is a target for and that these are now running to plan. In ad- J Cancer, 123: 2871-9 the transcription factors PPARγ/RXRα. In the dition, a skills laboratory has been established placenta of patients with these diseases, the ex- for students in the department. International Cooperation pression of syncytin-1 was reduced as a result These new structures have also made it possible Prof. Bruce Ponder, Prof. Doug Easton, Breast Cancer Con- sortium, Cambridge, UK of DNA methylation. In addition, it was shown to substantially improve the practical course in an investigation of the placenta in patients and expand the teaching program overall. Re- Prof. D. Slamon, MD, PhD, David Geffen School of Medi- cine, UCLA, Los Angeles, Ca., USA with intrauterine growth retardation (IUGR) lated to this, the introduction of a six-hour peer that the expression of the envelope genes syn- teaching program for participants in the practi- R. Weinshilboum, MD; L. Wang, MD; J. Ingle, MD, Mayo Clinic, Rochester, Minnesota, USA cytin-1, -2, and -3 was significantly reduced. cal course and the modification of the marked The Perinatal Centre is working in close coop- final examination into a small, objective, struc- Meetings and International Training eration with the Department of Pediatrics (Di- tured clinical examination (mini-OSKE) were Courses rector Prof. Rascher) on studies concerning the monitored using a prospective randomized 12.–13.05.2007: 8. Erlanger Kolposkopie Workshop, role of the placenta in fetal programming. It study. In addition, the department has been Erlangen, Arbeitsgemeinschaft Zervixpathologie und Kol- poskopie der Deutschen Gesellschaft fuer Gynaekologie was shown that simultaneously reduced gene running since 2007 a two-day intensive course und Geburtshilfe expression of cortisol-activating and -inacti- twice a year to provide preparation for the sec- 19.–20.10.2007: Intensiv-Fortbildungskurs “Geburtsmed- vating enzymes can be found in the placenta ond state examination. izin”, Erlangen, Deutsche Gesellschaft fuer Praenatal- und of small-for-gestational age (SGA) neonates. In Geburtsmedizin children with IUGR, there was an inverse cor- 18.–19.01.2008: FertiPROTEKT – Deutsches Netzwerk relation between placental gene expression of fuer fertilititaetsprotektive Maßnahmen bei Chemo- und Strahlentherapie, Erlangen 11β-HSD2 and the speed of growth during the first year of life. 07.–08.06.2008: 9. Erlanger Kolposkopie Workshop, In a large-scale collaborative project with the Erlangen, Arbeitsgemeinschaft Zervixpathologie und Kol- poskopie der Deutschen Gesellschaft fuer Gynaekologie Department of Psychiatry and Psychothera- und Geburtshilfe py (Director: Prof. Kornhuber) on pre-, peri-, and postpartal depression, it was shown that the development of postpartal depression, with all of its negative effects on the neonate’s later cognitive and intellectual performance, is significantly dependent on prepartal factors,

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 101 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Radiation Chair of Radiation Therapy University Hospital

Address pel), respectively. The research group “Medical Biological aspects of radiooncology Universitaetsstrasse 27 radiation physics” consists of five research as- 1. Individual sensitivity to radiation 91054 Erlangen sociates, one of whom is habilitated and four of (Dr. Distel) Phone: +49 9131 8533405 whom are PhD graduates, as well as four PhD Individual differences in the sensitivity of nor- Fax: +49 9131 8539335 students and two to three additional staff. Re- mal tissues to radiation are the most important www.strahlenklinik.uk-erlangen.de search work is carried out mainly by PhD stu- determinant for the occurrence of dose-limit- Head of Department dents under the individual supervision of re- ing side effects of radiotherapy. In a project run search associates. jointly with the University of Würzburg (Dr. T. Prof. Dr. med. Rainer Fietkau Djuzenova) the usefulness of of a bed-side test Contact in determining the β H2AX phosphorylation Prof. Dr. med. Rainer Fietkau Research status is compared to the established assay Phone: +49 9131 8533405 based on the analysis of chromosomal aberra- Fax: +49 9131 8539335 Clinical trials tions in peripheral blood lymphocytes. Patients [email protected] 1. Phase-III-multicentre trial: preoperative ra- with both rectal and breast tumours serve as diochemotherapy and adjuvant chemotherapy study population. Research Focus with 5-fluorouracil vs preoperative radioche- 2. Tumour infiltrating lymphocytes • Clinical trials motherapy and adjuvant chemotherapy with (Dr. Distel) • Biological aspects of radiooncology 5- fluorouracil combined with oxaliplatinum Sponsoring: IZKF • Physical aspects of radiooncology in patients with locally advanced UICC stage II The role played by tumour infiltrating lympho- and III rectal cancer. (Prof. Sauer) cytes in determining the efficacy of a course of 2. Phase-III-multicentre trial: comparison of radiotherapy is still largely unknown. In a proj- Structure of the Institution partial breast interstitial brachytherapy with ect run jointly with the Department of Pathol- whole breast external beam radiotherapy in pa- ogy at the University of Essen (Dr. Buettner) the Research in the department focuses on clinical, tients with low risk invasive and in-situ breast role of CD4, CD8, B-cells, macrophages and biological and physical aspects of radiooncol- carcinomas. (Prof. Strnad C. Polgar, Budapest) the influence of regulatory T-cells was studied ogy. Research on clinical aspects takes place Sponsoring Deutsche Krebshilfe in patients with head and neck tumours, gastric mainly within the framework of phase I, II and 3. Phase-III-multicentre trial: reducing total ra- cancer and carcinoma of the rectum. III trials and is carried out on the ward, in the diation dose in the context of a simultaneous 3. Non targeted effects of ionizing radiation outpatient department, the treatment plan- radiochemotherapy of head and neck tumours (PD Dr. Gaipl) ning department as well as the therapeutics (PacCis trial) (Prof. Fietkau and Prof. Iro) Sponsoring: Euopean Union department harbouring the linear accelerators Sponsoring Deutsche Krebshilfe The non targeted effects of low dose irradia- and the hyperthermia unit. A total of 5 regis- 4. Phase-III-multicentre trial: Nutritional ther- tion have an influence on a number of differ- trars and 12 residents are involved in running apy of patients with head and neck tumours ent immune cell types. The mechanisms under- the various trials and clinical studies. Coordina- (Supportan trial) (Prof. Fietkau) lying the anti-inflammatory immune response tion of the clinical trials is through the clinical Sponsoring company: Fresenius have not yet been sufficiently elucidated. The trials office which is staffed by a chief secretary, 5. Phase-III-trial: Assessing the influence of an project addresses the question of whether cells two assistant secretaries as well as a secretary adjuvant chemotherapy following a simultane- that have been exposed to low doses of radia- involved in documentation. For hyperthermia ous radiochemotherapy in patients with inop- tion have the ability to induce an immunosup- treatments the department has two machines erable lung tumours (GILT-CRT-1) (R. Huber, M. pressive state or to modulate inflammatory cells to administer deep tissue hyperthermia one of Flentje and R. Fietkau) 4. Cell death and immunogenicity of cells from which is equipped with an integrated MRI scan- Sponsoring company: Pierre Fabre colorectal tumours after combined treatment ner for non- invasive temperature monitoring. The department participates in the following with irradiation (X-rays) and hyperthermia (HT) In addition there is one appliance for intersti- externally- led phase-III-trials: (PD Dr. Gaipl) tial hyperthermia and one appliance for super- - Phase-III-trial: radiation dose intensity study Sponsoring: ELAN fonds of the university hos- ficial hyperthermia. Radiotherapy treatments in breast cancer young women pital. are carried out at one of four linear accelerators Randomized trial of additional dose to the tu- A combined anti-tumour therapy should lead and four brachytherapy afterloading machines. mour bed (Barteling) to the cessation of cell proliferation and cell Radiobiological research is done by two group - Phase-III-trial: hyperfractionated accelerat- death on the one hand and should stimulate leaders, one scientist, two post docs, 4 labo- ed radiotherapy (HART) with mitomycin C/5- an immune response to the surviving tumour ratory assistants, two PhD students as well as fluorouracil vs cisplatinum/ 5- fluorouracil in (stem) cells on the other. In this project the several medical students as part of their doc- locally advanced head and neck tumours (V. mode of cell death following individual (X- ray toral thesis work. The department of radiobi- Budach, J. A. Werner) or HT) or combined modality treatment (X- ray ology consists of two research groups who are - German Hodgkin trials, coordinated by Co- and HT) is thoroughly characterized in colorec- interested in classical aspects of radiobiology logne tal tumour cell lines and the immunogenicity (Project manager Dr. Distel) and in the field of In addition the department runs a number of of dying tumour cells is tested in a xenogenic radioimmunobiology (Project manager Dr Gai- phase I and II trials. mouse model.

102 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 5. Characterisation of stress signals induced by Physical aspects of radiooncology Selected Publications application of high pressure (HHD) and their in- Developing and setting up a tomotherapy Fietkau R, Roedel C, Hohenberger W, Raab R, Hess C, Liersch fluence on the immunogenicty of tumour cells treatment system T, Becker H, Wittekind C, Hutter M, Hager E, Karstens J, (Dr. Frey and Dr. Meister) Patents: D, EU, US Ewald H, Christen N, Jagoditsch M, Martus P, Sauer R, German Rectal Cancer Study Group (2007) Rectal cancer Sponsoring: ELAN fonds of the university hos- Businessplan Competition 2008-2009 delivery of radiotherapy in adequate time and with adequate pital BPWN, MBPW, Science4Life dose is influenced by treatment center, treatment schedule, In the treatment of tumour patients with Monte Carlo algorithm to plan treatments with and gender and is prognostic parameter for local control: results of study CAO/ARO/AIO-94. Int J Radiat Oncol Biol whole-cell tumour vaccines the application of carbon ions. Development of an “optimiser” Phys, 67: 1008-19 high pressure technology is thought capable for the calculation of treatment parameters in Wittlinger M, Grabenbauer GG, Sprung CN, Sauer R, Distel of making an important contribution by act- the planning of treatments with e.g. protons LV (2007) Time and dose-dependent activation of p53 serine ing as a tool to inactivate tumour cells while at and carbon ions. 15 phosphorylation among cell lines with different radiation the same time preserving or ideally even en- Measuring absolute temperature in hyperther- sensitivity. Int J Radiat Biol, 83: 245-57 hancing immunogenicity. The project looks at mia using MR- spectroscopy Ott OJ, Hildebrandt G, Poetter R, Hammer J, Lotter M, whether unfolded proteins accumulate in the Computer modelling in the development and Resch A, Sauer R, Strnad V (2007) Accelerated partial breast irradiation with multi-catheter brachytherapy: Local endoplasmic reticulum (ER) following HHD construction of a ring-shaped electron beam control, side effects and cosmetic outcome for 274 patients. treatment thus inducing an ER stress response CT (TOM’AGE) Results of the German-Austrian multi-centre trial. Radiother called the “unfolded protein stress response” Patents: D, EU, US Oncol, 82: 281-6 that causes cell death. The immunogenicity of Monte Carlo Algorithm addressing geometri- Achterberg N, Mueller RG (2007) Multibeam tomotherapy: tumour cells is analysed in the mouse model cal problems concerning structural radiation a new treatment unit devised for multileaf collimation, intensity-modulated radiation therapy. Med Phys, 34: and is correlated with the UPR. protection 3926-42 6. Influencing inflammatory states through low Cooperation partners: GSI, Darmstadt, GANIL, Frey B, Munoz LE, Pausch F, Sieber R, Franz S, Brachvogel dose radiotherapy Caen, France B, Poschl E, Schneider H, Rödel F, Sauer R, Fietkau R, Her- (PD Dr. Gaipl and PD Dr. Keilholz) Sponsoring: Spiral2 FP7 rmann M, Gaipl US (2009) The immune reaction against Sponsoring: Thomas-Wildey Institute e.V. allogeneic necrotic cells is reduced in AnnexinA5 knock out mice whose macrophages display an anti-inflammatory The project focuses on the study of the sys- phenotype. J Cell Mol Med 13:1391-9 temic effects of low dose radiotherapy. To this Teaching end we use in vitro cell culture models as well International Cooperation as in vivo mouse models such as the one trans- Apart from the traditional radiotherapy teach- Prof. Dr. P. Rovere-Querini, Prof. Dr. A. Manfredi, H.S. Raf- faele, Mailand, Italy genic for the pro-inflammatory cytokineT NF-α ing sessions embedded in the course covering where mice go on to develop a polyarthritis the related fields of medical imaging, radio- Dr. C. N. Sprung, Monash University, Clayton, Australia 7. Modulation of the NALP3 infammasome therapy treatment and radiation protection the Dr. Michael Lacniel, GANIL, Caen, France through low dose irradiation department organizes an interdisciplinary lec- (PD Dr. Gaipl) ture series in collaboration with the University Meetings and International Training Courses Sponsoring: DFG, GRK of the Collaborative Re- Cancer Centre (UCC). In these lectures tumours search Centre (SFB) 643 from different organs are considered from dif- 30.–31.03.2007: 33. Erlanger Weiterbildungsveranstaltung, Erlangen, DEGRO The immunasome is a multi-protein complex ferent perspectives (surgery, chemotherapy, that participates in the inflammatory response. pathology, epidemiology, medical imaging, 20.–22.09.2007: Interdisziplinaere Onkologie Rothenburg 2007, Rothenburg o.d.T., Verein zur Foerderung der Ra- The projects looks at whether and how low radiooncology) or an interdisciplinary discus- dioonkologie im Universitaetsklinikum Erlangen e.V dose irradiation modulates the immunasome sion revolving around defined tumor settings 10.–11.10.2008: 34. Erlanger Weiterbildungsveranstaltung, thereby exerting its anti-inflammatory effect. is held. In the context of this course a database Erlangen, Deutschland, DEGRO Stimulated macrophages are used as model is being generated that will allow student to system. familiarize themselves with the interdisciplin- Research Equipment ary approach by doing clinical case studies. A BSD Medical Corporation, Salt-Lake-City, Utah, USA course in radiation protection including prac- BSD2000/3D-MRI tical teaching sessions for students that is rec- Siemens, Deutschland Siemens Symphony MRT 1,5 Tesla ognized by the Medical council of Bavaria has BSD Medical Corporation, Salt-Lake-City, Utah, USA Sigma been set up. For students doing practical clini- 30 MRI cal work in their pre-registration year a comple- BSD Medical Corporation, Salt-Lake-City, Utah, USA Sigma mentary teaching programme is offered. 40 MRI

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 103 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Pediatrics Chair of Pediatrics

Address the bedsite. Patient care is based on close col- Genetic diseases of the neonate Loschgestrasse 15 laboration with the Division of Pediatric Cardi- Project manager: H. Schneider, H. G. Dörr, H. 91054 Erlangen ology as well as with various, mostly surgical Köhler Phone: +49 9131 8533118 subspecialties, often planned and carried out Our primary research goal is to identify patho- Fax: +49 9131 8533113 by interdisciplinary teams (Centre for Perina- genetic mechanisms underlying genoderma- www.kinderklinik.uk-erlangen.de tal Medicine, Centre for Epilepsy, Heart Cen- toses (hereditary disorders of the skin and its Head of Department tre, Cleft Lip and Palate Centre, Transplanta- appendages) at a molecular level and to devel- tion Centre). op appropriate therapeutic approaches. These Prof. Dr. med. Dr. h.c. Wolfgang Rascher diseases are rare, but may be associated with Contact life-threatening complications already in the Prof. Dr. med. Holm Schneider Research first weeks after birth. In addition to the skin, Phone: +49 9131 8533775 other organs such as eye, ear and lung are fre- Fax: +49 9131 8533013 Perinatal programming quently affected by the pathogenic processes. [email protected] Project manager: J. Dötsch, I. Knerr In a mouse model of Herlitz disease, present- The term “perinatal programming” refers to ing from birth with widespread blistering and Research Focus permanent modifications of physiological pro- erosions of skin and mucosae, we investigated • Perinatal programming cesses by the intrauterine or early postnatal for the first time the feasibility of gene thera- • Perinatal hypoxic-ischemic brain injury environment. Although the phenomenon has py in utero. The most important advantage of • Genetic diseases of the neonate been well described also in humans, its mech- this strategy proved to be the possibility to in- • Genomic aberrations in childhood malig- anisms have remained unclear. Using different duce long-lasting immune tolerance of thera- nancies animal models as well as data from a prospec- peutic proteins. • Pediatric cell therapy tive, multi-center clinical study (FIPS study) Long-term studies also include the documenta- • Involvement in the Collaborative Research we have been exploring possible pathoge- tion and retrospective analysis of prenatal treat- Centre 423 “Kidney injury: pathogenesis netic mechanisms of perinatal programming, ment of adrenogenital syndrome in Germany. and regenerative mechanisms” which may allow preventive strategies to be Another area of interest is in gastrointestinal established. diseases based on genetic defects predisposing Further research is aimed at understanding de- to diarrhea. Current investigations focus on he- Structure of the Institution velopmental abnormalities of the human pla- reditary factors contributing to necrotizing en- centa and the role of the fusion protein syncy- terocolitis (NEC) of preterm neonates. The Department of Pediatrics comprises five tin-1. Our studies have provided initial evidence specialized divisions (neonatology, neurope- that this protein may exert anti-apoptotic func- Genomic aberrations in childhood diatrics, paedeatric oncology/cell therapy, ne- tions at the mitochondrial level. malignancies phrology, and molecular paedeatrics), an en- Project manager: M. Metzler, T. Langer dowed professorship for paedeatric endocri- Perinatal hypoxic-ischemic brain injury Analysis of patient-specific genomic aberra- nology and diabetology, a social paedeatrics Project manager: R. Trollmann, M. Schroth tions in paedeatric tumors, particularly in child- unit, and a number of specialized outpatient Aiming at an early detection and prevention of hood leukemia, allows insight into tumor initi- clinics. Academic staff of the department in- perinatal brain injury caused by acute or chron- ation and clonal evolution. For clinical use, we cludes 91 physicians and scientists. Of these, ic hypoxia, we investigate the role of hypoxia- try to employ such individual genetic tumor 12 positions are financed by external funds. inducible transcription factors (HIF). Such fac- markers for quantifying the minimal residual Research continues to be focussed on the tors with strong impact on the adaptation to disease, a significant prognostic factor indicat- field of perinatal medicine, which has been hypoxic conditions have been characterized ing the response to therapy. strengthened by the recent establishment of a as placental indicators of severe hypoxic-isch- In addition to acquired mutations in the tumor professorship for experimental perinatal medi- emic CNS injury in term neonates. In a mouse genome, the impact of hereditary single nu- cine. Other main research activities are related model of perinatal brain hypoxia, gestational cleotide polymorphisms on the development to paedeatric oncology and nephrology. In ad- age-dependent and cell-specific molecular ef- of late adverse effects of current cancer ther- dition, clinical trials are conducted by all 5 di- fects of hypoxia on endogenous neuroprotec- apy such as hearing loss or cardiomyopathy is visions of the department and by the section tive mechanisms have been demonstrated. Fur- being investigated. of endocrinology/diabetology (e.g. studies on thermore, the impact of perinatal hypoxia on prenatal programming or infection epidemiol- early neuronal migration, astrocytic and blood- Pediatric cell therapy ogy, RECALTOX trial in children who received brain barrier function has been analyzed. Ex- Project manager: W. Holter, H. Schneider a kidney transplant, LESS study investigating perimental approaches to stabilizing HIF phar- Our main goal is to develop immunotherapies long-term effects of anti-cancer therapy, clini- macologically appear as a promising neuropro- directed towards viral infections and malignant cal trials testing growth hormone as a treat- tective strategy. disease. Experimental approaches are based on ment of short stature in children). The clini- In clinical studies, the potential of hypertonic- antigen presentation by TLR-matured dendritic cal studies are supported by the hospital’s site hyperoncotic saline solutions for minimizing cells, the expansion of peptide-specific T cells, management organization. Many medical ex- cerebral edema in paedeatric intensive care pa- and the transfer of chimeric receptors (derived perts work together to bring novel research to tients is being evaluated. from monoclonal antibodies and NKG2D) into

104 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) type 1 diabetes: a multicenter longitudinal survey in Ger- many and Austria. Diabetes Care, 31: 726-7 Müller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, Ponstingl H, Partsch J, Röllinghoff B, Köhler H, Berger T, Lenhartz H, Schlenck B, Houwen RJ, Taylor CJ, Zoller H, Lechner S, Goulet O, Utermann G, Ruemmele FM, Huber LA, Janecke AR (2008) MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polar- ity. Nat Genet, 40: 1163-5 Metzler M, Staege MS, Harder L, Mendelova D, Zuna J, Fronkova E, Meyer C, Flohr T, Bednarova D, Harbott J, Langer T, Gesk S, Trka J, Siebert R, Dingermann T, Marschalek R, Niemeyer C, Rascher W (2008) Inv(11) (q21q23) fuses MLL to the Notch co-activator mastermind- Immunofluorescence study of individual keratinocytes from a neonate: Healthy ke- like 2 in secondary T-cell acute lymphoblastic leukemia. ratinocytes (a) secrete laminin-5 leaving a distinct migration track behind (red). Leukemia, 22: 1807-11 This anchoring protein is absent in keratinocytes from a patient with Herlitz di Nüsken KD, Dötsch J, Rauh M, Rascher W, Schneider H sease (b), resulting in blistering and erosions of the skin subsequent to minor me- (2008) Uteroplacental insufficiency after bilateral uterine ar- chanical stress. Prof. Schneider 2007. tery ligation in the rat: impact on postnatal glucose and lipid metabolism and evidence for metabolic programming of the offspring by sham operation. Endocrinology, 149: 1056-63

International Cooperation effector cells by RNA-based and lentiviral gene impact of prenatal conditions on kidney func- Prof. Dr. Mats Ohlin, Department of Immunotechnology, transfer. Furthermore, we study the regulation tion and disease progression. Lund University, Sweden of apoptosis in dendritic cells and differentiated Prof. Dr. Mike Gibson, Biochemical Genetics Laboratory, T cells under the influence of cytokines. University of Pittsburgh, USA In another research project we demonstrat- Teaching Dr. Simon Waddington, Department of Haematology, University College London, U.K. ed that mesenchymal progenitor cells can be isolated from umbilical cord blood and – sub- Besides traditional forms of teaching (com- Prof. Dr. Max Gassmann, Centre for Integrative Human Physiology, University of Zurich, Switzerland sequent to expansion in vitro – are capable pulsory lecture series with case presentations of differentiating into osteoblasts, chondro- and hands-on training in paedeatrics), special Dr. Ornella Parolini, Fondazione Poliambulanza, Brescia, Italy cytes, skeletal myoblasts and cardiomyocytes. lectures, research seminars and interdisciplin- Prof. Dr. Terence H. Rabbitts, Institute of Molecular Medi- Such cells could be used for autografts e.g. in ary courses are offered to medical students. cine, University of Leeds, U.K. the treatment of cleft lip and palate, the most Individual members of the research staff par- Prof. Dr. Georg Simbruner, Department of Pediatrics, Inns- common congenital malformation, to reduce ticipate in lectures and practical courses for bruck Medical University, Austria the number of surgical interventions required. students enrolled in the graduate program in molecular medicine. An “emergency care Meetings and International Training Involvement in the Collaborative Research simulator” adapted to the needs of neonatol- Courses Centre 423 “Kidney injury: pathogenesis ogy and paedeatric intensive care enables the 13.–16.09.2007: 103. Jahrestagung der Deutschen Gesell- and regenerative mechanisms” training of emergency medical procedures and schaft fuer Kinder- und Jugendmedizin, Nürnberg Project manager: A. Hartner, C. Plank, J. Dötsch team-work analysis of the management strat- 05.–07.06.2008: 16. Jahrestagung der Deutschen Gesell- schaft fuer Paediatrische Infektiologie, Erlangen Typical features of progressive kidney diseases egies applied. This includes regular reviews of are fibrotic changes due to extracellular matrix real emergency situations experienced in our Research Equipment accumulation and hyperplasia. In this connec- hospital. Beckman Coulter DNA-Sequenzierautomat tion, integrins as matrix receptors are known to Becton Dickinson FACS Calibur play a pivotal pathogenetic role. Therefore we investigate the function of integrins and their Selected Publications Applied Biosystems 2 Tandem-Massenspektrometer Tecan Analyseplattform EVO 150 ligands which are relevant to the kidney. We Wixler V, Hirner S, Müller JM, Gullotti L, Will C, Kirfel J, Gün- ther T, Schneider H, Bosserhoff A, Schorle H, Park J, Schüle Carl Zeiss “Life cell imaging”-System were able to show that α8-integrin can regulate cell adhesion, migration, differentiation R, Buettner R (2007) Deficiency in the LIM-only protein Fhl2 impairs skin wound healing. J Cell Biol, 177: 163-72 and proliferation, thereby contributing significantly to the maintenance of renal tissue ho- Cisse B, Caton ML, Lehner M, Maeda T, Scheu S, Locksley R, Holmberg D, Zweier C, den Hollander NS, Kant SG, Holter meostasis. Further studies aim to clarify wheth- W, Rauch A, Zhuang Y, Reizis B (2008) Transcription factor er these results may provide a basis for the de- E2-2 is an essential and specific regulator of plasmacytoid velopment of new strategies for diagnosis and dendritic cell development. Cell, 135: 37-48 therapy of kidney diseases. Knerr I, Dost A, Lepler R, Raile K, Schober E, Rascher W, Because progression of renal disorders also Holl RW, Diabetes Data Acquisition System for Prospective Surveillance (DPV) Scientific Initiative Germany and Austria depends on the congenital endowment with (2008) Tracking and prediction of arterial blood pressure functional renal tissue that is capable of self- from childhood to young adulthood in 868 patients with regeneration, we attempt to characterize the

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 105 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Pediatrics Division of Pediatric Cardiology

Address Research Candidate gene approach for coarctation Loschgestrasse 15 of aorta 91054 Erlangen B-type natriuretic peptide as a diagnostic The coarctation of the aorta accounts for a Phone: +49 9131 8533750 and prognostic tool for patients with con- common type of heart defects with an inci- Fax: +49 9131 8535987 genital heart defects dence of about 7 % of all congenital heart www.kinderkardiologie.uk-erlangen.de B-type natriuretic peptide (BNP) and the N-ter- malformations. We are conducting a position- Head of Division minal fragment of its prohormone (NT-proB- al candidate gene approach on a gonosom- NP) are established sensitive markers for the al locus to get more insights into the genet- Prof. Dr. med. Sven Dittrich diagnosis and prognosis of heart failure. We ic mechanism of aotic isthmus stenosis. The Contact have assessed normal values of both BNP and genes we are interested in are so called homo- Prof. Dr. med. Sven Dittrich NT-proBNP from infancy to adolescence and logue genes. These genes encoded and ex- Phone: +49 9131 8533750 examined the distribution of both peptides ac- pressed on both gonosomal chromosomes and Fax: +49 9131 8535987 cording to age. Based on these data we inves- escape x-chromosomal inactivation in female. [email protected] tigate prospectively the diagnostic validity of Thus, everyone has two functional copies of plasma BNP on pediatric patients with acquired these genes, independent from once gender. Research Focus and congenital heart disease. There are sever- Homologues genes have no sex-specific func- • B-type natriuretic peptide as a diagnostic al prospective studies on BNP in patients with tion. Their role in organogenesis and congeni- and prognostic tool for patients with con- myocarditis, cardiomyopathy, and arrythmias tal malformations is mostly unknown. We are genital heart defects and, additionally, in patients with congenital currently screening a cohort of 86 patients with • A biomaterial bank for patients with con- heart defects before and after corrective sur- sporadic coarctation of the aorta and identified genital heart defects gery. Moreover, studies were assessed to elu- two different mutations in one of this homo- • Candidate gene approach for coarctation cidate the diagnostic role of BNP in the long- logue genes so far. The biological relevance of of aorta term follow-up of patients with systemic right the mutation is currently subject to our ongo- • Gene hunting in a monogenic form of ventricle, with functional univentricular heart ing investigations. arterial hypertension after total cavopulmonary connection, or after surgical repair of tetralogy of Fallot. Gene hunting in a monogenic form of arterial hypertension Structure of the Institution A biomaterial bank for patients with con- Genetic research in the field of arterial hyper- genital heart defects tension with mendelian inheritance is an es- The independent Division of Paedeatric Car- The evaluation of genetic factors and cellular tablished approach to investigate the genet- diology was newly established at the July 1st mechanisms responsible for congenital heart ic contributors of essential hypertension. We 2007. Clinical work and research activities are malformation are in the focus of Dr. Toka’s in- are investigating a large Turkish kindred with performed in close cooperation with the Di- vestigations. For this purpose, our department a monogenetic form of arterial hypertension vision of Pediatric Cardiac Surgery founded of paedeatric cardiology has established a bio- which co-segregates 100% with a complex at the 1st of September 2008, and the De- material bank consisting of DNA and cardiac type of brachydactyly (HBS) within a long- partment of Paedeatrics. A total of 9 medical tissue samples recruited during routine cardi- standing cooperation with Prof. Luft, Max-Del- doctors are employed splitting clinical work, ac surgery in children with congenital heart de- brueck-Centre for Molecular Medicine, Berlin. teaching, and research. At the moment, there fects. This has been enabled by collaboration Since 1994 numerous manuscripts have been are 3 graduate students studying for a doctor- with the department of paedeatric cardiac sur- published to describe this complex syndrome ate. There are several projects established to gery. Hereby we could recruit about 500 DNA (Omin 112410). HBS patients resemble essen- study the genetic mechanisms responsible for samples and about 250 cardiac tissue sample tial hypertension with normal water and sold congenital heart malformation. There is a col- of all four chambers of the heart and the great homeostasis with no evidence of reno-tubulare laboration with the Competence Network for vessels since September 2008. The recruitment defects. Investigating to evaluate the pathoge- Congenital Heart Defects in multicenter clini- of sample is still ongoing. Due to the high genetic pathways responsible for this phenotype cal trials, additionally we prepare an own mul- netic variability of cardiac malformations the are still ongoing. ticenter study to evaluate the efficiancy of drug establishment of a biomaterial bank will be a treatment for cardiac failure in patients with crucial element for our future investigations. Duchenne muscular dystrophy. It will be the fundament for a systematic ap- The clinical focus is on interventional therapy proach to identify genetic key players in cardio of congenital heart defects in the catheter lab- genesis and congenital malformation. oratory, on and surgical therapy of congenital heart defects in close cooperation with the Di- vision of Pediatric Cardiac Surgery, and on intensive care after cardiac surgery.

106 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) View of the Department of Pediatrics Source: University Hospital Erlangen

Teaching Selected Publications Koch A, Zink S, Singer H (2006) B-type natriuretic peptide The department takes part in the general in paediatric patients with congenital heart disease. Eur teaching program of the Division of Pediat- Heart J, 27: 861-6 rics (traditional main lecture, compulsory lec- Koch A, Kitzsteiner T, Zink S, Cesnjevar R, Singer H (2007) ture series with case presentations, seminars, Impact of cardiac surgery on plasma levels of B-type natriuretic peptide in children with congenital heart disease. Int hands-on training in pediatrics, practical train- J Cardiol, 114: 339-44 ing courses). Additionally, medical students are Baehring S, Kann M, Neuenfeld Y, Gong M, Chitayat D, Toka taught in pediatric cardiology within a special- HR, Toka O, Plessis G, Maass P, Rauch A, Aydin A, Luft FC ized training course “optional subject pediat- (2008) Inversion region for hypertension and brachydactyly rics”. Furthermore we offer the possibility to on chromosome 12p features multiple splicing and noncod- ing RNA. Hypertension, 51: 426-31 perform clinical electives or internships in our Koch AM, Zink S, Singer H (2008) B-type natriuretic pep- department. tide in patients with systemic right ventricle. Cardiology, 110: 1-7 Koch AM, Zink S, Singer H, Dittrich S (2008) B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavopulmonary connection. Eur J Heart Fail, 10: 60-2 Wolf CM, Arad M, Ahmad F, Sanbe A, Bernstein SA, Toka O, Konno T, Morley G, Robbins J, Seidman JG, Seidman CE, Berul CI (2008) Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations. Circulation, 117: 144-54

International Cooperation Seidman Laboratory, Department of Cardiovascular Genet- ics, Harvard Medical School, Boston, USA

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 107 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Dermatology Chair of Skin and Venereal Diseases

Address basis for innovative future clinical applications. DC subpopulation and T-cell response Hartmannstrasse 14 All these projects are manly financed by extra Project manager: D. Dudziak 91052 Erlangen mural fundings. In addition the Department of This research group focuses on the antigen Phone: +49 9131 8533661 Dermatology coordinates the collaborative representation of DC. In mice it could be shown Fax: +49 9131 8536175 search project Collaborative Research Centre that antigens can be targeted by antigen-cou- www.hautklinik.uk-erlangen.de (SFB) 643 “Strategies of cellular immune inter- pled antibodies against C-type lectins and en- Head of Department vention” sponsored by the German Research docytosis receptors to DCs in vivo. Depending Foundation (DFG). on the DC subpopulation we found that the Prof. Dr. med. Gerold Schuler T cell response could be directed and was ei- Contact ther a more prominent CD4 T-helper response Prof. Dr. rer. nat. Alexander Steinkasserer Research when CD11c+CD8- DCs presented the anti- Phone: +49 9131 8536725 gen or was a more dominant cytotoxic T-cell Fax: +49 9131 8535799 Dendritic Cell (DC) vaccination (notably [email protected] malignant melanoma) Project manager: B. Schuler-Thurner Research Focus The major aim of the “Experimental immuno- • Dendritic Cell (DC) vaccination (notably therapy” group is the development of new and malignant melanoma) innovative immunotherapies based on DC. DC • DC subpopulation and T-cell response are specialized white cells able to induce anti- • Interaction between DC and viruses, espe- gen-specific T-cell responses upon ex vivo an- cially HSV-1 tigen loading and injection into patients. DC, • Tolerance induction using modified DC Following dendritic cell vaccination (middle) lung metas- primarily those generated from monocytic pre- tases (arrow, left) regress (right side) • Basic research on DC‘s and T-cells cursors are currently used to vaccinate patients • Signal transduction and intercellular com- against cancer (melanoma as a prime model). munication in the tumor microenvironment The production of the vaccines is carried out in specialized clean room laboratories under GMP (Good Manufacturing Practice) standards. In Structure of the Institution 2007 and 2008 the “Experimental immunotherapy” group was especially engaged in ex- Over 70 medics and scientists work at the De- tending the manufacturing authorization (Dr. partment of Dermatology. The research activi- Koch) for DC from peptide-loaded DC to those ties are organized in three main areas, (i) “Ex- loaded with autologous tumor-RNA. Moreover perimental Immunotherapy”, (ii) “Experimen- we were preparing for a randomized, multi- tal Dermatology” group and (iii) “Biology of centric phase III trial for the indication uveal Dendritic Cells”. The Department of Derma- melanoma (with the collaboration of Prof. tology pursues several immunologically ori- Kaempgen). In addition a clinical trial, using ented research areas. (i) The development of DC loaded with defined RNA for the tumor an- new and innovative immunotherapies based tigens MAGE-3, MelanA und Survivin was car- on DC. DC are specialized cells, able to induce ried out for the treatment of patients suffering antigen-specific cytotoxic as well as helper T- from metastasized melanoma. Trogocytosis of a HIV Nef activated T-cell (red) onto rest- cell responses upon ex vivo antigen loading The RNA-project group (Dr. Schaft and Dr. Do- ing bystander T-cells and injection into patients. Such approaches errie) markedly improved the RNA transfection are currently used to vaccinate patients against approach to load DC not only with antigens, cancer (melanoma as a prime model). Sever- but also to endow them with functional pro- response, when CD11c+CD8+ DCs presented al clinical trials have already been conducted teins (“designer DC”). For example, a chimeric the antigen. This approach allows the mainte- using peptide-loaded DCs in over 200 mela- E/L-selectin fusion molecule which allows DC to nance/initiation of antigen-specific tolerance as noma patients. With the help of these studies migrate into all lymph nodes after intravenous well as the implementation of immunity. Now the “proof of principle”, i.e. that modified DC injection, was introduced into DC by RNA elec- the strategy concept of “in vivo antigen target- can induce potent immune responses in mela- troporation. This approach could enhance vac- ing“ of DCs will be translated into the human noma patients has been obtained. (ii) An addi- cine efficacy and is currently clinically tested. system. Thus, work has been started to char- tional research focus concentrates on basic im- Moreover, the RNA-group initiated the transfer acterize DC subpopulations of human periph- munological aspects in order to understand the of T-cell receptors (TCR) to bulk T cells by RNA eral blood and lymphoid organs. We have suc- role of specific cells involved in the regulation transfection. TCR, specific for several epitopes cessfully developed protocols for the prepara- of the immune system. New findings gained (e.g. tumor antigens gp100, MAGE-A3, MelanA tion of single cell suspension from the tissues. from these studies will firstly increase basic sci- and viral antigens HIV-gag, HIV-pol) were suc- With this established method as well as with entific knowledge and secondly represent the cessfully transferred by this technique. confocal microscopy studies we will be able to

108 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) analyze the tissues for distinct DC subpopula- dogenously encoded soluble CD83 molecule Teaching tions. Further, cell sorting and microarray anal- was increased in the serum of cancer patients ysis of the distinct DC subpopulations will help and certain viral infections. We will continue to The coworkers of the clinic teach students of to identify molecules in these subpopulations study and analyze the therapeutic potential of human medicine, dental medicine, molecular that can be used for specific antigen targeting the soluble CD83 molecule in additional auto- medicine and biology in the field of dermatol- in vivo. Further, we will focus our work on the immune and transplantation models. ogy and genital diseases as well as in molecular production of antigen-conjugated antibodies Using ChIP-chip™ microarray analyses we and cellular immunology including translation- to analyze T-cell responses in tissue culture. could further characterize the human CD83 al applications (GMP facility). The training takes These data will be important for an eventual promoter which in the long run should allow place in form of seminars, practical courses, implementation into the clinic. the targeted in vivo gene expression in mature lectures laboratory rotations as well as bach- DC. With the help of CD83 expressing reporter elor, master, M.D. and Ph.D. theses. The clinic Interaction between DC and viruses, espe- mice we will investigate the role of CD83 dur- organizes interdisciplinary dermatological lec- cially HSV-1 ing tolerance induction as well as in T- and B- ture series which serve as continuous medical Project manager: M. Kummer, A. Goldwich cell activation. Using the aptamer technology education program of medical doctors in the The project group “DC and viruses” analyses we will identify DC- and T-cell- (esp. Treg) spe- region. In addition the clinic coordinates the the interaction between DC and viruses, in par- cific surface molecule and characterize them Collaborative Research Centre (SFB) 643 (strat- ticular in respect to the HSV-1 infection. A new on functional level. egies of cellular immune intervention). immune-escape mechanism could be identified, namely that in HSV-1 infected DC, CD83 is Basic research on DC‘s and T-cells Selected Publications completely degraded, which interestingly cor- Project manager: A. Steinkasserer Erdmann M, Doerrie J, Schaft N, Strasser E, Hendelmeier relates with a reduced immuno-stimulatory ca- This research unit focuses on the basic research M, Kaempgen E, Schuler G, Schuler-Thurner B (2007) Ef- pacity of these infected DC. This degradation is of DC, antigen loading, induction of tolerance, fective clinical-scale production of dendritic cell vaccines by monocyte elutriation directly in medium, subsequent mediated by the viral immediate early protein as well as DC- and T-cell- mediated signalling culture in bags and final antigen loading using peptides or ICP0 and the cellular proteasome. In addition and transcription events. The aim of this re- RNA transfection. J Immunother, 30: 663-74 we could show that HSV-1 interferes with the search unit is several fold: (i) the establishment Prechtel AT, Turza NM, Theodoridis AA, Steinkasserer A of new scientific basics for future therapy con- (2007) CD83 knockdown in monocyte-derived dendritic cepts and (ii) the investigation of molecular cells by small interfering RNA leads to a diminished T cell stimulation. J Immunol, 178: 5454-64 mechanisms regulating immune responses. Albert H, Collin M, Dudziak D, Ravetch JV, Nimmerjahn F (2008) In vivo enzymatic modulation of IgG glycosylation Signal transduction and intercellular com- inhibits autoimmune disease in an IgG subclass-dependent munication in the tumor microenviron- manner. Proc Natl Acad Sci U S A, 105: 15005-9 ment Doerrie J, Schaft N, Mueller I, Wellner V, Schunder T, Haenig Project manager: A. Baur J, Oostingh GJ, Schoen MP, Robert C, Kaempgen E, Schuler The project group investigates MAP kinase- G (2008) Introduction of functional chimeric E/L-selectin by RNA electroporation to target dendritic cells from blood to dependent signal transduction and intercel- lymph nodes. Cancer Immunol Immunother, 57: 467-77 lular communication in the tumor microenvi- Reinwald S, Wiethe C, Westendorf AM, Breloer M, Probst- ronment of malignant melanoma. In our proj- Kepper M, Fleischer B, Steinkasserer A, Buer J, Hansen W ects we investigate novel mechanisms of inter- (2008) CD83 expression in CD4+ T cells modulates inflam- cellular communication between tumor-cells mation and autoimmunity. J Immunol, 180: 5890-7 and the immune system. In the course of these Witte V, Laffert B, Gintschel P, Krautkraemer E, Blume K, mechanisms cellular molecules are transferred Fackler OT, Baur AS (2008) Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta A dendritic cell interacts with a T-cell to bystander cells through nanotubes, mi- raft recruitment leading to activation of ERK1/2 but not NF crovesicles and by trogocytosis. The functional kappa B. J Immunol, 181: 8425-32 consequences of this cellular hardware trans- International Cooperation fer, as well as its molecular basis are not under- chemokine mediated DC-migration, which is stood. It is likely, however, that signal trans- Prof. Dr. R. M. Steinman, The Rockefeller University, New York, USA an absolutely essential step in order to induce duction events are transferred from one cell potent antiviral immune responses. to the other leading to functional changes in Prof. Dr. J. Banchereau, Dr. Karolina Palucka, Baylor Institute for Immunology, Dallas, Texas, USA the whole microenvironment. We hypothesize, Prof. Dr. T. Boon, Prof. Dr. P. Coulie, Prof. Dr. van der Brug- Tolerance induction using modified DC that these mechanisms serve the tumor im- gen, Ludwig Institute of Cancer Research, Bruessel, Belgium Project manager: E. Zinser, I. Knippertz, M. mune escape and are regulated at least in part Prof. K. Thielemanns, Dr. J. Corthals, Free University of Lechmann by a MAP kinase dependent signal transduc- Brussels, Belgium The project group “DC-specific molecules” fo- tion pathway. The preliminary data support- Prof. Dr. C. G. Figdor, Tumor Immunology, University cuses on new, functionally relevant DC-specific ing our hypothesis are based on findings ob- Hospital, Nijmegen, Netherlands molecules. A major aim is the functional char- tained through the functional and molecular acterization and elucidation of signal transduc- analysis of the Nef protein of HIV-1. As a result Meetings and International Training Courses tion and transcription events for CD83 which of these studies we found, that an hnRNPK-de- is one the best known cell surface markers for pend formation of a signaling complex leads to 16.–18.07.2007: DC2007 Kongress, Bamberg mature DC. In this respect, using CD83-specif- the activation of MAP kinase and subsequently Research Equipment ic siRNAs, we could show that CD83 is very im- to increased secretion of microvesicles and ac- Becton Dickinson FACS Aria II portant for the immunostimulatory capacity of tivation of trogocytosis. Preliminary data indi- mature DC. Furthermore we found that a sol- cate that these events also lead to the activa- uble form of CD83 completely blocks DC-me- tion of matrix metalloproteinase. These events diated T cell stimulation in vitro and in vivo. A are currently investigated in primary melano- recombinant soluble CD83 molecule showed ma cell lines. great therapeutic potential in the treatment of experimental autoimmune encephalomyelitis (EAE) and in transplant studies using animal models. Interestingly, the abundance of an en-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 109 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Ear, Nose and Throat – Head and Neck Surgery Chair of Otorhinolaryngology University Hospital

Address Further the dynamic, computerized posturog- 3. the description of a new mechanism for Waldstrasse 1 raphy was used not only to the improved diag- sound source segregation in the auditory cor- 91054 Erlangen nostics of vestibular disturbances but also very tex of the Mongolian gerbil which is based on Phone: +49 9131 8533156 successfully to the respective therapy of these the neurophysiological implementation of a Fax: +49 9131 8533833 diseases in cooperation with physiotherapists. winner-take-all-algorithm (in cooperation with www.hno-klinik.uk-erlangen.de the University of Ulm and the Leibniz Institute Head of Department Computer aided surgery/robotics for Neurobiology in Magdeburg). The group of computer aided surgery and ro- Prof. Dr. med. Heinrich Iro botics focused its research on the advancement Magnetic drug targeting/nanomedicine Contact of clinical navigation and robotic procedures. A The therapeutical and the toxic effects of che- Prof. Dr. med. Christoph Alexiou new software for intraoperative image-update motherapeutics are often closely connected. Phone: +49 9131 8533142 was evalutated and its applicability tested in a Therefore, even small changes of their distri- Fax: +49 9131 8534828 clinical setting. Possible errors, misleading pro- bution in favour of the respective body com- [email protected] cedures as well as advancements were docu- partment can result for the patients in a better mented. A sofar underrepresented field of nav- Research Focus igation was evalutated by applying navigation • Neurootology/vestibular laboratory techniques to soft tissues areas of the head and • Computer aided surgery/robotics neck. Foreign bodies were removed using navi- • Laboratory for sleep disorders/somnology gation procedures. • Experimental otolaryngology In collaboration with the Department of Neu- • Magnetic drug targeting/nanomedicine rosurgery, a modification of the Erlangen robot • Ultrasound and endoscopy A73 was developed and tested in a preclini- • Allergology/clinical immunology and cal setting. rhinology • Individual speech processor programming in Laboratory for sleep disorders/somnology cochlear implant users The projects are focused on a surgical treat- • Neurophysiology ment of primary snoring and obstructive sleep apnea. Besides the well known nCpap therapie in obstructive sleep apnea we try to find alter- Structure of the Institution native treatment options. Therefore we are in- venting a special nasopharyngeal stent in order In the Department altogether 255 act as co- to prevent obstruction in patients suffering of workers, out of these 31 coworkers are en- obstructive sleep apnea. Results are to be com- gaged the clinical-scientific area, 7 coworkers pared to nCpap therapy. exclusively within basic research and 217 co- Concerning the treatment of primary snoring Neurootology/Vestibulardiagnostics workers in nursing and administration. we are comparing a coblation assisted palato- Within different scientific groups clinical-rele- plasty to general uvulopalatopharyngoplasty vant research concerning neurootology, som- or other surgical methods such as laser assist- nology, oncology, ultrasound and endoscopy, ed uvuloplasty. treatment of the malignancy while a often se- allergology and neurophysiology is performed. vere side effects should be reduced. Magnet- Experimental otolaryngology ic drug targeting is a new and inovative cancer The research lab experimental otolaryngology therapy. Here, nanoparticles bound reversibly Research focused its research on projects on 1. patho- to cy-tostatic drugs are injected close to the genesis of juvenile angiofibromas (JA), 2. inner tumor into the tumor supporting vessels and Neurootology/vestibular laboratory ear biology, and 3. neurophysiology of the cen- are enriched under the presence of an exter- In the year 2007 the integration of a dynamic tral auditory system. Results yielded e.g.: nal magnetic field in the tumor. The nanopar- Posturography system (Smart Equi Test®, Neu- 1. evidence of tumor origin at early develop- ticles serve as vehicles for concentrating the roCom Int.) into the clinic was the main focus mental stage by specific laminin expression bound chemotherapeutic agents over the of the neurootology/vestibular laboratory. The patterns in tumor vessels and evidence that the blood stream in the desired target area which present equipment with videooculography prominent extracellular matrix component col- is in the focus of an appropriate external mag- combined to computernystagmography, laser lagen type VI may exert growth-stimulatory ef- netic field. In the laboratory for nanotechnolo- target projector, rotary-/pendularchair system fects on vascular as well as stromal cells in JAs. gy/local tumor therapy of the department ex- and static posturography could be extended 2. the first description of glycine receptors in tensive work is accomplished for the synthesis thus by this very important functional spec- the rat cochlea and its developmental regula- of biocompatible nanocarrier systems and their trum. The emphasis was in particular on the tion which supports our hypothesis of a gly- application in animal models. The aim of these pre- and postoperative diagnostics concern- cinergic component in cochlear efferent sig- studies is to lay the foundations for human tri- ing cochlear implants and oktavusneurinomas. nal transduction. als (“Translational cancer research”).

110 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Ultrasound and endoscopy Allergology/clinical immunology and In paresis or during accordant operations the A key issue of the high resolution ultrasound re- rhinology function of the facial nerve or the inferior laryn- mains identification and classification of head In patients with ASA intolerance therapeutic geal nerve is controlled. and neck disease and salivary gland altera- options are the endoscopic sinus surgery and tions. Using state of the art ultrasound devices adaptive desensitization to ASA. The diagnos- we were able to develop in cooperation with tic value of a functional blood test (FET-AIT®) Teaching the Competence Centre of Medical Technol- for measuring the eicosanoid dysbalance in pa- ogy of the Ruhr University of Bochum (Profes- tients with sensitivity to ASA is tested. Traditional instruction forms (main lecture with sor Ermert) computer-assisted diagnostic algo- A double-blind randomized placebo-controlled case-demonstration and live transmission of rhytms, which could detect different tumours trial on clinical and biological effects of oral operations, block practical courses) are supple- of the parotid gland with high sensitivity. Di- corticosteroids or doxycycline in patients with mented by interdisciplinary meetings. Further agnostic quality of parotid gland tumours was nasal polyps focuses on clinical and biologi- more all the year the possibility exists for hos- critically tested in a nation wide multicenter cal markers. The stimulation of functional in- pitation in the outpatient clinic and the oper- study. tact polyp tissue under in-vitro conditions with ating theater.

Ultrasound and Endoscopy

Immunofluorescence staining of glycine receptors in the The application of current sonographic appli- Schematic drawing of Magnetic Drug Targeting murine cochlea (P20) GlyRα protein (GlyRα, green) is de- cations such as tissue harmonic imaging and (www.siemens.de/pof) tected at the basolateral end of outer hair cells (OHCs), compound imaging are the subject of up-to- in close apposition to efferent synaptic terminals, which are labelled with an antibody against synaptotagmin date accomplished studies. Here these applica- (syt, red). Cell nuclei are counterstained with DAPI (blue). tions can contribute to clarify architecture and the biopsy mucosa oxygenator is used for in- improve contrasting pathologies. Analyses of vestigating relevant mediators of inflamma- contrast agent application in patients with un- tion. In a multi-centered double-blind place- Selected Publications clear lymph node enlargements could identify bo-controlled study patients oral corticoste- new objective characteristics in the distinction roids post-operative are evaluated, looking at Iro H, Wurm J, Zenk J (2004) Complications with inflammatory diseases of the nasal sinuses. HNO, 52: 395-408 of benign and malignant nodes. Minimalinva- the rate of recurrences. Study centres: Dpt.s Zenk J, Bozzato A, Steinhart H, Greess H, Iro H (2005) Meta- sive techniques in the treatment of obstruc- of Otolaryngology, Head- and Neck-Surgery static and inflammatory cervical lymph nodes as analyzed by tive salivary gland disease remained another in Kiel, Regensburg, Berlin Charite, Marburg contrast-enhanced color-coded Doppler ultrasonography: quantitative dynamic perfusion patterns and histopatho- mainstay of research of the endoscopy team. and Stuttgart. logic correlation. Ann Otol Rhinol Laryngol, 114: 43-7 In the context of an european-wide coopera- Alexiou C, Jurgons R, Seliger C, Iro H (2006) Medical appli- tion the experiences of this modern diagno- Individual speech processor programming cations of magnetic nanoparticles. J Nanosci Nanotechnol, sis and therapy procedure were evaluated and in cochlear implant users 6: 2762-8 published. Salivary duct-, and gland endoscopy Today cochlear implants (CI) provide an effi- Alexiou C, Jurgons R, Seliger, C, Brunke O, Iro H, Odenbach S. (2007) Delivery of superparamagnetic nanoparticles for and their areas of application could be corrob- cient treatment of profound hearing loss and local chemotherapy after intraarterial infusion and magnetic orated in their value of gland preserving treat- inner ear deafness. However, individual results targeting. Anticancer Res 27:2019-2022 ment options. vary substantially. The aim of this project is to Duerr S, Wendler O, Aigner T, Karosi S, Schick B (2008) Metalloproteinases in juvenile angiofibroma--a collagen Academic workshops and academic projects identify the individual differences by means rich tumor. Hum Pathol, 39: 259-68 enabled Erlangen to assume leading position of of cortical auditory potentials and enhance salivary gland diseases in Germany and Europe. speech and music perception by individual International Cooperation Many people visited the facilities and numer- speech processor adjustments. Prof. Mc Gurk, Salivary Research Unit, Maxillofacial Surgery, ous international invitations were used to refer Guy‘s, King‘s and St. Thomas‘ Dental Institute, King‘s Col- lege, London, UK our personal experiences. Neurophysiology The neurophysiology and electromyography Meetings and International Training (EMG) laboratory focuses on diagnosis and Courses therapy of cranial nerves involved in ENT pro- International Course on Aesthetic and Reconstructive Rhino- cedures. plasty and Otoplasty, Blepharoplasty and Face Lift, Erlangen

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 111 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Ear, Nose and Throat – Head and Neck Surgery Division of Phoniatrics and Pediatric Audiology University Hospital

Address device. Results correlate significantly with ex- for children with cleft lip and palate or adults Bohlenplatz 21 pert evaluation, and expert evaluation corre- with tumours of the head and neck. 91054 Erlangen lates significantly with an evaluation obtained Phone: +49 9131 8533146 from naïve listeners. Different measures of self Auditory evoked cortical potentials Fax: +49 9131 8539272 perception correlate significantly but not with Processing, perception, and analysis of heard www.phoniatrie.uk-erlangen.de the parameters extracted from voice analysis. speech is an enmeshed, partly hierarchical pro- Head of Division cess chain, in which numerous serial, parallel, Phonovibrography – objective analysis of and distributed neural networks are participat- Prof. Dr. med. Dr. rer. nat. Ulrich Eysholdt vocal fold vibrations ing. An impairment of this process chain affects Contact The causes of hoarseness are not yet complete- the linguistic development of children adverse- Prof. Dr.-Ing. Michael Doellinger ly understood. The presumed irregularities of ly. Focus of our workgroup is the development Phone: +49 9131 8533814 vocal fold oscillation cannot be proved with the of objective tests for the auditory processing Fax: +49 9131 8539272 conventional investigation instrument (strobos- of speech, which are independent of the pa- [email protected] copy) because this is only designed for periodic tients’ state of attention. As approach auditory events. Owing to funding of the German Re- evoked potentials were used, whereat event re- Research Focus serach Foundation (DFG) the novel approach lated voltage deflections are derived from the • Evaluation of tracheoesophageal voice of phonovibrography was developed which en- scalp (EEG). Our workgroup detected a previ- • Phonovibrography – objective analysis of ables a visualization and analysis of vocal fold ously unknown speech evoked component in vocal fold vibrations dynamics. In this approach digital high-speed the time course of auditory potentials (N170), • Quantitative evaluation of speech recordings of vocal fold vibrations are analyzed, which is supposed to be generated due to • Auditory evoked cortical potentials captured at a frame rate of 4000 Hz. For an ob- changes of spectral and temporal stimulus fea- • Biomechanical parameterization of vocal jective analysis a specialized image segmenta- tures. The successful reconstruction of complex fold vibrations tion algorithm was developed which extracts speech evoked potentials on the basis of acous- • Principles of voice production the vibrating vocal fold edges from the high- tic stimulus features confirms this assumption. speed recordings. The results of the procedure Thus, N170 allows conclusions about the audi- were extensively evaluated in a clinical trial. tory perception of speech. In children, N170 Structure of the Institution To visualize the relevant vibration information emerges over the years of infancy, i.e. it can be within a single image the so-called phonovi- interpreted as an attribute of maturation, and Phoniatrics and Pediatric Audiology is a medi- brogram (PVG) was developed. A PVG image support diagnostics of childish speech pro- cal field which addresses diseases and disorders contains the entire vocal fold oscillation pat- cessing. In another project, it was investigat- of voice, speech, language, hearing and swal- tern and enables a novel classification of vocal ed, how far the discrimination ability of speech lowing. Research deals basically with commu- fold vibrations. For further quantification a laser relevant stimulus features can be assessed elec- nication disorders on the perception side (hear- projection device was developed which en- trophysiologically. In fact, potentials could be ing research) and the production side (speech ables a quantification of the image data.T hus, evoked (mismatch negativity), whose occur- and voice research). The principle contents of absolute measures of vocal fold elongation and rence correlated with behavioural determined the reserach projects connect the medical field velocities can be performed. auditory functions. with applied natural sciences and technology. The head of the division is also member of the Quantitative evaluation of speech Biomechanical parameterization of vocal Technical Faculty of the University Erlangen- For the evaluation of speech disorders objec- fold vibrations Nürnberg and is supervising scientific works in tive, validated and simple evaluation methods The segmented vocal fold oscillations can be all of these fields. Totally, 21 employees work are missing. Speech disorders are usually as- analyzed with means of non-linear dynamics at the department, four financed via third- sessed by a perceptive evaluation with only re- by simulating vocal fold motion curves with a party funds. stricted reliability for clinical or scientific use. biomechanical two-mass model of the vocal The automatic speech analysis, as used for au- folds. The model simulates the principle prop- tomatic speech recognition systems, is a new erties of vocal fold vibrations with a system of Research objective method for global evaluation, i.e. for differential equations which establish the tem- the quantification of the intelligibility. Auto- poral process of the vocal fold oscillations. By Evaluation of tracheoesophageal voice matic evaluation agrees with the perceptive adapting the model oscillations to the extract- After laryngectomy, the loss of natural voice is estimation by a panel of human experts. It is ed vocal fold vibrations the asymmetry of vi- the most prominent functional defect. It can qualified to replace laborious subjective evalu- bration pattern can be quantified within a 2D be rehabilitated best by means of shunt valves. ations. Moreover, the application is tested for parameter domain. The model simulations So far, there is no consensus on how to evalu- different forms of speech disorders and adapt- were designed in that way to quantify station- ate tracheoesophageal voice. In a study funded for the automatic classification and quanti- ary and non-stationary vocal fold vibrations. ed by the German Cancer Aid Foundation it fication of different typical speech disorders. Thus, different kinds of dysphonia were quan- was shown that tracheoesophageal voice can The new method will improve outcome mea- tified within the parameter domain of the bio- be evaluated by an automatic speech analysis surements of different therapy strategies, e.g. mechanical model.

112 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Burger M, Hoppe U, Kummer P, Lohscheller J, Eysholdt U, Doellinger M (2007) Wavelet-based analysis of MMN responses in children. Biomed Tech (Berl), 52: 111-6 Lohscheller J, Toy H, Rosanowski F, Eysholdt U, Doellinger M (2007) Clinically evaluated procedure for the reconstruction of vocal fold vibrations from endoscopic digital high-speed videos. Med Image Anal, 11: 400-13 Lohscheller J, Doellinger M, McWhorter AJ, Kunduk M (2008) Preliminary study on the quantitative analysis of vocal loading effects on vocal fold dynamics using phono- vibrograms. Ann Otol Rhinol Laryngol, 117: 484-93 Lohscheller J, Eysholdt U (2008) Phonovibrogram visualization of entire vocal fold dynamics. Laryngoscope, 118: 753-8 Lohscheller J, Eysholdt U, Toy H, Dollinger M (2008) Pho- novibrography: mapping high-speed movies of vocal fold vibrations into 2-d diagrams for visualizing and analyzing the underlying laryngeal dynamics. IEEE Trans Med Imag- Assessment of vocal fold dynamics demands a computerized analysis of high-speed videos. After segmentation vocal ing, 27: 300-9 fold edges are transformed and the distances to the glottal midline become color coded. Applying this strategy to an entire high-speed video generates a color image, denoted Phonovibrogram (PVG) which can be regarded as finger- Wurzbacher T, Voigt I, Schwarz R, Doellinger M, Hoppe print of vocal fold dynamics. U, Penne J, Eysholdt U, Lohscheller J (2008) Calibration of laryngeal endoscopic high-speed image sequences by an automated detection of parallel laser line projections. Med Image Anal, 12: 300-17

International Cooperation Melda Kunduk (PhD), Department of Communication Sciences & Disorders, Louisiana State University, Baton Principles of voice production Teaching Rouge, USA Voice production within the larynx is still not D.A. Berry, PhD, Laryngeal Dynamics Laboratory, Division entirely understood neither in normal nor in Our division is dedicated to a first-class aca- of Head and Neck Surgery, University of California Los pathological voice. The goal of the interdisci- demic teaching which is of the same value be- Angeles, USA plinary DFG research unit FOR894/1 is to get sides patient care and scientific research. The Jan G. Švec, Department of Experimental Physics, Palacký substantiated knowledge on normal and path- offer of lectures follows the clinical focus of University, Olomouc, Czech Republic ological vocal fold dynamics and on the result- the area. ing acoustic signal. Human voice is the result of Phoniatrics and pediatric audiology is teached a complex process comprising fluid dynamics during both the pre-clinical and clinical phase. coupled with moving elastic tissue. Analysing Complementarily, practical trainings on voice, such complexities necessitates different model- swallowing, speech and hearing impairments ling approaches. Therefore, departments from are given. Additionally, lectures and trainings different research fields are working togeth- are given in physiology: “auditory system”, er to derive a better picture of the entire voice “voice, speech and language” and medical origination process. The different suggested psychology and sociology: “language develop- models allow a review and verification of the ment in children” and “rehabilitation”. results and assumptions. In the international The training of speech therapists takes place at fluid dynamics and voice research communi- the full-time vocational school for logopedics. ty, different approaches are still applied and discussed on their own. Hence, the research unit FOR894/1 is performing highly frontier research. For coordination and leading the interdisciplinary group, a DFG funded research W2- professorship was established.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 113 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Ophthalmology Chair of Ophthalmology

Address second laser, cataract surgery with innovative Corneal stem cells Schwabachanlage 6 intraocular lenses and intraocular injections of Project manager: U. Schloetzer-Schrehardt, 91054 Erlangen compounds to treat age related macular de- F. Kruse Phone: +49 9131 8534478 generation (AMD). The maintenance of a healthy corneal epithe- Fax: +49 9131 8536435 In the field of the conservative medicine special lium and transparent cornea is achieved by a www.augenklinik.med.uni-erlangen.de consultation areas are established. Special de- population of stem cells located at the corneal Head of Department partments (optometry, fluorescence angiogra- limbus. This research project explores the mo- phy and laser, ourpatients department and the lecular characteristics of corneal stem and pro- Prof. Dr. med. Friedrich E. Kruse cornea bank) are present. In addition, there is genitor cells together with their specific niches Contact support from different laboratories. and their utilization for novel stem cell based Prof. Dr. med. Friedrich E. Kruse At the outpatient department surgical proce- therapies for ocular surface reconstruction in Phone: +49 9131 8534478 dures are performed (ambulant surgical cen- patients with limbal stem cell deficiency. The Fax: +49 9131 8536435 tre, cataract operation, laser coagulation, sur- applicability of alternative autologous stem cell [email protected] gery of the eye lids using CO2 laser, refractive sources for corneal epithelial tissue engineering surgery and retino-vitreal surgery). New clini- strategies is investigated. Research Focus cal developments include the multidisciplinary • Pseudoexfoliation syndrome/glaucoma patient care with the electronic patient dossiers Ocular hem- and lymphangiogenesis and • Corneal stem cells available for all departments. their relevance for corneal transplant im- • Ocular hem- and lymphangiogenesis and munology and tumor metastasis their relevance for corneal transplant im- Project manager: C. Cursiefen munology and tumor metastasis Research The relevance of pathologic hem- and lym- • Biomorphometry of the optic nerve phangiogenesis for corneal transplant immu- • Clinico-pathologic concepts in diagnosis At the Department of Ophthalmology several nology after corneal grafting is evaluated. and management of ocular diseases aspects of ocular and eye diseases are investi- Novel anti(lymph)angiogenic therapies are • Circulation of the eye and the visual gated. The range of research includes studies evaluated and translated by performing sever- Pathway and Computer-aided-Diagnosis & on disease of the orbit and ocular media but al phase II and III clinical trials. The laboratory is Virtual Education also the retina and the central visual pathways. morphometric reading centre of several multi- • Functional aspects of retinal neuro A multitude of techniques are available for centre antiangiogenic trials. The role of patho- degeneration these studies, including molecular biological logic lymphangiogenesis for tumor metastasis • Retinal physiology methods, imaging techniques, electrophysi- of ocular tumors is examined. ological recordings and psychophysical procedures. Biomorphometry of the optic nerve Structure of the Institution Research in the Department of Ophthalmology Project manager: C. Mardin, R. Tornow is financially supported from various sources. The objective, measurable glaucoma damage In total 168 Persons are employed at the Eye The collaborative research centre 539 “Glau- at the optic disc and the peripapillary tissue Hospital. Of these, 42 are physicians, 10 scien- coma including pseudoexfoliation syndrome and its early progression often precede func- tific staff member. 7 of these are employed as (PEX)“ should be explicitly mentioned. In ad- tional defects. The project’s aim is to measure professor. In addition, 78 persons are employed dition many projects are supported by the Ger- the morphologic damage with new and estab- for nursing service and 38 as non-scientific staff man Research Council and other public and pri- lished techniques in vivo, to find progression (technicians etc.). vate institutions. In total 16 positions are exter- indicators and to differentiate between early The clinical expertise of the Department of nally funded: one professorship, 4 physicians, glaucoma tissue loss and age related changes. Ophthalmology includes the complete spec- 5 scientific and 6 non-scientific staff members. Current focus is to establish high-resolution trum of surgical and conservative ophthal- OCT to measure the retinal nerve fibre layer mology. Pseudoexfoliation syndrome/glaucoma as the earliest tissue to be lost in glaucomas. In the surgical ophthalmology a diverse spec- Project manager: U. Schloetzer-Schrehardt trum of operations are performed, including The focus of this research project is the molec- Clinico-pathologic concepts in diagnosis surgery of the frontal eye, cornea surgery, re- ular analysis of the generalized matrix process and management of ocular diseases constructive surgery of the frontal eye, glau- and its causally related glaucoma development. Project manager: L. Holbach, F. Kruse, G. coma surgery, oculoplastic, orbita, tumor, tear These investigations resulted in new findings Gusek-Schneider, A. Bergua gland and vitreo-retinal surgery. contributing significantly to an elucidation of 1. Diagnosis and management of orbital diseas- In the surgical area innovative surgical proce- pathogenesis, an improved understanding of es – a multidisciplinary approach. dures are developed and evaluated. These de- the symptoms, an earlier diagnosis, a reduction The goal of this study is to further improve the velopments include seamless transconjunctival of surgical complications, and the identification multidisciplinary approach in diagnosis and retinal-vitreal surgery (23-gauge-vitrectomy), of novel therapeutic targets. These findings es- management. minimal invasive glaucoma surgery employing tablished the group’s leading position in basic 2. Surgical management of periocular malig- implants, refractive surgery with the femto- research on PEX syndrome/glaucoma. nant tumors using frozen section control and

114 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) plastic reconstruction-indications, methods Functional aspects of retinal neuro In the course of the standard curriculum proj- and results. degeneration ect leader and research fellows are involved in The aim of this study is the long-term evalua- Project manager: A. Juenemann, J. Kremers, the regular student education and practical tion of surgical results following intraoperative F. Horn courses. Moreover they are involved in doctor- frozen section control and immediate plastic re- In this research centre new electrophysiologi- ates’ education and training. pair regarding recurrence rates and adequacy cal and psychophysical techniques are devel- Owing to the extensive contacts with col- of reconstructive techniques. oped to study the functional aspects of retinal leagues abroad many foreign students come to 3. Diagnosis and surgical management of epi- degeneration, especially in glaucoma. the Department of Ophthalmology for at least bulbar lesions. The responses from different retinal pathways a part of their study (graduate or post-gradu- The purpose of this study is to establish corre- are separated by appropriate stimuli. The stim- ate) and for further education. lations between morphologic, biomicroscopic, ulation of non-redundant systems allows the histologic and molecular genetic criteria and early detection of functional glaucomatous the long-term results of surgical excision and damage. Selected Publications plastic reconstruction. By using neuronal feedback one can make the Heindl LM, Naumann GO, Kruse FE, Holbach LM (2008) system particularly sensitive to the appropriate Aggressive metastasising adenocarcinoma of the retinal Circulation of the eye and the visual stimuli. Electrophysiological tests have the ad- pigment epithelium with trisomy 21. Br J Ophthalmol, pathway and computer-aided-diagnosis & vantage of objectivity, but they are less sensi- 92: 389-91 virtual education tive in comparison to the psychophysical tests. Hos D, Bock F, Dietrich T, Onderka J, Kruse FE, Thierauch KH, Cursiefen C (2008) Inflammatory corneal (lymph) Project manager: G. Michelson, S.Waerntges, The combination of multifocal LED stimulation angiogenesis is blocked by VEGFR-tyrosine kinase inhibitor M. Scibor and cyclic summation in the pattern-reversal ZK 261991, resulting in improved graft survival after corneal transplantation. Invest Ophthalmol Vis Sci, 49: 1836-42 Kremers J, Link B (2008) Electroretinographic responses that may reflect activity of parvo- and magnocellular post- receptoral visual pathways. J Vis, 8: 11.1-14 Laemmer R, Mardin CY, Juenemann AG (2008) Visualization of changes of the iris configuration after peripheral laser iridotomy in primary melanin dispersion syndrome using optical coherence tomography. J Glaucoma, 17: 569-70 Ritt M, Harazny JM, Ott C, Schlaich MP, Schneider MP, Michelson G, Schmieder RE (2008) Analysis of retinal arteriolar structure in never-treated patients with essential hypertension. J Hypertens, 26: 1427-34 Schloetzer-Schrehardt U, Pasutto F, Sommer P, Hornstra I, Kruse FE, Naumann GO, Reis A, Zenkel M (2008) Genotype- correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol, 173: 1724-35

International Cooperation 3-D imaging of a focal retinal nerve fibre layer defect in an early glaucoma eye with SPECTRALIS-OCT Claude Burgoyne, Devers Eye Institute, Discoveries in Sight Research Laboratories., Portland, USA Prof. Luiz Silveira, Universidade Federal do Pará, Belém, Brasilia Dr. K. Maruyama, Kyoto Prefectural School of Medicine, 1. Ocular circulation of the eye and the visu- ERG and the photopic negative response in Japan al pathway. the full-field flash ERG with coloured stimuli are Wolfgang Drexler, Institute f. Optometry, Cardiff, UK The tissues and vessels of the eye reflect sys- new developments to improve electrophysio- temic diseases are a merely perfect system for logical testing of retinal degeneration. Research Equipment the visualisation of physiologic processes of the Zeiss Transmissionselektronenmikroskop body. Immunological processes, diabetes and Retinal physiology Zeiss Lasermikrodissektionssystem arterial hypertension can be evaluated quanti- Project manager: J.Kremers, A.Juenemann Heidelberg Engineering SPECTRALIS-FLA und OCT tatively in the eye. The goal of this topic is to study the function of 2. Computer-aided-diagnosis & virtual edu- the normal and diseased retina. To reach that cation. goal we record electrophysiological responses Ophthalmology needs new methods for med- of the retina of rodent models of human dis- ical information processing to optimize diag- eases. In addition, we perform electrophysi- nosis and therapy. Automated analysis of oph- ological and psychophysical experiments with thalmic images combined with automated normal human observers and patients to iden- classification leads to a fast and bias-free eval- tify different signal pathways in the retina and uation, which is an important prerequisite for the changes caused by a disease. The results of screening. the animal and human experiments are related 3. Diffusion measurement of the visual path- with each other so that the pathophysiological way based on magnetic resonance images. processes can be better understood. Neurodegenerative eye diseases often involve the entirevisual system and may induce by cerebral macro- and microangiopathie and sub- Teaching sequent ischemic changes and degeneration of the visual pathway. The new non-invasive tech- Results of research are directly implemented in nique based on magnetic-resonance imaging medical student and postgraduate teaching. provides information about the integrity and There are several medical and biologic PhD stu- orientation of the visual pathway. dents in the laboratory.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 115 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Neurology Chair of Neurology University Hospital

Address Research information about resource use and health eco- Schwabachanlage 6 nomics of stroke for the health planning au- 91054 Erlangen Stroke thorities in Germany. Phone: +49 9131 8534563 Project manager: P. Schellinger, R. Kollmar, J. Fax: +49 9131 8536597 Bardutzky. Telemedicine and systems of care www.neurologie.uk-erlangen.de Intensive care medicine: A main focus of the Project manager: R. Handschu Head of Department neurocritical care unit consists of clinical re- The group is active in research on the use of search and transferring experimental research telemedicine and e-health on the care of neuro- Prof. Dr. med. Stefan Schwab into clinical practice. In a larger cohort we logical disease. Besides interdisciplinary work in Contact studied the benefit of intraventricular throm- the area of stroke prevention a large telemedi- PD Dr. med. René Handschu bolysis and lumbar drainage after intraven- cal network was initiated to improve acute care Phone: +49 9131 8534007 ticular haemorrhage. In a randomised clini- of 4000 stroke patients each year in the whole Fax: +49 9131 8536589 cal study of hypothermia treatment in patients region of Northern Bavaria. Research is now fo- [email protected] with large intracerebral haemorrhage, prelimi- cussing on the effects of the network and fur- nary data show a beneficial effect of therapeu- ther improvement of telemedical technology. Research Focus tic cooling. Further on, we conduct a through- Other projects deal with rehabilitation of neu- • Stroke out europe unique hypothermia trial in awake rological patients or teleconsultation for men- • Public health stroke patients. Other main fields of interest tal health. • Telemedicine and systems of care concern diagnostics of autonomic disorders • Neurocognition, headache and neuropathic and multimodal monitoring in severe neuro- Neurocognition, headache and neuro- pain logic disorders. pathic pain • Autonomic nervous system Stroke unit: After opening of the dedicated Project manager: C. Maihoefner • Neuromuscular diseases neuro emergency unit in 2006 and expansion Our research team investigates mechanisms of • Epilepsy of our stroke unit to 14 beds we are able to adaptive and maladaptive sensorimotor plastic- supply state-of-the-art stroke therapy in Erlan- ity in several diseases (neuropathic pain, head- gen around the clock. Therefore stroke patients ache, stroke). Employed methods are non-in- Structure of the Institution get immediate treatment according to guide- vasive functional brain imaging techniques lines and have the opportunity to participate (fMRI, MEG), neuropsychology, psychophysics The Department of Neurology of Erlangen in promising national and international clini- and repetitive transcranial magnetic stimula- University Hospital is one of the largest neu- cal trials. Main focus of research interest here tion (rTMS). Work done by the group has been rological centres in Germany treating 3500 in- are intraarterial and intravenous thrombolysis, several times awarded (European Pain Price patients and more than 7000 outpatients each advanced imaging guided therapy, treatment 2007, Sertuener Price 2007; poster awards). year. Our Stroke unit is the largest one in the with growth factors and management of body Main funding sources are the German Federal state of Bavaria, and there is a huge intensive temperature. Ministry for Education and Research (“German care unit integrated in the department. Addi- Research Network on Neuropathic Pain”) and tionally the department hosts one of the most Public health the German Research Foundation (clinical re- important units for specialized diagnosis and Project manager: P. Kolominsky-Rabas search unit “Determinants and modulators of treatment of epilepsy (ZEE) and runs a telemed- The public health research unit focuses on the postoperative pain”, KFO 130). ical network for regional stroke care. demographic impact of cerebro-vascular disor- Within all these features the department is able ders in the aging German population. Its pri- Autonomic nervous system to provide up to date and competent diagnosis mary objectives encompass outcomes research Project manager: M.-J. Hilz and treatment as well as scientific work within for national and international public health au- The autonomic research laboratory evaluates all areas of modern clinical neuroscience. thorities with regard to the evaluation of insti- cardiovascular autonomic sequelae of cere- tutions and systems of health care, advisory bral disorders involving the central autonomic service to parliamentary institutions and prep- network, e.g. after stroke, traumatic brain in- aration of expert options in the field of health jury, in epilepsy, or other autonomic diseases. services research and descriptive and analyti- We developed methods for an early diagnosis cal epidemiology of cerebro-vascular disorders. of altered cerebral autoregulation, e.g. in dia- Since 2000 the public health research unit is betes mellitus or in congenital autonomic dis- the reporting centre for stroke for the federal eases, such as familial dysautonomia which we health monitoring system of the German Fed- study in cooperation with New York University. eral Government. The data source for this reporting system is the Erlangen Stroke Registry. The register is the only epidemiological population-based register in Germany. The aim of register is to provide representative long-term

116 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Neuromuscular diseases veloped (cooperation with neurosurgery and Prof. Denise Paulin, Pierre et Marie Curie University, Paris, Project manager: D. Heuss, R. Schroeder radiotherapy). A new multi-channel MEG-sys- France The Neuromuscular Disease Centre provides a tem is currently installed. Prof. Lee Schwamm, Havard Medical School, Boston, USA specialized outpatient clinic and a neuropatho- Prof. S. Anderman, Montreal Neurological Institute (MNI), logical laboratory for diagnostic biopsies and Canada for the investigation of neuromuscular diseas- Teaching Prof. W. Theodore, National Institute of Health, Bethesda- es. The following studies are performed: (1) Maryland, USA pheno- and genotyping in autosomal reces- Clinical education has been restructured pri- Dr. G. Kraemer, Schweizerische Epilepsieklinik, Zuerich, sive CMT II in a Costa Rican family (2) CK2-de- marily in the practical week. Elements for prac- Swiss ficient myopathies (3) Vaskulitic neuropathies tical skill such as lumbar puncture training and Meetings and International Training / clinical follow up (4) Intermediate filament OSCE have been included. For the following Courses pathology and mitochondrial dysfunction in year, further state-of-the-art implementations 15.–16.06.2007: 3rd Epilepsy Colloquium Erlangen epidermolysis bullosa simplex with muscu- are panned according to student assessment 05.07.2007: STENO-Netzwerk Schlaganfall, Forchheim lar dystrophy and desmin related-myopathies. and recent knowledge of master of medical 06.10.2007: Eroeffnung Stroke Unit mit wissenschaftlichem (5) Identification of novel and disease related education studies. Symposium, Erlangen VCP binding partners and characterization of 17.04.2008: 1. STENO-Symposium, Erlangen the skeletal muscle and cardiac pathology in a R155C-VCP knock-in mouse. (6) Generation Selected Publications Research Equipment and characterization of a R155C-VCP knock-in Duetsch M, Burger M, Doerfler C,S chwab S, Hilz MJ (2007) Schwarzer Neurophysiologie Netzwerk mouse: a key to the understanding of VCP-re- Cardiovascular autonomic function in poststroke patients. Magnes MEG 4D Neuroimaging Biomagnetismusanlage lated frontotemporal dementia. (7) Establish- Neurology, 69: 2249-55 ment of a spodoptera frugiperda cell culture Hammen T, Schwarz M, Doelken M, Kerling F, Engelhorn model for the generation of recombinant des- T, Stadlbauer A, Ganslandt O, Nimsky C, Doerfler A,S tefan H (2007) 1H-MR spectroscopy indicates severity markers min protein. Therapeutical trials (A) A Study in in temporal lobe epilepsy: correlations between metabolic Early Onset ALS (SIRONA) ONO-2506POE014 alterations, seizures, and epileptic discharges in EEG. Epi- (B) Deflazacort in Dysferlinopathies – double- lepsia, 48: 263-9 blind, placebo-controlled study/BMBF-subproj- Hilz MJ, Devinsky O, Szczepanska H, Borod JC, Marthol H, ect R19 MD-NET. Tutaj M (2007) Right ventromedial prefrontal lesions result in paradoxical cardiovascular activation with emotional stimuli (vol 129, pg 343, 2006). Brain, 130: 879-879 Epilepsy Seifert F, Maihoefner C (2007) Representation of cold Project manager: H. Stefan allodynia in the human brain--a functional MRI study. As a degree-four-centre ZEE provides the high- Neuroimage, 35: 1168-80 est level of medical care for patients suffering Huttner HB, Janich P, Koehrmann M, Jászai J, Siebzehnrubl form therapy resistant seizures. A model pro- F, Bluemcke I, Suttorp M, Gahr M, Kuhnt D, Nimsky C, Krex gram for the management of epilepsy cen- D, Schackert G, Loewenbrueck K, Reichmann H, Juettler E, Hacke W, Schellinger PD, Schwab S, Wilsch-Braeuninger tres was developed. Important research goals M, Marzesco AM, Corbeil D (2008) The stem cell marker are further developments of non-invasive pre- prominin-1/CD133 on membrane particles in human cere- operative localization diagnosis with the help brospinal fluid offers novel approaches for studying central of a high resolution functional magnetic res- nervous system disease. Stem Cells, 26: 698-705 onance tomography and spectroscopy (MRS) Schellinger PD, Köhrmann M, (2008) MRS/DWI mismatch: a novel concept or something one coud get easier and and magnetencephalography, quantitative cheaper? Stroke, 39: 2423-4 EEG-analysis and SPECT- and PET registrations (cooperation with neuroradiology and nuclear International Cooperation medicine). Neurobiological and molecular ge- New York University, USA netic methods allow the examination of epi- Prof. P. Chauvel, Service de Neurophysiologie Clinique, leptogenic tissue gained by surgery. This opens Aix-Marseile-Université, France promising perspectives for experimental clini- Prof. Ch. Baumgartner, Neurologische Universitaetsklinik cal research and will further support the under- Vienna, Austria standing of epileptogenesis (cooperation with Prof. J. Duncan, National Hospital Queen Square London, the institute of neuropathology and biochem- United Kingdom istry). Analyzing the course of focal epilepsies Prof. Achten, Katholieke Universiteit Leuven, Belgium shall contribute to the recognition of pharma- Prof. Zong-Zou, Universitaet Chengdu, China coresistence mechanisms, therapy and prog- Prof. G. del Valle, University of Costa Rica, San José nosis. Innovation strategies for drug treatment Prof. G. Wiche, University of Vienna, Austria of epilepsy with new substances, new surgical procedures and focal radiotherapy will be de-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 117 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Neurology Division of Molecular Neurology

Address Research Clinical research and development Schwabachanlage 6 The outpatient clinic for movement disorders 91054 Erlangen Neurodegenerative diseases (in particular Parkinson‘s disease, Huntington‘s Phone: +49 9131 8539324 The scientific focus of the newly formed di- disease and hereditary spastic paraplegia) is Fax: +49 9131 8536597 vision emphasizes on adult neurogenesis and offering state of the art diagnostic procedures www.molekulare-neurologie.uk-erlangen.de neurodegenerative mechanism in Parkinson’s and long-term care for patients and their care- Head of Division disease, Huntington’s disease and hereditary givers. Furthermore, the integration of scien- spastic paraplegia. Neuroregenerative process- tific projects will be consequently followed up Prof. Dr. med. Juergen Winkler es with emphasis on adult neurogenesis (gen- in close cooperation with the Department of Contact eration of new neurons in the adult brain) are Neurology which provides the care for inpa- PD Dr. med. Jochen Klucken assessed in movement disorders using cell cul- tients. Using modern structural imaging and Phone: +49 9131 8539324 ture and transgenic models of Parkinson’s and functional diagnostics workups such as high- Fax: +49 9131 8536597 Huntington’s disease. In an complementary ap- resolution magnetic resonance tomography, [email protected] proach neurodegenerative mechanism in synu- SPECT and PET analysis, the precise diagnostic cleinopathies are analysed in order to under- classification of these movement disorders will Research Focus stand the molecular mechanism in the devel- be completed by a detailed molecular genetic • Neurodegenerative diseases opment of Parkinson’s disease and Lewy body testing. The ultimate goal of this combined ap- • Translational research dementia. proach is to develop an individualized therapy • Clinical research and development for each patient. Translational research In addition to the clinical and neurobiological The Division is interested in the molecular and activities deep brain stimulation (DBS) proce- Structure of the Institution cellular biology of adult neural stem and pro- dures for movement disorders is prepared in genitor cells in two regions of the adult brain, close cooperation with the Department of Neu- The Division of Molecular Neurology within the subventricular zone and the hippocampus, rology and Neurosurgery in order to provide the Department of Neurology, newly formed where new neurons are generated throughout the entire spectrum of therapies for movement in September 2008, aims to establish the link the whole life span. Adult neurogenesis is se- disorders at the University Hospital Erlangen. from daily patient care towards the neuroscien- riously altered in the context of neurodegen- tific development in the field of neurodegenerative diseases. Numerous findings indicate erative diseases. Main focus of the division is that impaired adult neurogenesis may be one on neurodegenerative diseases such as Parkin- of the underlying pathophysiological events in son‘s disease, Huntington‘s disease and heredi- the development of non-motor symptoms like tary spastic paraplegia. In addition, the division depression, cognitive impairment and olfacto- intends the integration of ongoing projects ry dysfunction. These symptoms are likely to with the neighbouring Departments of Neu- reflect the compromised ability of the brain to rology, Psychiatry, Neurosurgery, Ophthalmol- generate new neurons in the hippocampus as ogy, Neuropathology as well as the Division of well as the olfactory bulb. Moreover, cell and Neuroradiology. molecular techniques have been established to Clinically, an outpatient clinic for movement delineate and modify pathological mechanism disorders was established where the entire associated with protein aggregation of alpha- spectrum of clinical, electrophysiological, im- synuclein in Parkinson’s disease and atypical aging and genetic diagnostics is provided for Parkinson syndromes. This strategy may lead to patients affected with these diseases. a causal therapy of synucleinopathies.

118 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Kohl Z, Kandasamy M, Winner B, Aigner R, Gross C, Couillard-Despres S, Bogdahn U, Aigner L, Winkler J (2007) Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington‘s disease. Brain Res, 1155: 24-33 St Martin JL, Klucken J, Outeiro TF, Nguyen P, Keller- McGandy C, Cantuti-Castelvetri I, Grammatopoulos TN, Standaert DG, Hyman BT, McLean PJ (2007) Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. J Neurochem, 100: 1449-57 Nuber S, Petrasch-Parwez E, Winner B, Winkler J, von Ho- ersten S, Schmidt T, Boy J, Kuhn M, Nguyen HP, Teismann P, Schulz JB, Neumann M, Pichler BJ, Reischl G, Holzmann C, Schmitt I, Bornemann A, Kuhn W, Zimmermann F, Servadio A, Riess O (2008) Neurodegeneration and motor dysfunction in a conditional model of Parkinson‘s disease. J Neurosci, 28: 2471-84 Winner B, Couillard-Despres S, Geyer M, Aigner R, Bogdahn U, Aigner L, Kuhn HG, Winkler J (2008) Dopaminergic lesion View of the “Kopfklinikum” in the background with the Division of Molecular Neurology enhances growth factor-induced striatal neuroblast migra- Source: University Hospital Erlangen tion. J Neuropathol Exp Neurol, 67: 105-16 Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bog- dahn U, Couillard-Despres S, Masliah E, Winkler J (2008) Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging, 29: 913-25 Marxreiter F, Nuber S, Kandasamy M, Klucken J, Aigner R, Burgmayer R, Couillard-Despres S, Riess O, Winkler J, Winner B (2009) Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. Eur J Neurosci, 29: 879-90

International Cooperation Prof. Dr. B.T. Hyman, Massachusetts General Hospital – MIND, Harvard University, Boston, USA Dr. M. Ingelsson, Rudbeck Laboratory, Uppsala University, Sweeden Dr. T.F. Outeiro, Institute for Molecular Medicine – Cellular and Molecular Neuroscience Unit, University of Lisbon, Portugal Prof. Dr. F. Gage, Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA Prof. Dr. E. Masliah, Department of Neurosciences, Univer- sity of California San Diego, California, USA

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 119 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Neurosurgery Chair of Neurosurgery University Hospital

Address Research CaSR are tested in vitro whether they can rescue Schwabachanlage 6 the molecular defect of the mutated CaSR. This 91054 Erlangen Neuroendocrinology potentially offers a therapeutic approach spe- Phone: +49 9131 8534566 The Department of Neurosurgery represents a cifically tailored to patient´s molecular CaSR de- Fax: +49 9131 8534476 nationally and internationally specialized cen- fect (individualized medicine). Further projects www.neurochirurgie.uk-erlangen.de tre for the whole spectrum of sellar patholo- investigate various aspects of growth-hormone Head of Department gies. Clinically we investigate the influence secreting human adenoma cells in vitro like the of interventional/operative, radiotherapeutic, expression of certain membrane receptors (e.g. Prof. Dr. med. Michael Buchfelder and pharmacological approaches on normal somatostatin receptors) and the characteristics Contact and hypersecretory pituitary gland function in of signalling cascades (cAMP- and Ca2+-PI-sig- Dr. med. Ilker Yasin Eyuepoglu the course of the “Acrostudy” (treatment and nalling pathway). The in vitro data are related Phone: +49 9131 8544756 MRI follow-up of the medicinal therapy with to various clinical data in order to extract po- Fax: +49 9131 8534569 Somavert). Also, investigations on Somatosta- tential prognostic factors concerning therapeu- [email protected] tin analoga and their clinical relevance in the tic outcome and to define potential new ther- treatment of growth hormone secreting pitu- apeutic targets. Research Focus itary adenoma represent a central part. Our • Neuroendocrinology clinical and laboratory chemical analysis and Neurooncology • Neurooncology screening studies are supported by Pfizer and Gliomas are the most common primary tu- • Functional neuronavigation and Novartis. The efficacy of novel intra-operative mours of the brain, and about 70% of these intraoperative imaging technologies in pituitary adenoma surgery and tumours are malignant gliomas. Currently, craniopharyngiomas are evaluated. Novel pro- there do not exist any promising therapy for cedures include endoscopic surgery such as en- the treatment of malignant tumours which tar- Structure of the Institution doscopic assisted microsurgery and intraopera- gets the high proliferation and diffuse brain in- tive MRI. These techniques allow the possibili- vasion. Therefore, investigation and character- The Department of Neurosurgery of the Uni- ty of control of resections in cases of intrasellar ization of the molecular mechanisms of glioma versity of Erlangen-Nürnberg is one of the larg- and suprasellar tumours. Goal of these clinical growth and invasion are essential steps in de- est in Germany. There are a total of 78 beds for long term studies is to define the relapse fre- veloping novel therapeutic strategies. The neu- inpatients, including ICU beds. The number of quencies of sellar tumours including different rooncology research group deals with the bi- outpatients is 4000 per year. Up to 2600 pa- prognostic factors. ology and therapy of brain tumors and could tients get inpatient treatment. Caseloads in- The field of Neuroendocrinology in the Depart- demonstrate that malignant gliomas secrete clude approximately 2200 major neurosurgical ment of Neurosurgery was established in 2007 high amounts of the neurotransmitter gluta- procedures per year. The range of operations in the framework of a foundation professor- mate, which results in neuronal cell death in covers the whole of neurosurgery with a focus ship for clinical and experimental neuroendo- the peritumoral brain parenchyma and induc- in the microsurgical treatment of processes of crinology. In cooperation with the Institute of es perifocal edema. These data correlate with a the skull base, particularly in the sellar region, Radiology body composition, liver and muscle reduced quality of life of patients suffering from in eloquent brain areas (e.g. central region, fat content are determined by MRI in patients malignant gliomas. Another focus of the group brain stem), the vascular neurosurgery, spine with various hypothalamic-pituitary diseases is to decipher the interaction of different brain surgery, pediatric neurosurgery and epilepsy (e.g. pituitary deficiency, acromegaly and M. cells and glioma proliferation. One candidate surgery. Aside of modern microsurgical tech- Cushing). The results are correlated with var- molecule for tumour-associated cell interaction niques, endoscopic procedure, intraoperative ious metabolic characteristics and with novel represents the protein MIF. This cytokine is se- electrophysiological monitoring, neuronaviga- parameters involved in the metabolic control. creted by glioma cells and interacts with the tion and intraoperative MRI are used. A molec- The aims of these studies are to obtain novel adjacent parenchyma. The aim of this project ular biological laboratory with an integrated insights in the neuroendocrine control of met- is the analysis of MIF effects on immune com- cell culture and a wide range of cellular and abolic and energetic processes. Another trans- petent cells in the brain such as microglial cells molecular biological methods are available for lational scientific project involves the function- and its role in glioma proliferation and invasion. basic scientific issues. al characterization of mutations of the metabo- Moreover, the preliminary data indicate that tropic calcium-sensing receptor (CaSR), that microglial cells participate at edema forma- occur in patients with specific disorders of cal- tion surrounding malignant gliomas. The pre- cium homeostasis. The CaSR is also expressed sented studies are funded by a grant from the in pituitary cells and in hypothalamic nuclei in- “Wilhelm Sander-Stiftung” and from the “Insti- volved in the control of endocrine systems. In tut Danone Ernaehrung fuer Gesundheit e.V.”. this project the patients are screened for clinical evidence of neuroendocrine dysfunction, and clinical and in-vitro data are correlated to define a potential genotype-phenotype relation. Furthermore, agonists and antagonists of the

120 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Functional neuronavigation and intraoperative imaging The reseach group “functional neuronavigation and intraoperative imaging” is divided into three subgroups that work in part independently. The common interface represents the BrainSuite, consisting of intraoperative 1.5 T MRI-scanner and integrated navigation: Operation according to state-of-the-art technology Subgroup I (Intraoperative imaging): A major Source: University Hospital Erlangen effort of this group is the acquisition of all parameters that are connected to intraoperative imaging of brain tumors and epilepsy-associated procedures. The analysis of these data is currently in progress. In addition the group Teaching Selected Publications worked on the visualization of important elo- Stadlbauer A, Nimsky C, Buslei R, Salomonowitz E, Hammen quent brain areas with the implementation of Aside of the neurosurgical main lecture with T, Buchfelder M, Moser E, Ernst-Stecken A, Ganslandt O diffusion-tensor-imaging, functional MRI and case demonstrations and live broadcasts from (2007) Diffusion tensor imaging and optimized fiber tracking in glioma patients: Histopathologic evaluation of tumor- magnetoencephalographie. Moreover studies the operating theatre, neurosurgical diseases invaded white matter structures. Neuroimage, 34: 949-56 of implementation of tractography data in the are also discussed in smaller groups. As part of Tanrikulu L, Hastreiter P, Troescher-Weber R, Buchfelder surgical treatment of brain stem lesions were the practical course students learn how to ex- M, Naraghi R (2007) Intraoperative three-dimensional completed. Two important studies analysed amine neurosurgical patients. Moreover, they visualization in microvascular decompression. J Neurosurg, the connectivity of eloquent brain areas with have the possibility to participate on clinical 107: 1137-43 different DTI algorithms using probabililistica routines such as examination of outpatients, Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky fiber tracking and investigated the amount of inpatients and visit the operating theatre. C, Fahlbusch R, Buchfelder M (2008) Operative treatment of prolactinomas: indications and results in a current con- susceptibility artefacts in linear registration of secutive series of 212 patients. Eur J Endocrinol, 158: 11-8 fiber tracts. Rus R, Haag C, Bumke-Vogt C, Baehr V, Mayr B, Moehlig Subgroup II (Functional imaging): This group M, Schulze E, Frank-Raue K, Raue F, Schoefl C (2008) Novel made correlative studies for cortical plastic- inactivating mutations of the calcium-sensing receptor: the ity after resection of gliomas. Also the con- calcimimetic NPS R-568 improves signal transduction of mutant receptors. J Clin Endocrinol Metab, 93: 4797-803 nectivity of receptive and expressive language areas were investigated with fMRI and DTI fol- Savaskan NE, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Ganslandt O, Nimsky C, Buchfelder M, Eyuepoglu IY (2008) lowing reports of other groups with electrical Small interfering RNA-mediated xCT silencing in gliomas stimulation. inhibits neurodegeneration and alleviates brain edema. Nat Subgroup III (Metabolic imaging): major ef- Med, 14: 629-32 forts were studies of metabolic imaging for the Stadlbauer A, Buchfelder M, Nimsky C, Saeger W, Salo- characterization of the infiltration of gliomas monowitz E, Pinker K, Richter G, Akutsu H, Ganslandt O (2008) Proton magnetic resonance spectroscopy in pitu- with proton MR spectroscopy and FET-PET (in itary macroadenomas: preliminary results. J Neurosurg, collaboration with the Department of Nuclear 109: 306-12 Medicine). Furthermore studies of the tumor International Cooperation invasion into fiber tracts and its influence on their reconstruction and neurologic symptoms Prof. Dr. David L. Kleinberg, Department of Endocrinology, New York University Langone Medical Centre, USA and studies of metabolic changes in temporal lobe lesions with 1H MR spectroscopy were in- Prof. Dr. Ting Lei, Department of Neurosurgery, Huazhong University of Science and Technology, Tongji Medical Col- vestigated. lege, Wuhan, China In the forthcoming period we intend to investigate the following topics: correlation of fluo- Research Equipment rescence-guided resection of malignant glio- Zeiss Opmi Pentero mas, utilizing five-aminolevulinic acid (5-ALA) BrainLab Neuronavigationssystem VectorVision Sky and intraoperative MR imaging, studies of cor- BrainLab Neuronavigationssystem VectorVision Square tical plasticity after glioma resection adjacent Siemens Intraoperative Kernspintomographie Sonata to eloquent brain areas and intraoperative MR Siemens Patientenmonitoring Intensivstation spectroscopy in gliomas. The presented studies are funded by a grant from the “Wilhelm BrainLab Stereotaktischer Linearbeschleuniger Novalis Sander-Stiftung”. 4D Neuroimaging Magnes II Biomagnetometer

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 121 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Department of Psychiatry and Psychotherapy Chair of Psychiatry and Psychotherapy

Address Dementia Competence Network Society and sis of dementias. By using our newly-devel- Schwabachanlage 6 plays a leading role with its diagnostic centre oped two-dimensional Western-immunoblot 91054 Erlangen focusing on early and differential diagnoses. method (2D-Aβ-WIB) a complex pattern of Phone: +49 9131 8534166 Other european and national projects investi- 30 distinct Aβ peptide species was detect- Fax: +49 9131 8534862 gating neurodegenerative diseases are indica- ed in human blood plasma. Similarly, in su- www.psychiatrie.uk-erlangen.de tive of our particular research expertise in this pernatants from human mononuclear phago- Head of Department area. Regarding research in addiction, our work cyte (MNP) cultures a complex signature of rein the field of nicotine and alcohol dependence leased A peptides was observed. To improve Prof. Dr. med. Johannes Kornhuber β is to be emphasised. In the FARS (Franconian al- our understanding of immunological process- Contact coholism research studies), different neurobio- es in age-dependent neurodegenerative dis- Dr. rer. nat. Heidi Joao logical problems were investigated on a large eases, current research focuses on the identifi- Phone: +49 9131 8534143 patient population. The results are promptly cation of cellular and signalling molecule pat- Fax: +49 9131 8534000 implemented in treatment, as is the case with terns which may serve as biomarkers of demen- [email protected] nicotine research, demonstrated in the offered tias. The studies were supported by grants from courses to give up smoking. The laboratory the German Federal Ministry of Education and Research Focus for clinical neurochemistry and neurochemi- Research – Dementia Competence Network, • Depression research cal dementia diagnostic, the national refer- NGFN2-SMP Proteomics, HUPO – and the Eu- • Research in dementia ence centre for the neurochemical dementia • Addiction research diagnostic in the frame work of the Dementia • Clinical neurochemistry Competence Network, is a part of the psychi- • Psychometric research atric core clinic. In addition, the laboratories • Health services research in psychiatry for molecular neurobiology and sensorics are part of the Clinic. The Clinic strives at an above-average teaching Structure of the Institution performance. The courses are regularly evaluated as particularly good by Erlangen‘s students. All the psychosocial professions are united Nationwide, the Erlanger medical psychology under one roof and fall under the organisa- and medical sociology students regularly hold tional umbrella of the Department of Psychiat- first place. ric and Psychotherapeutic Clinic, and include the independent Division of Psychosomatics “MAKS aktiv!” – training in motion, activities of daily liv- and Psychotherapy and the Division of Child Research ing and cognition for dementia patients and Adolescent Psychiatry and Psychothera- py, as well as the area of medicinal psychology Depression research and medicinal sociology. The content network In Depression research, the stimulation pro- ropean Union – cNEUPRO, neuroTAS – (total is supported via the common quality manage- cedures electroconvulsion therapy, repetitive amount: 800,000 Euro). ment system, as certified according to DIN EN transcranial magnetic stimulation and vagus ISO 9001:2000. nerve stimulation were evaluated for their clin- Addiction research We provide a qualified, interdisciplinary team, ical efficacy. Significant improvements over In the area of addiction, scientifically impor- which are involved with engagement and com- common treatment procedures were found in tant findings were obtained in not only neuro- petence in the patients’ convalescence, for the clinical treatment of therapy-resistant de- biological foundations (genetics, epigenetics, treatment in our department. The collabora- pressions. Moreover, the cognitive concepts fMRI, event-correlated potentials) but also in tion of doctors, nursing staff, psychologists, “rumination” and “worry” were differential- clinical, epidemiological and supply research. social pedagogues, occupational therapists and ly analyzed in depression, anxiety disorders The research interest focused on processes of physiotherapists ensures a sure and complete and the high rate of comorbid occurrence chemoperception, “liking” and “craving” for diagnostic and concerted treatment. Patient of depression and anxiety disorders to clari- addictive substances, the vulnerability to ad- treatment is conducted on an in-patient, day fy the model presentations in order to enable dictive substances and the effect of substance patient, as well as ambulatory basis. The vari- improvement in psychotherapeutic interven- use and withdrawal on epigenetic, neurotroph- ous stimulation methods present a special clini- tions. The cell-biological basis of depressive ic and neuroprotective control systems. Like- cal offer for the treatment of patients with de- disorders, especially intracellular lipid-associ- wise, clinical questions about the treatment of pression. ated signal transduction mechanisms was in- withdrawal and also new aspects of classifica- The research activities of the department are vestigated. tion were addressed. multifaceted with a broad diversity. Particularly The vulnerability concept of alcoholism was in- visible research projects have been developed Research in dementia vestigated with respect to neuropsychological, in the disease areas depression, addiction and In this area, research focuses on the improve- neurobiochemical influence factors and comor- dementia. The department is a member of the ment of the early and differential diagno- bidity according to the classfication of Lesch

122 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) type I-IV. Third-party fundings were used. Sci- Bavarian Research Foundation BFS. In addition, Learning. Evaluation regularly rates psychiatry entists in this research area received two ERAB a novel performance test, the E-ADL Test, was among the best clinical disciplines. Curriculum travel awards and one ECNP Fellowship Award. developed, validated and published interna- organization and evaluation are planned on a tionally. This test enables for the first time mea- scientific basis at a high professional level.O ur Clinical neurochemistry surement of everyday practical capabilities in medical education is accompanied by a didac- Clinical neurochemistry focuses on the search dementia patients. tic research group (Professor Weih, master of for novel cerebrospinal fluid (CSF) and blood/ medical education (MME)) and based on prin- plasma biomarkers for improved early- and dif- Health services research in psychiatry ciples of quality management. In addition, ferential diagnosis of the diseases of the ner- Health Services Research in Psychiatry has be- medical psychology and medical sociology vous system, with particular focus on neurode- come increasingly important, as investigation are offered as subjects in the preclinical phase generative conditions (like Alzheimer‘s disease). of the effectiveness and efficiency of diagnos- of medical studies and taken by 480 students The goal is their integration into routine ana- tic, therapeutic and support services for paper semester. Professor Graeßel, Head of the lytical procedures. Furthermore, we are work- tients is becoming more important. The IDA above-named area, received a teaching prize ing to improve the analytical performance of project, “Dementia Care Initiative in Prima- in the 2006/07 winter semester, based on stu- already available biomarkers of neurodegen- ry Care”, with a total budget of € 3,200,000 dent evaluation. In 2008, the average results eration (amyloid β-peptides, tau proteins), for is one of the largest clinical trials ever about of the written examination in these subjects in example by optimizing the standard operating the homecare of dementia patients. The con- the preliminary medical examination in Erlan- gen took first place nationwide.

Selected Publications Frieling H, Gozner A, Roemer KD, Lenz B, Boensch D, Wilhelm J, Hillemacher T, de Zwaan M, Kornhuber J, Bleich S (2007) Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry, 12: 229-30 Henkel AW, Dittrich PS, Groemer TW, Lemke EA, Klingauf J, Klafki HW, Lewczuk P, Esselmann H, Schwille P, Kornhuber J, Wiltfang J (2007) Immune complexes of auto-antibodies against A beta 1-42 peptides patrol cerebrospinal fluid of non-Alzheimer‘s patients. Mol Psychiatry, 12: 601-10 Frieling H, Bleich S, Otten J, Roemer KD, Kornhuber J, de Senile plaques, composed predominantly of amyloid beta peptides, and neurofibril- Zwaan M, Jacoby GE, Wilhelm J, Hillemacher T (2008) lary tangles with hyperphosphorylated Tau proteins: the two hallmarks of Alzheimer‘s Epigenetic downregulation of atrial natriuretic peptide but disease neuropathology not vasopressin mRNA expression in females with eating disorders is related to impulsivity. Neuropsychopharmacol- ogy, 33: 2605-9 Kornhuber J, Tripal P, Reichel M, Terfloth L, BleichS , Wiltfang procedures (SOPs) for collection and storage of trolled, randomised longitudinal study “MAKS J, Gulbins E (2008) Identification of new functional inhibitors relevant body fluids, and by their integration aktiv!” – motor function and cognitive and of acid sphingomyelinase using a structure-property-activity relation model. J Med Chem, 51: 219-37 into novel analytical platforms, like e.g. mul- mental training coupled with managing ev- tiplexing. In parallel, we have organized and eryday practical activities – is sponsored with- Lewczuk P, Kamrowski-Kruck H, Peters O, Heuser I, Jessen F, Popp J, Bürger K, Hampel H, Frölich L, Wolf S, Prinz B, Jahn maintain one of the world-wide largest proin the framework of “Leuchtturm Demenz” an H, Luckhaus C, Perneczky R, Hüll M, Schröder J, Kessler H, spective multicenter biobank of human body initiative supported by the German Ministry of Pantel J, Gertz HJ, Klafki HW, Kölsch H, Reulbach U, Essel- fluids from patients with early dementias. The Health. We identified a general central mech- mann H, Maler JM, Bibl M, Kornhuber J, Wiltfang J (2008) research is funded by the BMBF and the EU. anism increasing the age-dependent percep- Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer‘s disease: a tion of olfactory pleasure which can be used to multicenter study. Mol Psychiatry, 2008 Jul 29. DOI 10.1038 Psychometric research protect against malnutrition in advanced age. Graessel E, Viegas R, Stemmer R, Kuechly B, Kornhuber J, Therapeutic success, especially in typical Long-term catamnestic studies over 6 decades Donath C (2009) The Erlangen Test of Activities of Daily age-associated diseases, depends on how ef- in patients with chronic posttraumatic stress Living: first results on reliability and validity of a short per- ficient the methods are which scientifically disorders revealed a significant increase of late formance test to measure fundamental activities of daily living in dementia patients. Int Psychogeriatr, 21: 103-12 deal with the individual links in the treat- onset schizophrenias in women. ment chain “awareness-prevention-early diag- International Cooperation nosis-therapy-rehabilitation.” It appears pos- Prof. Dr. med. J. Leszek and Dr. M. Zboch, Alzheimer‘s sible to achieve considerable strengthening of Teaching Disease Diagnostic and Therapy Centre, University of this treatment chain by including psychologi- Wroclaw, Scinawa, Poland cal methods and using art objects as part of In the clinical phase of the curriculum, we Prof. Dr. Dr. Klaus R. Liedl, Centre for Molecular Biosciences, awareness concepts and screening methods offer a wide range of learning opportunities Leopold-Franzens-University Innsbruck, Austria for information transport. This is the approach like lectures, seminars, electives, clinical rota- Dr. med. Trine Brogaard, Forschungsbereich Allgemeinmed- izin, Universitaet Aarhus, Denmark of the “informArtik Project” sponsored by the tions, postgraduate education and blended E-

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Department of Psychiatry and Psychotherapy Division of Child and Adolescent Mental Health

Address Research the central nervous system (EEG, event-relat- Schwabachanlage 6 and 10 ed potentials), the autonomic nervous system 91054 Erlangen Neurophysiology in child and adolescent (heart rate variability, skin conductance), and Phone: +49 9131 8539122 psychiatry the behavioural level (eye movements, speech). Fax: +49 9131 8539126 Project manager: H. Heinrich A study with adolescents with anorexia nervo- www.kinderpsychiatrie.uk-erlangen.de The working group “Neurophysiology in child sa and healthy controls compares their respons- Head of Division and adolescent psychiatry” carries out neuro- es to emotion inducing pictures and movies as physiological studies addressing the interac- well as their attentional focus when viewing Prof. Dr. med. Gunther H. Moll tion of brain functions, experience and behav- body scheme pictures. Contact iour. These studies aim at a better understand- Prof. Dr. med. Gunther H. Moll ing of developmental processes and the neu- Neurobiology in child and adolescent Phone: +49 9131 8539122 robiological basis of emotional and behavioural psychiatry Fax: +49 9131 8539126 disorders as well as the mechanisms underlying Project manager: R. Dawirs [email protected] therapeutic interventions. The main research One main focus of the working group “Neu- topics are neurofeedback, inhibitory processes robiology in child and adolescent psychiatry” Research Focus in children with attention deficit/hyperactiv- comprises investigations of structural neuro- • Neurophysiology in child and adolescent ity disorder, and the interaction of cognition plasticity in various regions of the mammali- psychiatry and emotion. an brain focusing on the role of monoamine • Neurobiology in child and adolescent Neurofeedback: training effects on the behav- neurotransmitter systems in development and psychiatry ioural and neurophysiological level. In a large function of said various brain regions. The ap- randomised controlled trial that was conduct- pearance of monoamine systems in early deed in cooperation with the Child and Adoles- velopment suggests that they may play a key Structure of the Institution cent Psychiatry at the University Clinic of Göt- role in morphogenesis of the mammalian CNS, tingen and the Heckscher-Klinik in Munich the wherein during postnatal development critical The Division of Child and Adolescent Mental clinical effectiveness of a neurofeedback train- periods exist in which crucial events may de- Health at the Department of Psychiatry and ing in children with attention deficit/hyperac- termine the way of subsequent development of Psychotherapy is a self-contained division of tivity disorder (ADHD) could be demonstrated. the brain. Therefore, the fundamental mecha- the University Hospital. It is subdivided in the On the clinical level the neurofeedback training nisms of postnatal activity dependent structur- areas research, outpatient division/policlinic, led to a larger reduction of the ADHD symp- al and functional development of the brain and day hospital and inpatient division. Further- tomatology (medium effect size) compared to their lifelong impact on CNS functions need to more, in cooperation with the Fuerth City a conventional computerised attention train- be clarified in more detail. Hospital another child psychiatric day hospital ing. A further study with healthy adults exam- In one study with gerbils, it could be detected is operated and professionally directed by the ines the effects of different neurofeedback pro- that subchronic administration of oral methyl- head of the department. tocols on attentional processes, the motor sys- phenidate during adolescence prevented sup- Research is structured into two working groups tem and well-being. pressive development of dopamine projections (neurophysiology and neurobiology in child Inhibitory processes in children with ADHD: into prefrontal cortex and amygdala induced and adolescent psychiatry) that investigate the event-related potentials and transcranial mag- by methamphetamine. In a further study with pathophysiological background as well as the netic stimulation. We developed a method- gerbils, it could be detected that environmen- neurobiological basis of child and adolescent ological approach combining transcranial mag- tal enrichment during adolescence and admin- psychiatric disorders. netic stimulation and event-related potentials istration of oral methylphenidate had no ef- Clinical focus lies on: attention deficit/hyper- to study inhibitory processes in a differentiat- fect on the development of dopaminergic and activity disorder, emotional disorders in child- ed manner. This approach is applied to inves- GABAergic fibers in the prefrontal cortex and hood, depressive disorders, post-traumatic tigate the neurophyisological basis of ADHD amygdala. In still a further study with gerbils, stress disorders, eating disorders, psychic dis- and the mechanisms of the medication that is it could be detected that early methamphet- orders in childhood with comorbid obesity, most commonly used for this disorder (meth- amine application (postnatal day 14) and sub- obsessive-compulsive disorders, tic disorders, ylphenidate). sequent postweaning rearing conditions inter- autistic disorders. Interaction of cognition and emotion in chil- fered with development of peripheral stress pa- dren and adolescents with emotional, affective, rameters and neural growth factors. anxiety and eating disorders. In cooperation with the Chair of Pattern Recognition (Tech- nical Faculty) a psychophysiological working station was established that allows to measure several levels of investigation simultaneously:

124 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Teaching Selected Publications Grund T, Teuchert-Noodt G, Busche A, Neddens J, Brum- The teachings are composed of lectures, semi- melte S, Moll GH, Dawirs RR (2007) Administration of oral nars, tutorials and case presentations that com- methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex prise the clinical disorders of child and adoles- and amygdala after an early pharmacological challenge in cent psychiatry and its therapy as well as the gerbils. Brain Res, 1176C: 124-132 research methods applied in this field. Year- Heinrich H, Gevensleben H, Strehl U (2007) Annotation: round students of medicine, psychology, edu- neurofeedback – train your brain to train behaviour. J Child cation science, and social pedagogy are being Psychol Psychiatry, 48: 3-16 educated and supervised. Lehmann K, Rodriguez EG, Kratz O, Moll GH, Dawirs RR, Furthermore, it is possible to do an internship in Teuchert-Noodt G (2007) Early preweaning methamphetamine and postweaning rearing conditions interfere with all subdivisions of our department at any time. Neurofeedback the development of peripheral stress parameters and neural A boy controls a computer game (goalkeeper at a pen- growth factors in gerbils. Int J Neurosci, 117: 1621-38 alty kick) by modulating his brain electrical activity. The Brummelte S, Grund T, Moll GH, Teuchert-Noodt G, Dawirs training intends to help children with ADHD to improve RR (2008) Environmental enrichment has no effect on the attention and self-control. development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils. J Negat Results Biomed, 7: 2 Gevensleben H, Holl B, Albrecht B, Vogel C, Schlamp D, Kratz O, Studer P, Rothenberger A, Moll GH, Heinrich H (2009) Is neurofeedback an efficacious treatment for ADHD? A randomised controlled clinical trial. J Child Psychol Psychiatry, 50: 780-9 Kratz O, Diruf MS, Studer P, Gierow W, Buchmann J, Moll GH, Heinrich H (2009) Effects of methylphenidate on motor system excitability in a response inhibition task. Behav Brain Funct, 5: 12

International Cooperation Prof. Dr. D. Brandeis, Dr. R. Drechsler, Kinder- und Jugend- psychiatrie, Universitaet Zuerich, Switzerland Prof. J. Yordanova, Prof. V. Kolev, Institut fuer Physiologie, Bulgarische Akademie der Wissenschaften, Sofia, Bulgary Psychophysiological working station EU Projekt COST Action B27, Bruessel, Belgium A girl is viewing an emotion inducing picture on the monitor. Her brain electrical activity, heart rate, skin conductance, speech and eye movements are measured.

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Department of Psychiatry and Psychotherapy Division of Psychosomatics and Psychotherapy University Hospital

Address also in the second funding period (2010-2012). (psychopathology, eating behavior, quality of Schwabachanlage 6 The 4 large randomized multi-center psycho- life) and the assessment of predictors of post- 91054 Erlangen therapy studies of the first funding period will surgery weight loss. Phone: +49 9131 8534596 be finished at the end of 2010. In the second Fax: +49 9131 8534153 funding period a new randomized multi-center Psycho-oncology www.psychosomatik.uk-erlangen.de trial for the treatment of Binge-Eating-Disor- Project manager: H. Sinzinger Head of Division der will be conducted with Erlangen being the This research area focuses on the problems and study centre. The efficacy of an internet-based needs for support of careers of patients with Prof. Dr. med. Martina de Zwaan therapist-guided intervention will be compared cancer and on the evaluation of screening in- Contact with individual cognitive-behavioral therapy. struments for patients to assess the necessity of Heike Dahlem Besides the engagement in EDNET we have psycho-oncological care. Phone: +49 9131 8534596 conducted and published studies covering Fax: +49 9131 8534153 different areas in the field of eating disorders Excessive behaviors/behavioral [email protected] in part in collaboration with the Department addictions of Psychiatry and the Department of Internal Project manager: A. Mueller Research Focus Medicine 1. These include: the need for sup- If normal behavior becomes excessive, sense- • Eating disorders port of carers of patients with eating disorders, less, impulsive, escalating and is associated • Obesity night eating, studies on epigenetic regulation, with significant distress it can be called “be- • Psycho-oncology and structural neuroimaging in patients with havioral addiction”. For example, compulsive • Excessive behaviors/behavioral addictions anorexia nervosa focusing on DTI tractography. buying, pathological gambling, and excessive • Somatoform disorders internet usage may be considered typical be- Obesity havioral addictions. The maladaptive behav- Project manager: M. de Zwaan iors cause psychological, social, occupational, Structure of the Institution The PI coordinates the consortium on “Weight financial, and often legal problems. A random- loss maintenance” within the Competence ized trial comparing the efficacy of a disorder In total, 24 scientific staff are working in the Network Obesity which has been funded since specific group cognitive-behavioral therapy Department, of whom 3 are entirely funded August 2008 by the German Federal Ministry (CBT) designed for the treatment of compulsive through grants. The Department offers inpa- of Education and Research (BMBF). In addi- buying disorder to a waiting list control group tient, day-patient, and outpatient treatment tion, Prof. de Zwaan is deputy speaker of the was completed in 2008. Sixty patients (51 settings, as well as a psychosomatic liaison ser- Competence Network. The Division of Psycho- women, 9 men; age 20-61 yrs) with compulsive vice. The main clinical focus of the Department somatics and Psychotherapy in Erlangen will buying participated in the study. The standard- surrounds eating disorders. Other areas of ac- initiate the German Weight Control Registry ized outpatient treatment lasted 12 weeks with tivity include obesity, excessive behaviors with (GWCR) with the goal to determine and ex- one group session per week. The therapy spe- a special emphasis on pathological buying, so- amine factors that support better long-term cifically aimed at reducing the number of buy- matoform disorders, pain treatment, and psy- weight loss maintenance. This will lay the foun- ing episodes, at identifying and modifying cues cho-oncology. The treatment consists of a mul- dation for more focused treatments. The reg- and consequences for compulsive buying, at timodal and multidisciplinary evidence-based istry will include clinical samples as well as restructuring maladaptive thoughts, and feel- psychotherapy. On April 1st 2008 we hired Dr. volunteers from the general population who ings associated with shopping, and at estab- Alexandra Martin to fill our new faculty profes- have intentionally lost at least 10% of their ini- lishing healthy purchasing patterns. The CBT sorship in “Psychotherapy Research”. We will tial body weight and have kept it off at least 1 intervention resulted in a reduction of the com- be able to expand our research capabilities by year. All participants will be subsequently fol- pulsive buying behavior, and the improvement utilizing her expertise in somatoform disorders lowed annually. For data capture a participant- was maintained during 6-month follow-up. and biofeedback. centered approach with secure data entry di- Poorer attendance of the group therapy ses- rectly by the participants is planned and a re- sions and higher pretreatment hoarding traits quirement specification for enhancing existing were significant predictors for non-remission. Research remote data entry (RDE) systems to cover for such aspects will be produced by Prof. Prokosch Somatoform disorders Eating disorders and his team from the Institute of Medical In- Project manager: A. Martin Project manager: M. de Zwaan formatics at the University Erlangen-Nürnberg. The common feature of the somatoform disor- The PI coordinates the “Research consor- A long-term follow-up investigation of 150 con- ders is the presence of physical symptoms that tium on psychotherapy of eating disorders secutive patients with obesity grade 3 pre and cannot be fully explained by a general medi- (EDNET)” funded by the German Federal Min- 2 years post bariatric surgery will be finished cal condition, resulting in considerable impair- istry of Education and Research (BMBF). The at the end of 2009. The goals of the study are ment and suffering. Our research addresses ep- first 3-year funding period will end 2009; how- the examination of the long-term course of idemiology, diagnostic procedures, and etio- ever, the research consortium was successful psychosocial parameters after bariatric surgery logical aspects of somatoform disorders as well

126 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) as the development and evaluation of psychological treatment approaches. One of the current research projects is a longitudinal survey aiming at clarifying predictors of health care utilization and symptom persistence in somatoform disorders, and is conducted in cooperation with the Universities of Marburg and Leipzig (DFG grant to Rief, Brae- hler and Martin). Additional studies regarding unspecific chest pain and body dysmorphic disorder have been Competence Network Obesity, funded by the BMBF started in 2008: 1) Unspecific chest pain: More than 50 % of patients in cardiology are found to have no cardiac basis for their persisting chest pain. As a result patients often suffer from emotional distress and significant restrictions in daily life both leading to an increased health care utilization. Routine reassurance about normal test results often does not seem to be within the practical course the Division offers Selected Publications sufficient to prevent chronic manifestations in order to teach students basics aspects of a Mueller A, Mueller U, Albert P, Mertens C, Silbermann A, of chest pain; therefore a brief and early cog- professional doctor-patient-relationship. The Mitchell JE, de Zwaan M (2007) Hoarding in a compulsive nitive-behavioral intervention is developed Division also participates in several cross dis- buying sample. Behav Res Ther, 45: 2754-63 and evaluated in terms of pain characteris- cipline teaching efforts within the curriculum de Zwaan M, Hilbert A, Herpertz S, Zipfel S, Beutel M, tics, cognitive and physiological parameters of the medical school and also offers courses Gefeller O, Muehlhans B (2008) Weight Loss Maintenance in a Population-based Sample of German Adults. Obesity in patients with non-cardiac chest pain. In for psychology students. Medical students can (Silver Spring), 16: 2535-40 addition relevant cognitive factors are ex- chose psychosomatic medicine as a clinical Graap H, Bleich S, Herbst F, Trostmann Y, Wancata J, de amined in an experimental design to expand elective and as an internship during their final Zwaan M (2008) The needs of carers of patients with existing study results. year rotation. The Division also offers courses anorexia and bulimia nervosa. Eur Eat Disord Rev, 16: 21-9 2) Body dysmorphic disorder (BDD): BDD is for advanced training in psychotherapy for Mewes R, Rief W, Braehler E, Martin A, Glaesmer H (2008) characterized by excessive concerns about psychotherapist with a university degree in Lower decision threshold for doctor visits as a predictor of health care use in somatoform disorders and in the general and preoccupations with an imagined or psychology. population. Gen Hosp Psychiatry, 30: 349-55 minor defect in physical appearance which In the newly created study program Medical Mueller A, Mueller U, Silbermann A, Reinecker H, Bleich S, causes clinically significant distress or impair- process management the Division of Psycho- Mitchell JE, de Zwaan M (2008) A randomized, controlled ment in important areas of functioning. The somatics and Psychotherapy is responsible for trial of group cognitive-behavioral therapy for compulsive concerns can focus on general aspects of ap- a seminar on “communication and cooperation buying disorder: posttreatment and 6-month follow-up pearance or specific locations, e. g. skin, hair, aspects within the health care system”. results. J Clin Psychiatry, 69: 1131-8 nose, face shape, breasts. Often BDD is ac- Nestoriuc Y, Martin A, Rief W, Andrasik F (2008) Biofeedback treatment for headache disorders: a comprehensive efficacy companied by strong feelings of shame and review. Appl Psychophysiol Biofeedback, 33: 125-40 low self-esteem, compulsive checking behaviors (e.g. mirror checking), or attempts International Cooperation to hide the imagined defect (e.g. cosmetic Prof. Dr. J.E. Mitchell, Chairman and Professor of Psychiatry, camouflage). Dysfunctional cognitions are Neuropsychiatric Research Institute and University of North assumed to be important in maintaining the Dakota School of Medicine and Health Sciences, Fargo, USA disorder; therefore we aim to identify disor- Prof. Dr. Johannes Wancata, Klinische Abteilung fuer Sozi- alpsychiatrie und Evaluationsforschung, Universitaetsklinik der specific characteristics of BDD in com- fuer Psychiatrie, Medizinische Universitaet Wien, Austria parison with a clinical control group (eating disorders) and healthy controls. Meetings and International Training Courses 21.–24.03.2007: 58. Jahrestagung des Deutschen Kol- Teaching legiums fuer Psychosomatische Medizin (DKPM) und 15. Jahrestagung der Deutschen Gesellschaft fuer Psychoso- matische Medizin und Aerztliche Psychotherapie (DGPM), The Division is significantly involved in the cur- Erlangen-Nürnberg, DKPM und DGPM riculum of the medical school. We test new methods of instruction and teaching formats

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Department of Oral and Maxillofacial Surgery Chair of Dental, Oral and Maxillofacial Medicine – especially Oral and Maxillofacial Surgery

Address surgery, traumatology of the facial skeleton, es- serve nerval structures during surgery such as Glueckstrasse 11 thetic surgery as well as dental implantology. the nervus mandibularis during osteotomy of 91054 Erlangen the lower jaw. Phone: +49 9131 8533601 Biomedical technics Fax: +49 9131 8536288 Project manager: E. Nkenke, K. A. Schlegel Tumor research www.mkg-chirurgie.uk-erlangen.de The focus “biomedical technology” comprises Project manager: E. Nkenke Head of Department research projects on regeneration of soft and Research aims at improving function as well as hard tissues, intraoperative imaging, and laser facial esthetics following resection of tumours Prof. Dr. Dr. Friedrich W. Neukam applications. of the head and neck. In addition the identifi- Contact Bone substitutes promote formation of new cation of clinical, immunohistochemical, and Prof. Dr. Dr. Friedrich W. Neukam bone in pre-existing osseous defects by differ- molecular indicators of prognosis in patients Phone: +49 9131 8533601 ent biologic mechanisms including inflamma- diagnosed with oral squamous cell carcinoma Fax: +49 9131 8536288 tory and proliferative cellular reactions. As op- of the oral cavity is a prime focus. [email protected] posed to autogenous bone, the application of Resection of tumours of the oral cavity often anorganic bone substitutes results in a prolon- leads to an impairment of speech function. For Research Focus gation of the inflammatory phase. The project evaluation and analysis of different degrees of • Biomedical technics “biomimetic materials” funded by the German speech intelligibility an automatic and objec- • Tumor research Research Foundation (DFG) aims at creation, tive tool was developed in cooperation with • Infection and inflammation application, and evaluation of biomimetic ma- the Chair of Pattern Recognition (University of terials in an interdisciplinary approach includ- Erlangen-Nürnberg). The tool was applied in a ing the School of Sciences and the School of cohort of patients following resection of oral Structure of the Institution Engineering of the University of Erlangen- squamous cell carcinoma (grant by Wilhelm- Nürnberg. Modification of titanium surfaces Sander-Stiftung). Prospective follow-up will The Department of Oral and Maxillofacial Sur- (e.g. nano tubes) for adsorption of several cells yield insight into the degree of dependence gery is responsible for teaching oral and max- populations, poly-ether-ether-ketone (PEEK), as between speech disorders and tumor stage, lo- illofacial surgery including dental surgery and well as ceramic materials based on biodegrad- calization, and type of reconstruction. Further dental radiology, research, as well as patient able polysaccharide templates were applied in development of the technique will allow addi- care. Faculty includes twenty medical doctors/ in vitro and in vivo experiments. tional analysis of spectral and temporal charac- dentists and two biologists. Optical three-dimensional (3D) imaging has teristics of distorted phones. This will improve been validated for the assessment of the facial diagnostics of the individual speech disorder surface (former Collaborative Research Cen- and in the long run enhance therapeutic op- Research tre (SFB) 603). Using the principle of phase tions for these patients. measuring triangulation, volume changes fol- The tumour specific antigen MAGE-A is part of Research mainly focusses on biomedical tech- lowing craniofacial operations were measured the apoptotic pathway and capable of inducing nology, infection and inflammation as well as quantitatively and used to predict the result a humoral and cellular immune response. Cur- tumours of the head and neck. Topics of par- of surgical interventions. By fusing optical 3D rent research focusses on detection of tumour ticular interest are augmentation of osseous de- data with ultrasound measurements of tissue cells in histology and zytology as well as evalu- fects by transplantation of autogenous tissues thickness in patients undergoing maxillary ad- ation of the prognostic value of MAGE-A in pa- or vector transfected bone marrow stromal vancement, it could for example be shown tients undergoing resection and adjuvant ther- cells, the pathoetiology of osteonecrosis of the that maxillary advancement leads to a more apy for oral squamous cell carcinoma. Also the jaw as well as the evaluation of therapeutic op- pronounced shifting of the soft tissues in the association of phosphorylated AKT (pAKT) ex- tions in sites displaying compromised healing, malar-midfacial area than of the upper lip. The pression and radiation resistance as well as tu- and the identification of indicators of prognosis new parameters will help to assess normative mour specific outcome is currently being eval- in patients undergoing resection of oral squa- soft tissue data based on 3D imaging with a uated in a cohort of patients diagnosed with mous cell carcinoma view to an improved three-dimensional pre- squamous cell carcinoma of the head and neck. The research laboratory (S1-facility) of the diction of the operative outcome of orthog- Dept. of Oral and Maxillofacial Surgery allows nathic surgery. Infection and inflammation a wide range of immunohistochemical and mo- In cooperation with the Bavarian Laser Centre Project manager: E. Nkenke, K.A. Schlegel lecular biological techniques. For experimental a sensor-assisted laser system for selective bone Research adresses etiology, pathogenesis, and trials concerning bone histology and biomedi- ablation was tested in cadaver bone as well as therapeutic options in inflammatory reactions cal technology, a specialized facility is shared in an in vivo setting. By connecting the Er:YAG of the facial skeleton. Also the osseous regen- with the Dept. of Prosthodontics. laser to a process control for material-specific eration of bone defects in sites displaying com- Clinical focus is the surgery of malformations ablation, the system is able to differentiate cor- promised wound healing is being investigated. of the head/ neck and cleft lip palate in partic- tical and cancellous bone as well as soft tissues. A relevant focus is the bisphosphonate-associ- ular, oncologic and reconstructive surgery for In oral and maxillofacial surgery the selective ated osteonecrosis of the jaw (BONJ). tumours of the head and neck, orthognathic bone ablation offers a new perspective to pre-

128 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Nkenke E, Eitner S, Radespiel-Troeger M, Vairaktaris E, Neukam FW, Fenner M (2007) Patient-centred outcomes comparing transmucosal implant placement with an open approach in the maxilla: a prospective, non-randomized pilot study. Clin Oral Implants Res, 18: 197-203 Ries J, Toyoshima T, Neukam F, Wiltfang J, Nkenke E (2007) Expression pattern of MAGE gene families in oral squamous cell carcinoma: Identification of diagnostic markers and potential targets for immunotherapy. Oral Oncol, 2 Suppl. S: 184-185 Nkenke E, Vairaktaris E, Kramer M, Schlegel A, Holst A, Hirschfelder U, Wiltfang J, Neukam FW, Stamminger M (2008) Three-dimensional analysis of changes of the malar- midfacial region after LeFort I osteotomy and maxillary advancement. Oral Maxillofac Surg, 12: 5-12 Aseptic operations as a precondition for clinical research Ponader S, Vairaktaris E, Heinl P, Wilmowsky CV, Rottmair Source: University Hospital Erlangen A, Koerner C, Singer RF, Holst S, Schlegel KA, Neukam FW, Nkenke E (2008) Effects of topographical surface modifications of electron beam melted Ti-6Al-4V titanium on human fetal osteoblasts. J Biomed Mater Res A, 84: 1111-9 Schlegel A, Hamel J, Wichmann M, Eitner S (2008) Com- As BONJ is restricted to craniofacial bone struc- Teaching parative clinical results after implant placement in the posterior maxilla with and without sinus augmentation. Int tures, research focusses on jaw bone specif- J Oral Maxillofac Implants, 23: 289-98 ic signal transduction processes during devel- Oral and maxillofacial surgery is part of both von Wilmowsky C, Vairaktaris E, Pohle D, Rechtenwald T, opment, bone remodelling and disease. Cra- medical and dental curriculum. The Chair of Lutz R, Muenstedt H, Koller G, Schmidt M, Neukam FW, nial neural crest derived pluripotent progeni- Oral and Maxillofacial Surgery provides com- Schlegel KA, Nkenke E (2008) Effects of bioactive glass tor cells are of scientific and clinical interest in pulsory and elective courses for medical and and beta-TCP containing three-dimensional laser sintered polyetheretherketone composites on osteoblasts in vitro. J experimental approaches to develop regen- dental students during clinical education. In Biomed Mater Res A, 87: 896-902 eration strategies in craniofacial bone struc- clinical dentistry these involve oral and max- tures. In addition patient-related factors are illofacial surgery, dental surgery, and dental International Cooperation being evaluated which may promote onset radiology. Prof. Dr.Dr. Vairaktaris, Department of Oral and Maxillofacial and course of bisphosphonate-associated os- Traditional methods of teaching (lectures, lec- Surgery, University of Athens, Greece teonecrosis of the jaw. The outcome of surgi- tures with case demonstrations, practical train- Prof. Dr. K. Smetana, Institut fuer Anatomie, Universitaet cal therapy (i.e. osteotomy and primary wound ing for medical and dental students) are com- Prag, Czech Republic closure) was recorded in a prospective cohort pleted by problem based and interdisciplinary Dr. E. Felzshegy, Gerichtsmedizinisches Institut, Semmel- of patients. approaches. Topics of interdisciplinary educa- weiss-Universitaet Budapest, Hungary For modelling compromised osseous healing tion include among others emergency medi- Dr. U. Thams, Chair for Animal Pathology II, University of the clinical and histologic changes following cine, classes as part of the Graduate School in Complutense, Madrid, Spain high-dose irradiation were determined in an Advanced Optical Technologies (SAOT), and Research Equipment experimental trial. External hypofractionat- automated analysis of speech disorders in co- BrainLab, Heimstetten Neuronavigationsgeraet Vector ed irradiation with a total dose of 60 Gy was operation with the Chair of Pattern Recognition Vision II shown to be feasible in rats and yielded all his- of the Technical Faculty. tologic changes attributed to osteoradione- crosis after a follow-up of six weeks. The animal model is currently used for an assessment of regenerative options (e.g. implantation of BMP-2 transfected bone marrow stromal cells) in critical size defects.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 129 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Dental Department 1 - Operative Dentistry and Periodontology Chair of Dental, Oral and Maxillofacial Medicine – especially Operative Dentistry, Periodontology and Pediatric Dentistry

Address Research guide the peptide synthesis. Adhesive prop- Glueckstrasse 11 erties, behaviour and bonding effectiveness 91054 Erlangen Wear simulation on dental mastication to human collagen as well as to oxidic surfac- Phone: +49 9131 8533632 surfaces es will be investigated by analytic techniques, Fax: +49 9131 8533603 Project manager: U. Lohbauer fractography, high resolution microscopy and www.zahnerhaltung.uk-erlangen.de Dental filling materials in direct contact with quantitatively described in terms of microten- Head of Department the antagonist teeth suffer from a continuous sile bond strength measurements. wear process due to mastication. Wear can be Prof. Dr. med. dent. Anselm Petschelt categorized into direct interaction of two sur- Prospective clinical study on glassionomer- Contact faces (2-media abrasion: chewing simulation cements using the a.r.t. – technique PD Dr.-Ing. Ulrich Lohbauer (artificial mouth)) and further interaction by Project manager: J. Ebert Phone: +49 9131 8543740 an abrasive slurry (3-media-abrasion: tooth- Glass carbomer cement is taking advantage of Fax: +49 9131 8533603 brush abrasion, ACTA abrasion). Defined con- the improvement of mechanical values by in- [email protected] tact area between test material and human creased temperature and integrates the tooth enamel antagonists account for a standardized component hydroxylapatite into the material. Research Focus in-vitro testing in 2- or 3- media test setup. In the course of a prospective clinical study in • Wear simulation on dental mastication Worn volumina will be quantitatively analyzed close co-operation with our partner universi- surfaces under a confocal laser scanning microscope ty in Joinville / Brazil this innovative glassiono- • Development of peptide-based bioadhesives (CLSM) and qualitatively assessed under scan- mercement is to be examined in comparison to • Prospective clinical study on glassionomer- ning electron microscopy (SEM). This research the “gold standard” Fuji IX in proximal defects cements using the a.r.t. – technique project is focused on assessment of direct, re- within deciduous teeth using the “Atraumatic • Cyclic fatigue principles of resin composite storative dental materials with respect to three- restauration technique” (A.R.T.). The treatment restoratives body wear. phase of this study took place in spring of 2009. • Current problems in adhesive dentistry Evaluations are planned after 6 months and 1, • Restoration of endodotically treated teeth Development of peptide-based 2, and 3 years. using frc-posts bioadhesives • Dentoalveolar trauma Project manager: U. Lohbauer Cyclic fatigue principles of resin composite The aim of this joint research project with restoratives the University of Jena and the IFAM in Bre- Project manager: U. Lohbauer Structure of the Institution men is focused on the development of novel Modern restorative materials were developed bio-inspired nanohybrid adhesives for medical with a focus on amalgam like characteris- The Dental Department 1 – Operative Dentist- and dental applications based on decapeptide tics, excellent aesthetics and biocompatibili- ry and Periodontology – employs 50 staff mem- structures derived from the Mytilus edulis foot ty. These materials were improved for an ap- bers, thereof 6 professors and associate profes- protein 1 (Mefp-1, Fig.). Polymerspacers link plication in stress bearing areas. Therefore me- sors, 13 assistant professors, 19 dental nurses the Mefp-1 decapeptides to functionalised hy- chanical properties under masticatory load and and 4 dental technicians. The Dental Clinic 1 droxyapatite nanoparticles which in turn serve above all fatigue resistance are an important further hosts a Research Laboratory with 10 as centres of cohesion. Thus, chemical bind- property. Fatigue fractures after years in clini- Research Associates (3 by external funding). ing in addition to micromechanical anchorage cal use were found to be a common failure rea- The research is generally conducted by 3 clini- should be responsible for stronger adhesion to son. Damages of restorations like bulk, cusp, cally oriented and 1 dental materials, pre-clin- dentin. Insensibility to wetness is one big ad- or marginal fractures were reported frequent- ically oriented work groups. Eight post-doc- vantage of this kind of adhesives for extended ly. Fatigue in dental restoratives is influenced toral researchers, 55 dental post-graduate and dental indications. by corrosive water attack at a certain temper- graduate students and 5 technical assistants Central targets are the preparation and varia- ature (37°C) and by cyclic masticatory forces. are in charge of the manifold research activi- tion of peptide structures by solid phase pep- Contemporary approaches to fatigue princi- ties in the lab section. The main focus is based tide synthesis, the coupling of the peptides ples consider a fracture process in three phas- on dental materials research with fields of ex- to polymer spacers and onto functionalised es: crack initiation, slow crack growth and fast pertise in basic science of operative and peri- nanoparticles. Fundamental insight is expect- fracture. The latter phase is very short in dura- odontal treatment procedures and correlation ed by investigating the process of synthesis, the tion and thus the time of crack initiation and of experimental findings with clinical outcome. surface modifications of oxidic dental ceramics, of slow crack growth account for the useful fa- Independent, pre-clinical assessment of den- developing the funtionalisation of nanoparti- tigue resistance of a material. The purpose of tal materials is a further area of interest of the cles and controlling adhesive mechanisms on this work is to determine the strength of to- lab section. collagen scaffolds. Interactions between pep- day’s resin composite materials under fatigue tides, polymers and oxidic ceramics will be ex- conditions, simulating the clinical situation. amined using novel IR and VCD techniques. The methodology is developed considering Molecular simulation approaches will be ap- the findings on materials degradation above. plied to investigate adhesion mechanisms and

130 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Selected Publications Frankenberger R, Kramer N, Lohbauer U, Nikolaenko SA, Reich SM (2007) Marginal integrity: Is the clinical performance of bonded restorations predictable in vitro? J Adhes Dent, 9 Suppl. 1: 107-116 Muller FA, Gbureck U, Kasuga T, Mizutani Y, Barralet JE, Lohbauer U (2007) Whisker-reinforced calcium phosphate cements. J Am Ceram Soc, 90: 3694-3697 Roggendorf MJ, Ebert J, Petschelt A, Frankenberger R (2007) Influence of moisture on the apical seal of root canal fillings with five different types of sealer. J Endod, 33: 31-3 Lohbauer U, Kraemer N, Petschelt A, Frankenberger R (2008) Correlation of in vitro fatigue data and in vivo clinical performance of a glassceramic material. Dent Mater, 24: 39-44 Lohbauer U, Nikolaenko SA, Petschelt A, Frankenberger R (2008) Resin tags do not contribute to dentin adhesion in self-etching adhesives. J Adhes Dent, 10: 97-103 Adhesion of a mussel on Teflon via the Mytilus edulis foot protein Mefp-1 Thaler A, Ebert J, Petschelt A, Pelka M (2008) Influence of Source: Ingo Grunwald, IFAM. tooth age and root section on root dentine dye penetration. Int Endod J, 41: 1115-22

International Cooperation Prof. R. Braga, University of Sao Paulo (USP), Brasil Prof. G. Eliades, University of Athens (UOA), Greece Prof. J. Powers, University of Texas, Houston, USA Current problems in adhesive dentistry Dentoalveolar Trauma Prof. E. Schubert, University of Joinville (Univille), Brasil Project manager: R. Frankenberger Project manager: C. Berthold Prof. N. Baratieri, University of Santa Catarina, Florianopo- Major goal of the WGAD is a consequent in vitro Since 2002, in vitro and in vivo investiga- lis, Brasil and in vivo evaluation regarding adhesive po- tions involving diagnostics and therapy of PD Dr. S. Scherrer, University of Geneva, Switzerland tential of biomaterials, i.e. resin composites and dentoalveolar trauma were performed. The re- ceramics. It is our main interest to thoroughly search focussed specifically on the methods link preclinical and clinical investigations. Be- for tooth mobility measurement and investi- side a standardized portfolio of in vitro investigations about mechanical properties of dental gations, primarily prospective clinical trials are trauma splints. conducted. Central publications in this field were awarded with the Walkhoff Award of the German Association of Conservative Dentistry Teaching and the Research Award Full Ceramics of the Workgroup Ceramics in Germany. The main lectures of the Dental Department 1 focus on basic science in operative dentistry Restoration of endodotically and periodontology as well as on endodontol- treated teeth using frc-posts ogy and pediatric dentistry. In the specific lec- Project manager: C. Berthold tures, the most recent international scientific As a result of the research that took place be- opinions and trend are embedded and contro- tween the University of Texas Houston and the versially discussed. This of course, highly corre- University of Erlangen, since 2005, different sponding on own measured data and scientific biomaterial research aspects of bonding for outcome of the dental materials lab. fiber reinforced composite posts (FRC-posts), Next to the conventional lectures, the dental were investigated. These are used for restora- education is highly practical oriented. There- tion of endodontically treated teeth. In 2008, fore, the Dental Department 1 has established three young researches and the project leader practical blockseminars in the graduate cours- conducted studies at the UT Houston. es teaching endodontic treatment strategies Particular studies are third-party founded (7. Semester) and indirect inlay manufacturing (ELAN-fund of the university hospital, Staedler- skills (10. Semester). Students as well as doc- Foundation, Ilse and Dr. Alexander Mayer Foun- toral students are required to report in special dation, Fritz and Maria Hofmann-Foundation). seminars on recent scientific trends in restorative dentistry.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 131 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Dental Department 2 - Prosthetic Dentistry Chair of Dental, Oral and Maxillofacial Medicine – especially Prosthetic Dentistry University Hospital

Address Research Glueckstrasse 11 91054 Erlangen Biomechanical factors of implant retained Phone: +49 9131 8533604 superstructures Fax: +49 9131 8536781 Project manager: M. Karl www.prothetik.uk-erlangen.de Biomechanical factors greatly affect the long Head of Department term prognosis of implant supported restorations. Possible effects of non-passively fitting Prof. Dr. med. dent. Manfred Wichmann superstructures on restorations and peri-im- Contact plant bone are poorly understood. During the Klara Kroeppel report period, the structural integrity of ceram- Phone: +49 9131 8533604 ic-veneered implant restorations has been anal- STL-matching: Verification of scan precision Fax: +49 9131 8536781 ysed showing substantial predamage as a result [email protected] of static loading caused by superstructure fixation. Strain gauge measurements on CAD/CAM Research Focus fabricated fixed dental prostheses revealed that Dental CAD/CAM systems and high- • Biomechanical factors of implant retained computer aided manufacturing may lead to strength oxide ceramics superstructures significant improvements in the precision of fit Project manager: S. Holst, M. Karl, J. Schmitt • Evaluation of full-field three-dimensional as compared to conventionally fabricated res- Dental restorations generated with comput- optical inspection systems in dentistry torations. The obtained values are now being er aided design/computer aided manufactur- • Dental CAD/CAM systems and high- used for finite element analyses on the effect ing (CAD/CAM) are making a considerable im- strength oxide ceramics of different dimensional error types on strain pact in dentistry. Advantages related to mate- • Assessment of psychogenic influence on development. A randomized clinical trial has rial and manufacturing will promote the con- dental health and alternative treatment been set up to study the effects of static im- tinuous adoption of CAD/CAM systems over methods plant loading on bone adaptation. conventional casting techniques. The advantages CAD/CAM technology offers include: Evaluation of full-field three-dimensional standardized quality guaranteed by industrial Structure of the Institution optical inspection systems in dentistry fabrication methods, excellent precision of fit, Project manager: S. Holst, M. Goellner and outstanding biocompatibility, combined The Dental Department 2 is responsible for Quantitative assessment of biomechanical ef- with adequate mechanical strength and provi- teaching undergraduate students in several fects in vivo intraoral required highly complex sions for aesthetic design. The research group areas of fixed and removable prosthodontics, reaserch set-ups due to lack of adequate mea- focuses on assessment and analysis of various dental laboratory technology, occlusion and surement technology in the past. The aim of segments of industrial manufacture of current TMJ dysfunction, dental implants, CAD/CAM the research group is to establish and evalu- dental CAD/CAM systems. At the same time technology and ceramics, as well as maxillofa- ate full-field three-dimensional (3D) optical in- high strength oxide ceramics are applied more cial prosthodontics. The department is staffed spection systems for clinical application in bio- frequently as framework materials in dentist- with 21 full-time faculty with a wide range of mechanic research. The system will allow real ry. Several research projects assess the clini- expertise and a total of 50 employees. The de- time quantitative depiction of biomechanical cal application and factors influencing long- partment is involved in several areas of research influences in the oral cavity. 3D image correla- term success. including dental materials, biomechanics, den- tion provides strain measurements in all dimen- tal implants, and CAD/CAM technology. sions, which are critical for accurate strain and Assessment of psychogenic influence on Due to the high demands and quality stan- loading response measurements in objects. dental health and alternative treatment dards of research projects synergistic effects of The results of these optical measurements are methods highly qualified specialist is mandatory. This is compatible with finite element analysis soft- Project manager: S. Eitner reflected in the general orientation and a focus ware, and facilitate verification and iteration of Patients requests for so called “alternative treat- on future demands, as well as in extensive co- models that solely cannot be used to draw gen- ment methods” are ever increasing. However, operation with other fields of research. eral conclusions regarding specific questions there is very little sound research available at One key focus of research takes the ageing related to biomechanics. The system available the moment. No statistical data can be found population and the resulting demographic in the Dental Department 2 uses photogram- on the effectiveness of such methods. The changes into consideration and investigates metric principles. Relevant parameters for fu- area of research is divided in two main focal the relation between oral and general health. ture in vivo applications were identified in cur- points. One evaluates psychogenic influence, rent and completed studies and firstin vivo ap- one treatment planning and outcome of den- plications revealed promising results. tal disease patterns with a psychogenic back-

132 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Area of research biomechanics: 3-dimensional FEA-model based on µCt and construction data

ground. Amongst other factors are a subjects Selected Publications appraisal of his own body, or the aetiologic Eitner S, Wichmann M, Schlegel A, Holst S (2007) Clini- correlation of gag reflexes during dental treat- cal study on the correlation between psychogenic dental ment. Another focal point regards the thera- prosthesis incompatibility, oral stereognosis, and the psychologic diagnostic tools SCL-90-R and CES-D. Int J peutic intervention via acupuncture and hyp- Prosthodont, 20: 538-45 nosis in dental treatment and the influence of Holst S, Blatz MB, Bergler M, Goellner M, Wichmann M external stress factors on the anxiety and de- (2007) Influence of impression material and time on the pressive behaviour, as well as sociological fac- 3-dimensional accuracy of implant impressions. Quintes- tors of dental patients. sence Int, 38: 67-73 Karl M, Graef F, Taylor TD, Heckmann SM (2007) In vitro effect of load cycling on metal-ceramic cement- and screw- Teaching retained implant restorations. J Prosthet Dent, 97: 137-40 Nickenig HJ, Eitner S (2007) Reliability of implant placement after virtual planning of implant positions using cone beam The main focus of traditional prosthodontic ed- CT data and surgical (guide) templates. J Craniomaxillofac ucation will shift from a technically oriented to- Surg, 35: 207-11 wards an interdisciplinary treatment approach Holst S, Geiselhoeringer H, Wichmann M, Holst AI (2008) in the future. Prophylaxis and biology will be The effect of provisional restoration type on micromove- in the focus as well as minimally invasive treatment of implants. J Prosthet Dent, 100: 173-82 ment concepts. Clinically relevant topics will Karl M, Fischer H, Graef F, Wichmann MG, Taylor TD, Heck- mann SM (2008) Structural changes in ceramic veneered be introduced into the preclinical curriculum three-unit implant-supported restorations as a consequence focussing on biologic interactions and materi- of static and dynamic loading. Dent Mater, 24: 464-470 al properties. While theoretical knowledge remains integral part of dental education, man- International Cooperation ual manufacture of dental restoration will be Weber, HP, University of Harvard, Boston, USA taught exemplarily. Taylor, TD; Kelley JR, University of Connecticut, Farming- ton, USA Blatz, MB, University of Pennsylvania, USA

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 133 UNIVERSITYUNIVER HOSPITALSITY HOSPITAL

Dental Department 3 – Orthodontics and Orofacial Orthopedics Chair of Dental, Oral and Maxillofacial Medicine – especially Orofacial Orthopedics

Address ment and complex interdisciplinary problems. Glueckstrasse 11 We offer an extensive spectrum of international 91054 Erlangen accepted therapy-concepts and modern appli- Phone: +49 9131 8533643 ances for the respective age groups. Fax: +49 9131 8532055 The “Dental Department 3 - Orthodintics and www.kieferorthopaedie.uk-erlangen.de Orofacial Orthopedics” is authoritatively in- Head of Department volved in the Interdisciplinary Centre of Cleft Lip and Palate of the University of Erlangen- Prof. Dr. med. dent. Ursula Hirschfelder Nürnberg. In this interdisciplinary centre, ther- Contact apy concepts are continuously updated and ini- Dr. med. dent. Klaus Hertrich tiated by the team. Phone: +49 9131 8536779 Fax: +49 9131 8532055 [email protected] Research

Research Focus 3D-morphometrical evaluation of complex • 3D-morphometrical evaluation of complex craniofacial deformities craniofacial deformities Project manager: U. Hirschfelder, K. Hertrich • 3D-evaluation of orthodontic casts using the Volumetric CT-based 3D-data analysis In context of these scientific emphasis cranio- “fringe projection system” facial deformities and asymmetries are charac- • Cleft lip palates (CLP) terized by using modern imaging techniques • Evalutation of morpho-functional relations with respect to differential diagnostic typed to establish realistic computer-aided 3D meth- • Material-scientific investigations with application modern imaging procedures od for evaluating diagnostic orthodontic casts. • Quality based evaluation of orthodontic in craniofacial diagnostics. In context with the treatment therapy concepts application of a new CT software (Voxim®) Cleft lip palates (CLP) • Distractionosteogenesis available CT data are reevaluated. The possi- Project manager: U. Hirschfelder, A. Holst, K. • Investigation of biomechanical aspects of bility of three-dimensional measurements will Strobel-Schwarthoff orthodontic compontents arise new metrical possibilities concerning the In the framework of a long-term study a cur- face morphology in cases of craniofacial de- rent project is to evaluate the facial develop- formities. The anatomically based evaluation ment in cases with cleft lip palates also accord- Structure of the Institution of the facial skeleton is completed by applica- ing to secondary osteoplasty. A further project tion of the new VRT technique (Volume Ren- deals with a measurement system of the pneu- The Chair of Dental Department 3 is integrated dering technique) and the “Inspace Software matisation of the petrosus bone and the proz- in the department of dentistry since 2004 with program” in order to assess muscular and skel- essus mastoideus on the basis of computerto- regular rotation of the head of department etal parameters correlatively on the basis of CT mographic data in relation to the Division of every second year. data records. Phoniatrics and Pediatric Audiology. Further- All together, 27 employees are working in the Different subjects of this topic research area will more the result of a growth control study of Dental Department 3. The research is carried be evaluated by in actual thesis works using the the upper jaw development is evaluated in the out by 11 scientists and 22 doctorates. Techni- Voxim® software program. context to the early orthodontic therapy in ba- cal assistants are not available. bies with cleft lip palates using optical scanning The prime alignment of our research is the 3D- 3D-evaluation of orthodontic casts using method by the “fringe projection system” of evaluation of dentofacial anomalies with devel- the “fringe projection system” study casts and subsequent measurements of opment of practice near 3D-analysis methods. Initially the optical scanning method of diag- well defined 3D distances, angles and volumes Referring to this there are internal and external nostic study models will be applied in cases of of the jaws (detailed description of the proj- university cooperation’s. CLP patients by applicating an optical sensor ect, see above). Other research projects have their focus on based on coded illumination. The surface shape In a further project the dimension of the bony morphology orientated and interdisciplinary of the object is calculated according to the dis- cleft defect will be analysed metrically on the themes involving several disciplines of dentist- placement of the fringes. After data acquisition basis of CT data acquisition with the Voxim® ry and medicine. well definied 3D measurements are carried out software program. The clinical main emphasis is the orthodontic (3D distances, angles and volumes of anatom- treatment of patients of all age groups: babies ical areas) by using the Voxim® software pro- and small children with cleft lip palates and gram (Fa. IVS Solution, Chemnitz) in order to syndrome malformation, children and ado- analyse changes of the study casts threedimen- lescents with various tooth misalignment and sionally by means of high accuracy (resolution: jaw malpositions, also including craniofacial 175 μm, measurement error: 30 μm). It is also malformation and adults with tooth misalign- the aim of this scientific project to develop and

134 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 3D-CT-based localization of a dislocated upper right ca- CT-based craniofacial 3D-diagnosis nine (23) in relation to a virtual reference system

Evalutation of morpho-functional relations Investigation of biomechanical aspects of Selected Publications In context of a current project functional se- orthodontic compontents Greiner M, Greiner A, Hirschfelder U (2007) Variance of quences with the maxillo-facial complex are Another special research area is the investiga- landmarks in digital evaluations: comparison between evaluated by applications of sonographic and tion of biomechanical aspects of orthodon- CT-based and conventional digital lateral cephalometric radiographs. J Orofac Orthop, 68: 290-8 electromyography procedures and bite force tic components and their biocompatibility. In measurements. cooperation with the Institute of Mineralogy, Holst S, Hegenbarth EA, Schlegel KA, Holst AI (2007) Restoration of a nonrestorable central incisor using forced studies concerning the corrosive potential of orthodontic eruption, immediate implant placement, Material-scientific investigations metallic brackets were initiated. and an all-ceramic restoration: A clinical report. J Prosthet Project manager: U. Hirschfelder Additionally, correlations between biomechani- Dent, 98: 251-5 In the year 2004 the present scientific project cal characteristics of orthodontic mini-implants Lovrov S, Hertrich K, Hirschfelder U (2007) Enamel Demin- was dealing with the adhesive bond strength and bone-features are examined in coopera- eralization during Fixed Orthodontic Treatment – Incidence and Correlation to Various Oral-hygiene Parameters. J Orofac of different adhesive materials were tested, as tion with the Institute of Medical Physics and Orthop, 68: 353-363 well as the adhesive bond strength using dif- the Anatomical Institute, Chair II. Stec-Slonicz M, Szczepa?ska J, Hirschfelder U (2007) Com- ferent ceramic brackets. This project was pro- parison of caries prevalence in two populations of cleft moted by the industry. Within this framework patients. Cleft Palate Craniofac J, 44: 532-7 also the tooth surface was examined by using Teaching Holzmeier M, Schaubmayr M, Dasch W, Hirschfelder scanning electron microscopy. U (2008) A new generation of self-etching adhesives: In the year 2006 began a second present sci- Traditional teaching methods (curricular teach- comparison with traditional acid etch technique. J Orofac Orthop, 69: 78-93 entific project. Examination of the efficien- ing programs, patient-orientated preparatory Stauber I, Vairaktaris E, Holst A, Schuster M, Hirschfelder U, cy of GC Tooth Mousse to reduction and to and clinical courses and seminary’s, policlini- Neukam FW, Nkenke E (2008) Three-dimensional analysis of avoid to ‘White Spots’ during the orthodon- cal programs and optional teaching programs) facial symmetry in cleft lip and palate patients using optical tics treatment. are completed with interdisciplinary programs surface data. J Orofac Orthop, 69: 268-82 and psychosomatic-orientated teaching offers. Meetings and International Training Quality based evaluation of orthodontic Additionally, chair side-lectures are offered dur- Courses treatment therapy concepts ing the entire semester to allow the students to 19.–20.04.2007: Lingualtechnik – Dr. Wiechmann, Erlangen In the context of introduces quality manage- gain insight in the clinical practice. 08.–10.11.2007: Troubleshooting – Prof. Hasund, Erlangen ment system several studies are executed on Diagnostic material of selected cases (plaster the evaluation of orthodontic handling success models, photos and x-rays) is offered to the 01.01.–31.12.2007: Curriculare Weiterbildung zum Fachzahnarzt fuer Kieferorthopaedie – Erlangen with application internationally of valid indices. students for self-study. The development of a workable e-learning- 20.–22.11.2008: Klasse III – Behandlung – Prof. Hasund, Erlangen Distractionosteogenesis platform is in progress and will be explicitly In the context of a current research project supported. 01.01.–31.12.2008: Curriculare Weiterbildung zum Fachzahnarzt fuer Kieferorthopaedie – Erlangen long term studies are made on facial development of distraction osteogenesis of the mid- face and the mandible on the basis of lateral teleradiographs.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 135 DFG Collaborative Research Centres and Research Groups

Collaborative Research Centre (SFB) 423: Kidney injury: pathogenesis and regenerative mechanisms

Speaker (A2) deals with cell matrix interactions in the tify a novel, drugable therapeutic target for this Prof. Dr. med. Kai-Uwe Eckardt mesangium and in the renal tubular interstiti- serious disease, which can so far only be trea- um focusing on the special role of α8 integrin. ted with unspecific immunosuppression. The Address Project A12 is focusing on the regulation of the 8th project within this area (A18) deals with the Department of Medicine 4 - Nephrology and epithelial sodium channel (ENaC) in distal tu- analysis of syndromal diseases characterized by Hypertensiology bular cells and addresses mechanisms which congenital or infantile nephrosis. Using com- Loschgestrasse 8 are potentially relevant for the pathogenesis of plex genetic approaches, this project aims to 91054 Erlangen secondary hypertension in patients with kid- identify critical, pathogenetically relevant mo- Phone: +49 9131 8536259 ney disease. lecules that may also play an important role in Fax: +49 9131 85-39202 Two projects (A14, A16) deal with the regulati- noninheritable nephrotic diseases. [email protected] on and pathophysiological relevance of hypo- www.sfb423.uk-erlangen.de xia inducible gene expression mediated by HIF Section B: Mechanisms of progressive renal disease Section B focuses on complex mechanisms Aims and Structure that influence the progression of renal disease. These studies also aim to identify novel targets Acute and chronic kidney diseases play an infor intervention. Project B5 uses experiments creasing medical and health economic role in in transgenic animals and studies in humans to all parts of the world. In Germany approximate- assess endothelial dysfunction in the renal cir- ly 85.000 patients require chronic renal repla- culation and to determine the role of oxidative cement therapy in the form of dialysis or kid- stress for the progression of diabetic nephro- ney transplantation. In addition approximate- pathy. Project B6 deals with the functional re- ly 10 million people in Germany suffer from levance of Thrombospondin 1 and 2 in the re- less severe chronic kidney disease. In view of Fig. 1: Staining for Survivin in proximal tubular cells of gulation of chronic kidney disease and during the relevance of kidney disease and the insuf- the kidney under normal, physiological conditions (left) this funding period focuses on the impact of ficient knowledge about the pathophysiologic and following the application of the nephrotoxic drug these molecules on chronic allograft nephro- basis, the Collaborative Research Centre (SFB cisplantinum. While the protein is normally strictly loca- pathy. Two additional projects in this project lized to the brush border, it is distributed over the whole 423) was founded in 1999 under the leader- area study different modulators of inflamm- cytoplasm following injury. ship of Prof. R. B. Sterzel. In 2004, his successor atory processes. Project B12 deals with the Prof. Dr. K.-U. Eckardt became coordinator of functional relevance of renal afferent neurons the centre grant. Currently scientists from nine for mechanisms of inflammation and sclerosis clinics and institutes are collaborating in this transcription factors. Project A14 focuses on within the kidney. This project combines com- research centre at the University of Erlangen- studying the expression, regulation and func- plex neurophysiological investigations with the Nürnberg. The aim of the SFB 423 is to iden- tional relevance of HIF prolylhydroxylases, en- application of pharmacological modulators of tify mechanisms of tissue injury and regenera- zymes that are of the critical relevance for oxy- neurotransmitter release and function. Project tion of renal tissue with the long term goal to gen-dependent destabilization of HIF transcrip- B13 deals with effects of intrauterine growth develop novel diagnostic and therapeutic stra- tion factors. While one of the long term aims restriction and perinatal programming and tegies. The SFB 423 is the first and single colla- of this project is to validate the HIF pathway as reprogramming on the susceptibility towards borative research centre founded by the Ger- a potential novel target for nephroprotection, renal injury during subsequent development. man Research Foundation (DFG) and one of the project A16 deals with the adverse consequen- few research consortia in Europe, focusing on ces of HIF overexpression in renal cancer. Two The two Sections A and B are complemented kidney disease. Funding period: 1999 – 2010. genes that have been identified as being cons- by a third area, which includes an administra- titutively upregulated due to VHL loss of func- tive project and two core units that focus on tion in clear cell renal carcinoma and which methodological aspects. The goal of these core Research may play important roles in cancer progressi- units is to rationalize and structure the coope- on, are characterized in detail. Project A15 ana- ration between different projects in two im- Section A: Pathophysiology of renal cells lyzes the functional relevance of the antiapop- portant areas. Prof. Dr. K. Amann leads a core and initial mechanisms of renal injury totic protein Survivin in the kidney. A marked unit for quantitative structural analysis of kid- Section A encompasses 8 projects that focus on accumulation of this protein in the brush bor- ney injury and Prof. Dr. T. Winkler coordinates the pathophysiology and mechanisms of initial der of proximal tubular epithelial cells has first the development of genetically modified mice. injury of glomerular and tubular cells. The first been described during the preceding funding project (A1) analyses mechanisms of the initia- period (Fig. 1). tion of lupus nephritis, in particular the role of anti-DNA autoantibodies and how they bind Project A17 deals with the role of p38MAPK du- in the glomerulum and induce subsequent in- ring the development of rapid progressive glo- flammation and damage. The second project merulonephritis and thereby attempts to iden-

136 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Collaborative Research Centre (SFB) 466: Lymphoproliferation and Viral Immunodeficiency

Speaker Research on and the T cell response against HIV proteins. Prof. Dr. med. Bernhard Fleckenstein Further work is focused on the analysis of in- The SFB 466 deals with mechanisms of con- tracellular signal cascades that are controlling Address trol in lymphocyte activation and proliferati- the proliferative expansion and differentiation Institute of Virology – on, with the transformation by viral gene proin early B lymphoid cells under the control of Clinical and Molecular Virology ducts as well as apoptosis and destruction of the pre-B cell receptor and the analysis of sig- Schlossgarten 4 lymphatic cells. Lymphocyte activation and nal transduction from cytokine receptors and 91054 Erlangen destruction are largely following similar signa- signaling cascades in B lymphocytes. Phone: +49 9131 8523563 ling cascades. Thus, the SFB 466 finds its iden- Fax: +49 9131 8522101 tity in research projects on the molecular and Section C: Lymphocyte transformation and [email protected] cellular biology of pathogenesis in immunode- malignant progression www.viro.med.uni-erlangen.de/sfb466/ ficiency and leukemogenesis. This is aiming at The Section C consists of five subprojects and sfb466.htm a molecular understanding of the pathogenesis is oriented at molecular oncology. Two sub- in viral immunodeficiency and in the controlled projects are dealing with basic mechanisms of and autonomous proliferation of lymphocytes. transformation in T lymphocytes by the human Aims and Structure The SFB 466 contributes to understanding the T cell leukemia virus and signalling cascades in transformation of hematopoietic cells and the T cell transformation by retroviral oncoprote- The AIDS epidemy is threatening the world. An progression in tumors of the lymphatic system. ins. A further project investigates a rhadino- effective preventive vaccine would be requi- The SFB 466 is the sole German cooperative virus, the human Kaposi’s Sarcoma-associated red, but there is no sufficient biological basis German Research Foundation (DFG) project herpesvirus 8. Finally, a subproject investigates so far. Antiretroviral therapy made enormous that deals with the molecular biology of acqui- how Epstein-Barr-virus is persisting in B lym- progress during the past years. However, this red immunodeficiency. phocytes in the organism. is very expensive and remains dependent on comprehensive diagnostic therapy steering. A Section A: Structure and function of retro- health problem of this dimension requires more viral proteins fundamental research on virus replication and The Section A encompasses five subprojects on immunobiology. Research on the pathogene- structural and regulatory proteins of human sis of immunodeficiency relates in numerous as- immunodeficiency viruses. It deals with the pects to the basic problems of activation, dif- persistence of HIV under highly active anti-ret- ferentiation, growth control and destruction of roviral therapy. The projects try to understand the cells of the lymphatic system and other he- what cell compartments are containing the vi- matopoietic elements. Thus, immunodeficien- ruses and how the variability of HIV quasispe- cy research is closely interconnected with the cies develops. Further studies deal with the mo- mechanisms of oncogenic transformation by lecular structure and function of the viral po- viral gene products and cellular oncogenes in lyprotein Pr55Gag and its functions for matu- the hematopoietic system. The program of the ration of the human immunodeficiency viruses SFB 466 is oriented towards the basic problems and the interaction of HIV with the native im- relevant for pathogenesis at an intersection of mune system, as well as the role of Dendritic cell biology. The SFB 466 consists of research Cells (DC) in pathogenesis for mechanisms of groups of the Medical Faculty and the Depart- immune evasion in immunodeficiency viruses. ment of Biology in the University of Erlangen- The Junior Research Group investigates the role Nürnberg as well as structural biologists of the of DC in pathogenicity. The lectin DC-SIGN ap- University of Bayreuth. It includes the junior pears relevant for the DC-mediated transmis- research group of PD Dr. Stefan Poehlmann, sion of HIV. whose laboratory was localized in the Nikolaus- Fiebiger-Research Centre until March 2008. Section B: Signaling cascades in T cell acti- Funding period: 1996 – 2008. vation and destruction The Section B consists of six individual projects that are dealing with signal transduction in hematopoietic cells and investigating activation and destruction in hematopoietic cells. One subproject investigates multiprotein complexes that are formed with NFAT transcription factors in lymphoid cells, and further projects are investigating the function of the soluble CD83 protein that influencesT cell activati-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 137 DFG Collaborative Research Centres and Research Groups

Collaborative Research Centre (SFB) 473: Switch Processes of Transcription

Speaker Research this transcriptional switch. These projects have Prof. Dr. rer. nat. Wolfgang Hillen in common that more or less complicated sig- The interdisciplinary SFB integrates a wide nalling pathways, related to the physiological Address range of biological and medical problems in state of the cell or the cell cycle transfer their Chair of Microbiology, Department Biology various organisms. The study of different orga- signals to transcription factors. The molecular Faculty of Natural Science nisms has proven to be very fruitful, because details of these events are the subject of this Staudtstrasse 5 the regulatory mechanisms themselves are research area. 91058 Erlangen quite similar, while their cell specificity main- Phone: +49 9131 8528081 ly results from their participation in individual Section D: Transcription factors in Fax: +49 9131 8528082 communication patterns operating in the res- differentiation [email protected] pective organisms. The individual projects pro- The projects grouped in this section have the www.biologie.uni-erlangen.de/mibi/sfb fit from the exchange of mechanistic principles goal to molecularly understand transcripti- and the large variety of methods in integrating on factors involved in cell differentiation. The similar regulatory mechanisms into their par- projects deal with differentiation in mammali- Aims and Structure ticular cellular activities. This has led to many an systems and study the MLL/ENL oncopro- new insights for each project. The SFB is subdi- tein in haematopoiesis and leukemia, the GCM Transcription factors are the central regulators vided into three research topics. protein in embryonic development and human of gene expression and play essential roles in disease and the Sox-8 transcription factor in the biology of all organisms including humans Section B: Modulation and interaction of mesodermal differentiation. Additional em- and, thus, are also relevant for human disease. transcriptional regulators phasis is placed on changes of DNA topology Transcription factors represent the main topic This section combines research strategies as a means of transcription factor function and of the SFB 473 “Mechanisms of Transcriptional dealing with the molecular analysis of transcrip- transcriptional control, and on snoRNA-depen- Regulation“, which is funded since 1997 and re- tional switch proteins. The switches can either dent alternative splicing as a further regulatory presents a scientific conglomerate of 13 groups be triggered by covalent modification or chan- mechanism of gene expression with important from the Faculty of Natural Science and the Fa- ges of localization of viral transcription fac- implications for human disease. culty of Medicine. tors, or an allosterical conformational change In the SFB 473, structural, biochemical and in case of the Tet repressor. The combination theoretical approaches are used to characteri- of bacterial and human regulators is reasona- Teaching ze regulatory proteins in transcription, as well ble because Tet repressor is widely used to re- as their effectors, mechanisms of regulation, gulate genes in nearly all organisms. Tetracyc- All groups of the SFB participate in curricular and their integration into signalling chains. line dependent gene regulation is one of the teaching activities. Over the years they have The regulatory proteins of interest are derived most intensely studied and best understood provided an attractive environment for Diplo- from bacteria, plants and mammals, and are transcriptional regulatory systems. Therefore, ma, Master, MD and PhD theses, and continue either transcription factors or sensors of pro- it has paradigmatic character for transcriptio- to do so. Joint teaching efforts include a week- teins processing information to be passed on nal switches. In addition, the results may also ly seminar series, a guest scientist program and to transcription factors in response to the phy- contribute to the understanding of more fun- biannual international symposia with leading siological state of the cell, the presence or ab- damental properties of proteins in general, like scientists in transcriptional research. sence of hormones or nutrients outside the cell, the plasticity of effector binding sites, the dy- or communication with other cells. namics and conformational changes of allos- Funding period: 1997 – 2009 terical proteins, and protein-protein recognition. We address this problem in a collaborative effort, combining applied and theoretical chemistry with molecular genetics.

Section C: Signalling pathways to transcriptional regulatory proteins The transcription factors studied in these projects have their coupling to signalling pathways in common, so that their switching reaction is dependent on a number of signalling proteins. Molecular genetic and theoretical aspects of signalling are cooperatively studied to elucidate catabolite repression in Gram-positive bacteria, nitrogen metabolism in Corynebac- teria and the role of ß-catenin in tumorigenesis, lending substantial medical importance to

138 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Collaborative Research Centre (SFB) 539: Glaucomas including Pseudoexfoliation Syndrome

Speaker nical practice (e.g. Spectral domain OCT, FDT were further improved by novel approaches of Prof. Dr. med. Elke Lütjen-Drecoll perimetry) or have even been developed into computerized learning, mathematic modeling, commercially available instruments (e.g. Erlan- and strategies of classification. Finally, the cli- Address ger flicker test, RETI-Port). The combination of nical data collected from more than 1500 pati- Anatomical Institute II telemedicine and methods of automated patents since 1991 were adjusted and coordinated Universitätsstrasse 19 tern recognition have enabled the systematic into a unique glaucoma registry by creation of 91054 Erlangen screening of a large number of individuals for networked and integrated IT systems in order Phone: +49 9131 8522864 a population-based early glaucoma detection. to improve both health care and research acti- Fax: +49 9131 8522862 Basic research projects have analyzed the mole- vities, particularly the evaluation of the prog- [email protected] cular pathomechanisms of retinal ganglion cell nostic and predictive value of diagnostic pro- www.anatomie2.med.uni-erlangen.de death, e.g. receptor mechanisms of neurotoxic cedures in long-term analyses. processes, mechanisms of oxidative cell damage, ion transport mechanisms, and alterations Aims and Structure in gene and protein expression of glaucoma- Teaching tous ganglion cells. Glaucomas are chronic neurodegenerative di- The study groups of the SFB 539 are involved in seases which, if untreated, lead to blindness by Section B: Pathogenetic factors the training of doctoral students in medicine, a progressive irreversible loss of retinal gangli- Projects in this section aim at the investigation molecular medicine, natural science and tech- on cells and optic nerve axons. The Research of multifactorial pathogenetic factors contribu- nical science. Supervision of doctoral theses Centre, which has been funded by the German ting to glaucoma development, particularly reis in part integrated into the graduate school Research Foundation (DFG) since 1997, integ- garding the ocular outflow pathways and ocu- “Advanced Optical Technologies”. In addition, rates one clinical department (Department of lar microcirculation. Analyses of human glauco- the principal investigators participate in lectu- Ophthalmology) and five clinical-theoretical ma eyes, in vitro models and established mouse res for students of different fields of study (me- institutions (Anatomical Institute II, Institute of models lead to the identification of crucial mo- dicine, biology, engineering), in the research- Biochemistry, Institute of Human Genetics, In- lecular pathomechanisms of intraocular pres- oriented study course of molecular medicine, stitute of Experimental and Clinical Pharmaco- sure rise, including extracellular matrix compo- and in the mentoring program ARIADNEmed logy and Toxicology, Institute of Medical Infor- nents, growth factors, oxidative stress, immune for young female scientists. matics, Biometry and Epidemiology) of the Me- mechanisms, and COX-2-regulated prostaglan- dical Faculty, the Institute of Animal Physiology dins and matrix metalloproteinases. The mole- of the Faculty of Natural Science, and the Chair cular analysis of pseudoexfoliation syndrome, of Computer Science 5 of the Technical Faculty. a generalized disorder of the extracellular ma- The SFB 539 represents the only Research Cen- trix and frequent cause of glaucoma, yielded a tre in Ophthalmology. conclusive and generally accepted pathogene- The focus of the Research Centre lies on the tic concept of a stress-induced elastosis. Chan- methodological improvement of early diagno- ges in various intraocular vascular beds inclu- sis and follow-up monitoring of chronic glau- ding their accompanying innervation were ana- comas as well as on the analysis of etiologic lyzed in glaucomatous donor eyes and animal and pathogenetic factors contributing to the models by using morphologic methods. Taken multifactorial causes and structural damage in together, the studies identified various disease- order to identify targets for novel therapeutic related target molecules providing the basis approaches. for further translational research projects, pre- Funding period: 1997 – 2009. clinical and clinical trials, and novel therapeutic approaches.

Research Section C: Clinical biometry and genetic analyses Section A: Glaucomatous damage of optic This section comprises both, the analysis of nerve and retina genetic factors for glaucoma and the medical- This section deals with the structural and func- bioinformatic integration, processing and ana- tional glaucomatous damage of the sensory lysis of clinical data. The identification of novel retina and optic nerve head. It comprises pro- glaucoma genes by means of genetic linkage jects developing and evaluating novel diag- and genome-wide association studies allowed nostic tools for the detection of early structural new insights into the etiology and pathoge- changes and functional deficits.T he most spe- nesis of glaucomas. Instructed planning and cific and sensitive imaging methods and phy- evaluation of clinical-epidemiologic studies as siological tests have been implemented in cli- well as the statistical analysis of research data

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 139 DFG Collaborative Research Centres and Research Groups

Collaborative Research Centre (SFB) 603: Model-Based Analysis and Visualization of Complex Scenes and Sensor Data

Speaker Research Prof. Dr. Ing. Günther Greiner This research centre aims to develop an uni- Address form and practically approved methodology Chair of Computer Graphics for analysis and design of information proces- Faculty of Engineering Sciences sing systems which interprete and visualize pic- Am Weichselgarten tures, sensor data, and scene descriptions of 91058 Erlangen realistic complexity. Application examples will Phone: +49 9131 8529199 be taken from medicine and engineering sys- Fax: +49 9131 8529131 tems which autonomously recognize, analy- [email protected] ze, model, track in motion or use in a simulati- www9.informatik.uni-erlangen.de on real objects and relations between objects have to meet high requirements. Innovative solutions of corresponding problems should be applicable for image analysis and computer Aims and Structure graphics. Central topics of long term research programs are model based approaches, opti- Participating institutions from the Faculty of mization procedures, resolution hierachies and Engineering Sciences: Chair of Pattern Reco- fusion of sensor data. Models for time invariant gnition, Chair of Computer Graphics, Chair of 3D-surfaces, for time variable 3D-surfaces, and Manufacturing Technology, Chair of Flow Me- for volumes and structures of higher dimensi- chanics, Chair of Quality Management and on will be investigated in three project fields. Production Measurement Technology, Chair of Sensorics. Participating institutions from the Faculty of Natural Science: Chair of Optics. Participating institutions from the Faculty of Medicine: Department of Oral and Maxillofa- cial Surgery, Division of Phoniatrics and Paedi- atric Audiology. Funding period: 1998 – 2007.

140 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Forschungsbericht SFB 643: Sprecher: Stellvertr. Sprecher: Prof. Dr. med. Univ. Gerold Schuler Prof. Dr. Alexander Steinkasserer Anschrift: Hartmannstraße 14 91052 Erlangen Tel.: +49-9131-85-33819 Fax: +49-9131-85-33701 E-Mail Kontakt: [email protected] http://www.sfb643.uk-erlangen.de

Aufgaben und Struktur: Der SFB 643 „Strategien der zellulären Immunintervention“ besteht seit Juli 2004 und befindet sich zurzeit in der zweiten Förderperiode. Das gemeinsame langfristige Forschungsziel ist die erfolgreiche Umsetzung immunologischen Wissens in Behandlungsverfahren, die auf einer Manipulation des Immunsystems, d.h. auf Immunintervention beruhen. Die Umsetzung von Ergebnissen der immunologischen Grundlagen- und präklinischen Forschung in die Klinik ist von beträchtlicher sozialer und ökonomischer Bedeutung. Immunologische Mechanismen spielen bei vielen Erkrankungen eine zentrale Rolle. Sie stellen einen Ansatzpunkt zur Entwicklung neuer Therapien von Krebs, entzündlichen und Autoimmunerkrankungen dar, die sicherer, effektiver und billiger sein werden als die zurzeit zur Verfügung stehenden Strategien. Das Forschungsprogramm umfasst drei stark vernetzte Schwerpunkte: A) die Immunologischen Grundlagen, B) die DFG Collaborative Research CentreImmuninterventions and Research Gr imoup Tiermodells und C) die therapeutische Applikation im Menschen. Forschung: In Folge werden repräsentativ einige Projekte kurz dargestellt. Im Teilprojekt von Prof. U. Collaborative ResearchSchubert Centre wird die Bedeutung (SFB) des Ubiquitin-Proteas643: om-Sytems (UPS) für die Präsentation von antigenen Peptiden über den Major Histocompatibility Complex Class I (MHC-I)-Pathway Strategies of Cellularuntersucht. Immune Intervention Frau Prof. D. Dudziak entwickelt in ihrem Teilprojekt neue Strategien zur Antigenbeladung von Dendritischen Zellen (DZ). Diese Untersuchungen sollen wichtige Erkenntnisse für das Verständnis von DZ-Subpopulationen im humanen Gewebe sowie für neue Möglichkeiten in der Tumor-Therapie beim Menschen aufzeigen. Im Teilprojekt von Herrn Prof. F. NimmerjahnDas Teilprojekt stehen von Prof.Antikörper T. Winkler im und Mittelpunkt. Prof. M. Mach Diese beschäftigt sind sich mit dem Speaker against invading pathogens and show promi- ed a very interesting therapeutic potential and Prof. Dr. med. Gerold Schuler singein resultsessentieller in the therapy Bestandteil of human des tumors. körpereigenen suppressedadoptiver Zelltransfer paralysisVerteidigungssystems associated von Gedächtnis with experi gegenB-Lymphozyten- eingedrungene als ein neues Zelltherapeutikum bei Inpathogene depth knowledge Mikroorganismen about the cell types und in ze- igenmentalInfektionen viel autoimmune versprechende mit Zytomegalievirus encephalomyelitis Resu ltate(CMV) (EAE), in nach der Transplantation.Tumortherapie. Ein wesentliches Ziel der volved in phagocytosis and ADCC reactions whichTransplantationsmedizin is an animal model for ist, human das Immunsyste Multip- m im Kampf gegen das Virus zu unterstützen. Die Zelltypen welche hierbei die entscheiUm diedende humorale Rolle Immunität spielen, der sollen Patienten unter zu Verwendungstärken, werden vonhierbei neuartige zell-basierte Address inin vivo vivo is theModellsystemen basis for the generation näher of novelcharakterisiert le Sklerosis, weandrden. in transplant Als Modellsystem studies in muri- für die Antikörper- Hartmannstrasse 14 therapeutic strategies aiming at modulating neTherapieformen models. This represents untersucht. the basis Im Tierexperiment for further konnte gezeigt werden, dass Gedächtnis B- 91052 Erlangen thesevermittelte reactions. Zytotoxizität wird ein MelanompreclinicalLymphozytena-Tumormodell and clinical das Virus developments. sehr verwendet schnell kontrollieren (siehe Abb. können 1). (siehe Abb.2). Dies stellt die Basis Phone: +49 9131 8533819 zur Umsetzung dieser Strategie im Menschen dar. Fax: +49 9131 8533701 [email protected] TA99 www.sfb643.uk-erlangen.de I IgG2a g IgG IgG G2b

Aims and Structure

The SFB 643 “Strategies of cellular immune intervention” exists since July 2004 and is cur- Fig. 2: Memory B lymphozytes are able to protect rently in its second funding round. The goal of immunoAbbildung deficient 2. Gedächtnis mices against B-Lymphozyten CMV infection können immundefiziente Mäuse vor einer CMV Infektion schützen (in vivo Biolumineszenz-Analysen). the research centre is the successful implemen- Fig. 1: Pulmonary metastasis in mices after injection of tation of immunological knowledge in treat- melanomaAbbildung cells, which 1. Gezeigt were treated sind with different Lungenmetastasen versi- von Mäusen nach Injektion von Melanomzellen, die mit ments that are based on a manipulation of the onsverschiedenen of the therapeutic Varianten antibody TA99 eines therapeutischenIm Antikörpers Teilprojekt von(TA99) Prof. behandelt L. Nitschke wurden. werden neu entwickelte Liganden-Analoga für CD22, immune system, i.e. on immune intervention. einem mit dem B-Zellrezeptor assoziierten inhibitorischen Ko-Rezeptor, im Hinblick auf eine Immune therapeutic approaches to treat tu- therapeutische Manipulation von B-Zellen, untersucht. CD22 spielt wahrscheinlich beim mors and infectious diseases require the enhan- „homing“ von zirkulierenden B-Zellen und Plasmazellen ins Knochenmark eine wichtige cement or stimulation of the immune response. The project of Prof. T. Winkler and Prof. M. TRolle.he aim Die of theBlockade project des conducted „homings“ by PDwird Dr. als neuer Therapieansatz für das Multiple Myelom Conversely, innovative treatments of inflamm- Mach is concentrating on the adoptive trans- B.exploriert. Schuler-T hurner, Dr. N. Schaft and Prof. G. atory diseases, including autoimmune diseases, fer of memory B cells as a new cell based the- SImchuler Teilprojekt is the development von Frau Dr. of newE. Zinser and inno und- Herrn Prof. A. Steinkasserer steht das allergic diseases and transplantation reactions rapy for infection with Cytomegalovirus after vativeimmunmodulatorische immunotherapies basedPotential on DCsdes löslichen espe- CD83-Moleküls im Mittelpunkt. Dieses Molekül call for novel and improved immunosuppres- transplantation. Support of the patient’s im- ciallyist in for der the Lage treatment die Lähmungserschei of patients with cancernungen der Experimentellen-Autoimmun- sive strategies. The research program is con- mune defense against the virus is a major goal (melanomaEnzephalomyelitis, as a prime (= model).Modell Sfüreveral die clinihumane- Multiple Sklerose) effizient zu hemmen und die ceptually structured in three closely intercon- in transplantation medicine. Memory B cell calAbstoßungsreaktion phase I-trials have already von Transplantaten been conducted deutlich zu verringern. Diese Befunde stellen die Basis nected project areas: A) basic immunology B) transfer provided long-term protection from usingfür die peptide-loaded weitere präklinische DC and now und an klinische additio- Entwicklung dar. immune intervention in animal models and C) the lethal course of the infection that is invaria- nalZiel clinical des Projekts study using von DCs Frau which PD Dr.have B. been Schuler-Thurner, Herrn Dr. N. Schaft und Herrn Prof. therapeutic applications. bly seen in immunodeficient animals.T he data electroporatedG. Schuler ist with die defined Entwicklung RNAs encoding und klinische Prüfung innovativer immunologischer Funding period: since 2004. provide evidence that a cell based strategy to theTherapieansätze tumor associated insbes. antigens zur MAGE-3, Behandlung Me- maligner Tumoren mittels modifizierter, autologer support the humoral immune response can be lanADZ. and Es Survivin wurden has bereits been initiated. mehrere In addi klinische- Phase I Studien mit Peptid-beladenen DZ effective to combat infectious pathogens in se- tiondurchgeführt new and advanced und eine antigen weitere loading Studie, stra bei- welcher die DZ mit RNAs für die Tumorantigene Research verely immunodeficient hosts. tegiesMAGE-3, have MelanA been developed und Survivin using RNAbeladen elec -wurden, wurde initiiert. Darüber hinaus werden neue troporation.und verbesserte Methoden zur Antigenbeladung und DZ-Modulation mittels RNA- Several representative projects will be descri- The project of Prof. L. Nitschke studies the Transfektion entwickelt. bed shortly: The project of Prof. U. Schubert newly developed sialic acid derivatives as high- TImhe Teilprojektability to adoptively von Herrn transfer Prof. T cells A. Mackense to treat n steht der adoptive T Zell Transfer im investigates the role of the ubiquitin proteaso- affinity ligand analogs for CD22, a B-cell recep- cancerMittelpunkt. is in the In focus einer of erstenthe project klinischen of Prof. Phase A. I/II Studie zum adoptiven Transfer von TAA- me system (UPS) for antigen presentation via tor-associated inhibitory co-receptor, in order Mackensen.spezifischen In T-Zellen recent studies wurde the die efficacy Machbarkeit of und Antitumoraktivität bei Patienten mit the MHC class I (MHC-I) pathway. to therapeutically manipulate B-cells. CD22 can adoptivefortgeschrittenem T-cell transfer malignem therapies Melanom for the treat gezeigt- . Voraussetzung für eine effektive T- interact in trans with the CD22 ligands on bone ment of patients with metastatic melanoma has Zelltherapie ist die in vivo Persistenz und/oder Expansion der transferierten T-Zellen und ein The project of Prof. D. Dudziak will translate the marrow endothelial cells, which might control been shown. Effective cell therapy demands in Homing in den Tumor. Daher werden verschiedene Strategien entwickelt, um die strategy concept of in vivo “antigen targeting“ the homing of circulating mature B cells and vivo persistence and/or expansion of the trans- Proliferation, Migration und Persistenz infundierter T-Zellen zu verbessern. of Dendritic Cells (DC) into the human system. plasma cells into the bone marrow. The thera- ferred TAA-reactive T cells and homing to the Thereby, the work will focus on the production peutic potential of these modified derivatives tumor. Several strategies will be developed to of antigen-conjugated antibodies to analyze T will be explored as a novel therapeutic tool to enhance proliferation, migration, and persis- cell responses in tissue culture. These data will treat patients with multiple Myeloma. tenceResearch of infused report tumor-reactive SFB 643: T cells. These be important for an eventual implementation approachesSpokesman: could improve the efficacy of ad- Vice-Spokesman: into the clinic. The project of Dr. E. Zinser and Prof. A. Stein- optive T-cell therapy for cancer. kasserer concentrates on the immunomodula- Prof. F. Nimmerjahn will focus on antibodies tory potential of the soluble CD83 molecule. which are essential for defending the body Recombinantly expressed soluble CD83 show-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 141 DFG Collaborative Research Centres and Research Groups

Clinical Research Unit (KFO) 106: Target Organ Damage in Hypertension

Speaker vascular disease, and apply modern methods Prof. Dr. med. Roland E. Schmieder of molecular and cell biology.

The role of the hormone aldosterone for the de- Address velopment of target organ injury was the main Department of Medicine 4 - Nephrology and focus of subprojects 2 and 5. In animal experi- Hypertensiology ments, we demonstrated that mineralocortico- Krankenhausstrasse 12 id effects contributed directly to kidney injury, 91054 Erlangen independent from blood pressure. In patients Phone: +49 9131 8536245 with resistant hypertension, a placebo-cont- Fax: +49 9131 8539209 rolled trial showed that blockade of mineralo- [email protected] corticoid effects improved left ventricular hy- www.crc-erlangen.de pertrophy independent from blood pressure effects. Further clinical studies supported the in experimental studies. This effect of the in- notion that aldosterone exerts important, non- nvervation is partly but not completely due Aims and Structure genomic, direct vascular effects. to sympathetic, efferent nerve activity. Proin- flammatory factors are also released from affe- The contributing institutions are the Division Impaired endothelial function and vascular in- rent peptidergic nerves which may thus exert of Nephropathology, Department of Medici- flammation were investigated in subprojects. a local, paracrine function. Members of our ne 2, Department of Medicine 4, Department We improved the methods for analysis of vas- group are now part of a consortium which of Nuclear Medicine and the Department of cular structure and endothelial function in re- started a clinical trial on percutaneous cathe- Ophthalmology. sistance arteries of patients. In particular, we ter-based transluminal high-frequency ablation demonstrated that laser-doppler flow measu- of the renal innervation in patients with hyper- rement of the retinal arteries is highly suitab- tension and kidney disease („Native Kidney De- Research le to analyze impaired endothelial function in nervation in Patients with End Stage Renal Di- this important vascular bed. Structural altera- sease“, Clinical.Trials.gov NCT00551304). Arterial hypertension induces clinically relevant tions of retinal vessels were associated with car- injury in several target organs, including heart, diovascular risk. We identified several factors In summary, the translational studies pursued kidney, eye and blood vessels. The highly va- which mediate the impaired endothelial func- by our clinical research unit provided evidence riable extent of injury to these target organs tion in hypertension. In a subproject, we obtai- that non-hemodynamic factors play a very im- cannot be explained solely by the degree of ned evidence that patients with impaired en- portant role in determining the extent of tar- blood pressure elevation. Our clinical research dothelial function display an impaired cellular get organ injury in hypertension. In addition, unit identified pathogenetic factors other than uptake of L-arginine. A further factor causing we improved the methods to assess endothe- blood pressure which contribute to the deve- impaired endothelial is asymmetric dimethy- lial function as a prognostic parameter in pati- lopment of hypertensive target organ injury. larginine (ADMA), an endogenous inhibitor of ents with hypertension. Further, we used interdisciplinary approaches NO-synthase. We started experimental studies to analyze whether hormonal, neural and inin a transgenic animal model which will permit flammatory factors can be affected by thera- to analyze the role of ADMA for hypertensive Teaching peutic interventions. As a central part of our re- target organ injury. search group, we established a specialized cli- Junior scientists were educated in methods of nical research unit devoted exclusively to clini- In patients with hypertension, an increase of patient-oriented clinical research in our clinical cal studies in patients with hypertension and/ serum markers of inflammation became evi- research unit. Between 1.5 and 2.0 positions or vascular diseases. After the scheduled end dent only with severe hypertension. Experi- per year for junior physician-scientists were of funding by the German Research Foundati- mental studies in rodents provided clear evi- continuously used. For the most part, these po- on (DFG; 2 periods of 3 years each), continu- dence that local inflammation, in particular in- sitions were used for full-time or part-time rota- ed funding for the clinical research unit will be filtration of macrophages, contributed to hy- tions in the clinical research unit. Some junior provided by the University Hospital Erlangen. pertensive target organ injury. Statins exerted scientists in our team obtained additional edu- The clinical research unit will continue its mis- anti-inflammatory and protective effects in cational or research grants by the DFG which sion to perform clinical studies in patients with these experimental models. Local inflamma- permitted research abroad for up to two years. hypertension and/or vascular disease according tion was particularly evident when the renin- Most of these scientists rejoined our clinical re- to the regulatory framework and quality con- angiotensin-aldosterone system was stimula- search group after completion of their grants, trol standards of investigator-sponsored clinical ted, and this effect was not due to high blood and some of them became leaders of indepen- pharmaceutical studies. In an interdisciplinary pressure alone. dent subprojects. Medical students were inte- and translational approach, we will also per- grated in our team to perform MD thesis work. form experimental studies in models of cardio The autonomic innervation of the kidney can also stimulate local inflammation, as shown

142 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Clinical Reserach Unit 130: Determinants and Modulators of postoperative pain

Speaker Research Teaching Prof. Dr. med. Dr. h. c. Jürgen Schüttler The focus of the interdisciplinary research team In December 2007, the clinical research unit Address is postoperative pain that persists beyond the has hosted an international Winter School “Me- Department of Anaesthesiology expected healing period. Persistent pain has thods in Pain Research”. This event aimed to Krankenhausstrasse 12 an incidence of up to 50%, depending on the offer interdisciplinary training in methods of 91054 Erlangen type and extent of surgery, and is linked to an pain research as well as inspiration for a more Phone: +49 9131 8533677 increased risk for the development of chronic effective translation of preclinical knowledge Fax: +49 9131 8539191 pain. Continuous inflammatory processes or into clinical practice to students and young sci- [email protected] accidental or hazarded intraoperative nerve entists. The clinical research unit also regularly www.anaesthesie.uk-erlangen.de/e169/e2368 injuries contribute to the pathobiology of per- hosts research colloquia and Journal Clubs for sistent pain. Risk factors for persistent pain are scientists and guests. pre-existing pain, repeated surgery and severe Aims and Structure postoperative pain. Largely unknown is the influence of intra- and postoperative applied an- Contributing Departments are: Anaesthesio- esthetics and analgesic drugs, genetic factors, logy, Pharmacology, Physiology, Neurology, and psychological susceptibility. Human Genetics, Physiological Psychology In an interdisciplinary and translational ap- (University Bamberg), Pharmacology (Univer- proach, modern methods of molecular and cell sity Zurich) biology as well as experimental pathophysiolo- The clinical research unit KFO 130 has been es- gy and clinical studies are combined to iden- tablished at the Department of Anaesthesiolo- tify neurobiological, pharmacological, gene- gy in August 2005. In July 2008, on the ground tic, and psycho-social factors of postoperative of a re-evaluation process, it has been decided pain, and to characterize clinical and pathophy- to fund the clinical research unit for a second siological situations that may facilitate the de- period from 2008 – 2011. velopment of persistent pain. Long-term goal is the development of perioperative screening parameters, therapies and interventional strategies to treat postoperative pain more effectively and to prevent the development of persistent pain in patients at risk. The scientific management has Prof. Dr. med. Carla Nau.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 143 DFG Collaborative Research Centres and Research Groups

Clinical Research Unit Bavarian Immunotherapy Network (BayImmuNet): Adoptive Immunotherapy

Speaker Prof. Dr. med. Andreas Mackensen Selection Expansion

Address Department of Medicine 5 – Haematology and Oncology Lymphodepletion Krankenhausstrasse 12 in vivo by 91054 Erlangen chemotherapy Phone: +49 9131 8535954 Adoptive Fax.: +49 9131 8535958 T-Cell Transfer [email protected] www.bayimmunet.de DONOR PATIENT (Lymphocytes ) (Lymphocytes ) Antigen -specific T-cell stimulation Aims and Structure

Immunotherapy – therapeutic influencing of Schematic description of the goals of the Clinical Research Group “Adoptive Immuntherapy” the human immune system – is one of the most important cornerstones of modern medical research. One of the current challenges is the translation of innovative therapy approaches from the laboratory into clinical application. In the area of immunotherapy – particularly anti- Recent success using adoptive transfer of tu- the induction of lymphopenia before adopti- body therapy and cellular therapy – Bavaria has mour-specific T cells has fuelled optimism that ve T cell transfer. excellent scientific teams and, consequently, a this approach may find a place as a targeted Changing the equilibrium of various immune high degree of scientific potential. Many of the therapy for some human cancers. Furthermo- system populations may result in a selective ad- projects carried out by those teams are already re, it is well established that the curative po- vantage being given to adoptively transferred at a stage in which rapid translation into clini- tential of allogeneic bone marrow transplanta- T cells. Successful accomplishment of the aims cal application can be expected. However, on tion (BMT) is due to immunocompetent donor could yield a new treatment option for patients the part of the university hospitals there is an T cells inducing potent antineoplastic effects with certain types of cancer, particularly mali- investment bottleneck due to the Medical Pre- against host tumour cells [graft versus tumour gnant melanoma and haematologic diseases parations Act that is preventing rapid and ef- (GvT) reaction]. after allogeneic BMT. ficient translation into clinical application. Bay- However, GvT reactions are mostly associa- ImmuNet, a unique network established by ted with the graft-versus-host disease (GvHD), the Bavarian state government in 2008 with which is the major cause of morbidity and mor- Teaching a start-up financing of 10 Mio. €, has set itself tality after allogeneic BMT. the goal of achieving faster translation of new This project aims to develop new strategies for The head of the clinical research group is invol- approaches in immunotherapy into clinical ap- the priming, selection and expansion of anti- ved in the traditional teaching program (lectu- plication. Five clinical research units were esta- gen-specific effector T cells under the guideli- res, seminars, practica) covering all subjects in blished at the University of Erlangen, Regens- nes of good manufacturing procedure (GMP) the field of medicine and molecular medicine burg, Würzburg and Munich. that will be used for adoptive T-cell therapy in and the PhD and MD programme for basic and patients with solid and hematologic malignan- translational research. cies. CTLs generated with peptide-pulsed an- Research tigen presenting cells are often peptide reactive but not reactive with tumours that express The realization that cellular immune reactions, the gene of interest due to low level expressi- mediated primarily by activated T lymphocytes on or impaired antigen processing by the tu- recognizing defined antigens, are responsible mour cells. for the rejection of tumours in experimental To circumvent this, we will focus on an ap- models has led to multiple attempts to develop proach of full-length proteins or overlapping effective immunotherapies for the treatment of peptides to generate T-cell lines with a broa- cancer patients based on stimulating T cell re- der antigenic repertoire. The focus of the cli- activity against cancer antigens. nical study will be on the comparative analysis of different chemotherapeutic strategies for

144 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Research Unit (FOR) 661: Multimodal Imaging in Pre-clinical Research

Speaker Research In the Division of Neuroradiology at the Uni- Prof. Dr. habil. Dr. med. h. c. Willi A. Kalender versity Hospital Erlangen the work focus on the Using the field of small animal imaging, a multi- field of medical biological basic research and Address disciplinary team endeavors to improve the as- clinical application. To scrutinize the sensitivity Institute of Medical Physics sessment of structure-function relationships in of micro-CT in correlation to a 64 slice CT and Henkestrasse 91 the same animal under comparable conditions a small animal MRT during the acute phase of 91052 Erlangen and in repetitive sequences using CT, MR, PET, cerebral ischemia is one topic. The intention is Phone: +49 9131 8522310 US and OI, both organ- and pathology-orien- to deploy CT that is widely available to encircle Fax: + 49 9131 8522824 ted. The combination of biochemical, functio- ischemic tissue that is not yet irreversibly dama- E-Mail: [email protected] nal and morphologic information shall improve ged and still treatable. At the Institute of Phar- www.imp.uni-erlangen.de the possibilities for early non-invasive diagno- macology the researchers focus on the impro- sis and can finally lead to improved and often vement of functional MRI (fMRI) respectively more cost-efficient patient care. angioplasty by recording and merging data of Aims and Structure It is the central goal of the research unit to en- vascular trees of rodents and optimizing mo- hance and to transfer the recent developments deling. This work enhances not only resolution The German Research Foundation (DFG) is sup- in the field of X-ray computed tomography but also the understanding of the translation porting a team of researchers from different (CT), and to augment them with further ef- of neuronal activities into signals that are de- faculties and research areas working on mul- forts in basic CT research and the combination tected in MR. The Department of Medicine 3 – timodal imaging in pre-clinical research with of CT with other slice imaging modalities such Rheumatology and Immunology is working on emphasis on computed tomography and small as Magnetic Resonance Tomography (MR), Po- the high resolution imaging of bone damages animal imaging. This research unit is objected sitron Emission Tomography (PET), Ultrasound due to arthritis with micro-CT and micro-MR for three years and funded with 3.5 million €. (US) and Optical Imaging (OI), in order to im- in small animal. The research focus is to be ex- The Research Unit 661 consists of the following prove the visualization and evaluation of new panded on the quantification of vasculogenese subprojects: therapy methods in chronic pain, stroke or main arthritic inflamed joints in correlation to ar- TP1: Contrast, dose, spatial and temporal reso- lignant tumors. The cooperation of the partici- chitecture and extent of the vessel net. lution in computed tomography focusing on pating institutions offers considerable synergi- micro CT and small animal imaging (W.A. Ka- stic effects by the alliance of basic research and lender, Institute of Medical Physics) clinical application (P3, P4 and P7). TP2: 3D and 4D statistical CT image recon- At the Institute of Medical Physics the projec- struction (M. Kachelriess, Institute of Medi- ted CT developments, in particular for mic- cal Physics) ro-CT, focus on optimization of image qua- TP3: Multimodal imaging in the acute phase of lity at minimal dose, the implementation of cerebral ischemia: Micro CT and Micro MR ex- dual-energy methods, and the development aminations with the focal ischemia model (A. of tools for dynamic micro-CT. New approa- Doerfler, T. Engelhorn, Department of Neuro- ches to CT image reconstruction aim at maxi- radiology) mal low-contrast detectability for a given dose TP4: Optimized multimodal imaging of the ce- or, alternatively, minimal dose for a given level rebral vessel to improve functional imaging of of image quality. The combination of modern pain induced activity (A. Hess, K. Brune, Insti- optical procedures with fluorescence imaging tute of Pharmacology and Toxicology) that allows for minimally invasive investigations TP5: Development and evaluation of ultra- of molecular, cellular and physiological proces- sound imaging modalities for small animal ima- ses in vivo with micro CT imaging is an additi- ging (H. Ermert, Institute of High Frequency onal goal to evaluate its potential for display- Technology, Ruhr-University Bochum) ing functional and anatomical information of TP6: Combination of optical fluorescence ima- physiological processes in vivo. At the Institu- ging with Micro CT procedures for fusion ima- te of High Frequency Engineering at the Ruhr ging on small animals (A. Langenbucher, Insti- University Bochum the application of various tute of Medical Physics) ultrasound imaging modalities in small animal TP7: The interaction between Tumor-Nekro- imaging, the comparison of these modalities to sis-Factor (TNF) and Interleukin-1 (IL-1) in the MRT, micro-CT and PET, are further subjects. structural lesion of joints in the context of in- Another research topic is the technical combi- flamed joint diseases (G. Schett, Department nation of ultrasound and micro-CT in a multi- of Medicine 3, Faculty: Immunology/Rheuma- modal system to make use of the spatial reso- tology; K. Engelke, Institute of Medical Physics) lution of micro CT and the contrast resolution of soft tissue of ultrasound.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 145 DFG Collaborative Research Centres and Research Groups

Research Unit (FOR) 832: Regulators of humoral immunity

Speaker: group participate in all of the events and cour- Prof. Dr. rer. nat. Thomas Winkler ses of the research training group. This is inten- Faculty of Natural Science ded to ensure an excellent education for the Prof. Dr. rer. nat. Hans-Martin Jäck new generation of scientists, also in the context Faculty of Medicine of international networking.

Address: Research Nikolaus-Fiebiger-Centre Glückstrasse 6 The B cell is at the centre of attention for the 91054 Erlangen research group FOR832. During its maturati- Phone.: +49 9131 8529136 und on in the bone marrow, the genes for the anti- +49 9131 8535912 body molecules are assembled by rearranging Histology of a B cell follicle in the spleen Fax: +49 9131 8529106 und the corresponding DNA segments. This pro- +49 9131 8539343 cess creates millions of B cells, all of which pro- [email protected] duce a different type of antibody. This mole- www.for832.uni-erlangen.de/ cule is either directed at a specific pathogen or suitable animal models through appropriate at a molecular structure that generally signals cell-sorting methods. Consequently, one expe- an attack. The mature B cell initially carries its rimental focus of the research group is the use Aims and Structure antibody to the cell surface, which allows it to of the mouse as an animal model for the humo- detect an appropriate signal. In this case, the B ral immune response. The research of the pre- Since 2008, the German Research Foundation cell is activated in the peripheral lymphatic or- vious years has clearly demonstrated that the (DFG) has been sponsoring a new interdepart- gans and releases large amounts of soluble pro- processes of antibody formation occur in a very mental research group with the main topic of tective antibodies into the blood. The research similar manner in the mouse and in humans. “Regulators of the humoral immune response” group concentrates its work on these complex The possibility of using and also establishing and granted a total volume of 2 million Euros regulatory processes during the maturation “genetically tailored“ mouse models here in Er- for it. Eight scientists from the Institute for Bio- and activation of B cells. langen will be employed by the research group logy (three projects) of the Natural Sciences On the one hand, congenital and acquired dis- in a special way, especially for better understan- Faculty and the University Hospital of the Me- orders of the complex differentiation scheme ding such molecular and cellular processes du- dical Faculty (five projects) are participating in can lead to immune deficiencies – which means ring the humoral immune response that can- the research group. Five of the eight participa- to a special susceptibility to conditions ranging not be specifically investigated in either the cell ting project leaders, which include both biolo- from infectious diseases to life-threatening im cultures or the human being. gists and clinicians, are based at the Nikolaus- mune defects. However, excessive and misdi- Fiebiger-Centre for Molecular Medicine. In rected immune responses, such as those of al- close cooperation, the eight projects research lergies and autoimmune diseases, are caused Teaching the molecular circuits that are involved in the by disorders in the regulation of the immune control and regulation of antibody-producing response. In autoimmune patients, the immu- In addition to classic lectures (such as con- B-lymphocytes. Cell-culture and mouse models ne system frequently develops antibodies that cepts of immunology, literature seminars, etc.) are used. Meetings on a regular basis (such as react to structures of their own body instead and practical courses within the bachelor and the monthly B-Cell Club), a mutual concept for of pathogens. The research group directs the master programs in biology, molecular and cell the education of doctoral students analogous focus of its work towards the clarification of biology (Department of Biology) and molecu- to the program of the DFG Research Training such undesirable developments. The approach lar medicine (Medical Faculty), all of the pro- Group 592, the participation in supervisory of the research group is initially focused on fun- ject leaders also participate in a methods semi- commissions for doctoral students, as well as damental research because it will only be possi- nar organized by one of the doctoral students scientific colloquia, additionally promote the ble to develop new types of therapy through a of the research group. Furthermore, all project mutual scientific objective. better understanding of the molecular circuits leaders are directly and actively integrated into The educational concept for the doctoral stu- and complex cell-cell interactions in the immu- the supervision of the respective doctoral students can be seen as a special feature of the ne defense that is imparted by the antibody. dents as members of the doctoral superviso- DFG research group. The structured educa- At the present time, an efficient humoral im- ry commissions. All of the members of the re- tion of doctoral students occurs in cooperation mune response cannot be adequately recons- search group are also actively involved in the with the Research Training Group 592 on “Lym- tructed “in the test tube”. The high degree of public relations work of the Research Training phocytes: differentiation, activation and devi- complexity and the multitude of cellular and Group GK 592 (such as the 2008 “International ation.” The doctoral students of the research molecular interactions between B cells and Day of Immunology”). other cells of the immune system require studies on the living organism, on both tissue sections and cells that have been isolated from the

146 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Research Unit (FOR) 894: Fundamentals on Fluid and Physical Dynamics in Human Voice Production

Speaker Research Prof. Dr. rer. nat. Dr. med. Ulrich Eysholdt The strategy of the group is the application of Address different experimental and numerical models Division of Phoniatrics and Paediatric Audiolo- yielding a comprehensive description of voice gy at the Department of Ear, Nose and Throat production. The basis for the models is endo- Bohlenplatz 21 scopic high speed digital video recordings from 91054 Erlangen healthy and pathological subjects. At the de- Phone: +49 9131 8532782 partment for Phoniatrics and Pediatric Audio- Fax: +49 9131 8532687 logy biomechanical models are fitted to the re- [email protected] corded dynamics for receiving quantitative in- for894.forschung.uni-erlangen.de formation on the severity of diseases. For analysing fluid mechanical causalities an air driven physical model was developed by the Aims and Structure Institute of Fluid Mechanics (Fig.) presenting a realistic model of human voice production. Participating Institutions: Division of Phoni- Vocal folds consisting of a silicon mixture are atrics and Paediatric Audiology, Chair of Ap- set into vibration and enable to experimentally plied Mathematics II, Chair of Sensorics, Chair analyse the entire chain of fluid-structure-acou- of Flow Mechanics; Institute of Mechanics and stic interaction. The material parameters of the Fluid Dynamics, (TU Bergakademie Freiberg); synthetic vocal folds are adapted to human la- Applied Mechatronics (Alpen-Adria University ryngeal tissue by numerical optimization algo- Air driven channel for simulation of human vocal fold Klagenfurt). Funding period since 2008. rithms (Institute of Applied Mathematics II). dynamics. The vocal folds consist of a silicon mixture. The model enables the variation of pressure, Adjustment of the laser doppler anemometry (LDA) hard- Voice production within the larynx is still not air flow, and elongation of the synthetic vocal ware for supraglottal volume flow measurements. (Picture: Institute of Fluid Mechanics) entirely understood neither in normal nor in folds. Hence, impacts on dynamics and acou- pathological voice. The goal of the interdiscip- stics can be observed and analysed. However, linary group Research Unit (FOR) 894 is to get irregularities cannot be separated regarding substantiated knowledge on normal and pa- their cause and resulting effect. thological vocal fold dynamics and on the re- For investigation pre defined clinical observed Teaching sulting acoustic signal. Human voice is the re- irregularities and their impact on voice quali- sult of a complex process comprising fluid dy- ty a water driven model was developed by the The participating groups in FOR 894 supervise namics coupled with moving elastic tissue. group from Freiberg. Here, the fluid dynamics mathematical, technical and medical thesis, as Analyzing such complexities necessitates diffe- are easier to observe due to the increased time well as interdisciplinary master thesis and stu- rent modelling approaches. Therefore, depart- scale. This model is especially appropriate for dent research projects. The principal investiga- ments from different research fields are wor- observing eddy induced acoustics. tors of the different projects are involved in lec- king together to derive a better picture of the The experimental work is supplemented by a tures of three different faculties: medical, engi- entire voice origination process. The different numerical finite element method model of the neering sciences and natural sciences. suggested models allow a review and verifica- Institute of Sensorics. Hereby fluid volume as tion of the results and assumptions. In the in- well as mechanical induced acoustics can be ternational fluid dynamics and voice research directly analysed. However, this model is only community, different approaches are still ap- two dimensional due to the high computati- plied and discussed on their own. Hence, the onal costs. research unit FOR 894 is performing high- By these approaches the different acoustic ly frontier research. For coordination and lea- sources can be investigated and analysed. In ding the interdisciplinary group, the German future, conclusions based on the cause-and-ef- Research Foundation (DFG) established a W2- fect chain, for medical conservative as well as professorship. The scientific management has surgical treatments will be driven. Prof. Dr. Ing. Michael Doellinger.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 147 DFG Collaborative Research Centres and Research Groups

National Reference Centre for Retroviruses

Speaker virus, sequencing the V3-loop of the viral env Research Prof. Dr. med. Bernhard Fleckenstein gene has to be performed before the treatment with CCR5 antagonists is started. For this drug In December 2008 a database was generated Address class, discrepancies between the results obtai- in cooperation with the HIV competence net- Institute of Virology – Clinical and Molecular ned from functional tests and sequence ana- work, and the collection of HIV-1 sequences Virology lyses have been observed, indicating that it is has been started which may facilitate the sur- Schlossgarten 4 essential to make possible further comparisons veillance of emerging resistance pattern in the 91054 Erlangen and validation of the methods. In parallel, the- future. Further epidemiologic research at the Phone: +49 9131 8526429 rapy response data were generated by more NRC is also focused on HIV-1 drug resistance. Fax: +49 9131 8526485 than ten clinical centres in Germany and were In close cooperation with the Robert Koch In- [email protected] collected and analyzed under the coordination stitute, the NRC continues to study the role of www.viro.med.uni-erlangen.de of the NRC in order to support and validate the transmission of HIV-1 drug resistance on the more cost effective and faster sequence analy- European level. Finally, the efforts of the NRC ses based method. According to this data, the are broadened by a huge number of projects Aims and Structure method is now recommended in first line and focused on basic and clinical research and has been implemented in the German thera- addressed by the scientific groups localized at In 1996, the Robert Koch Institute (RKI) esta- py guidelines. A similar development can be the institute. These projects are supported by blished the National Reference Centre for Ret- expected for the European guidelines within grants from the German Research Foundation roviruses (NRC) at the Institute for Clinical and this year. (DFG), the German Ministry of Education and Molecular Virology, University of Erlangen- Research, the European Union and by several Nürnberg, headed by Prof. Bernhard Flecken- In order to assure standardized testing, the companies. stein. The main tasks of the reference centre NRC is engaged in quality control trials concer- focus on epidemiologic surveillance and the ning diagnostic methods for human retroviru- generation and provision of standards for dia- ses. In cooperation with the German Society for Teaching gnostic methods and therapeutic procedures. Virology, a standardized operational protocol In addition, they distribute reference materials was developed how to analyze a quality con- The members of the NRC offer a broad range (like virus stocks) and give advice how to hand- trol trial based on sequence analyses in order to of HIV-related seminars to students of human le unclear and rare clinical cases. detect HIV-1 drug susceptibilities. The protocol medicine, molecular medicine and bioscien- can be transferred to other microbiological pa- ces. There are lectures about HIV-1 replica- thogens and may contribute to a higher level of tion, pathogenesis and therapy, a HIV seminar Diagnostic standardization in future quality control trials. addressing recent scientific results performed by members of the institute, and experimental The NRC has extensive experience in testing In cooperation with several other institutions, training courses in the laboratories. antiretroviral drug susceptibility. A major topic the NRC could show that one of the commer- of the NRC is the identification and characteri- cially available HIV-1-RNA detection systems zation of HIV-1 drug resistance associated mu- was not able to quantify some isolates appro- tations. Besides the continuous updates of the priately. Meanwhile, an updated version of the bioinformatically supported resistance inter- system is distributed by the company, which pretation system geno2pheno, the NRC coor- seems to overcome most of the disadvantages dinates a team of clinical virologists generating described before. the German HIV-1 resistance interpretation system HIV-GRADE. Both interpretation tools are The NRC quarterly publishes the Retrovirus- freely online available (www.geno2pheno.org Bulletin to provide scientific and clinical infor- bzw. www.hiv-grade.de). mation on HIV, AIDS and other retroviral infections like HTLV-1/2. The Bulletin is freely distri- Within the last two years, the repertoire of me- buted by mail to a broad and diverse readership thods was expanded to test the two most re- like specialized clinicians, members of the pu- cently approved antiretroviral drug classes, the blic health system and of the HIV community. CCR5-coreceptor antagonists and the integra- All published articles can be downloaded from se inhibitors. During the last year, sequence the institute’s homepage. analyses of the HIV-1 integrase gene derived from patients’ plasma viruses were sufficient to explain therapy failures in Raltegravir treated patients. In contrast, due to a higher natural level of alternate coreceptor usage by the

148 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

National Genome Research Network – Infection and Inflammation – Work package “Viral Infections”, Erlangen

Speaker Prof. Dr. rer. nat. Ulrich Schubert Institute of Virology – Clinical and Molecular Virology Prof. Dr. rer. nat. Alexander Steinkasserer Department of Dermatology

Address Institute of Virology Schlossgarten 4 91054 Erlangen Phone: +49 9131 8526478 Fax: +49 9131 8526182 [email protected] Left: experimental tridimensional structure of Vpr www.viro.med.uni-erlangen.de Right: evaluated conformation of the P35A-mutant where both helices 1 and 2 fusion to a antiparallel helix Department of Dermatology Hartmannstrasse 14 91052 Erlangen decomposed very quickly, maybe viral IE-pro- cellular factors have been identified: (1) the 26S Phone: +49 9131 8536725 teins could be responsible therefore. Infection proteasome, (2) the ubiquitin ligase POSH, (3) Abb.1: Links: Experimentelle dreidimensionale Struktur von Vpr. Rechts: Berechnete Fax: +49 9131 8535799 experiments with diverse HSV specific deletion the peptidyl-prolyl-isomeraseKonformation der P35A-Mutante, bei der die (PPlase) Cyclo- beiden Helices 1 und 2 zu einer antiparallelen [email protected] mutants have shown that the infection with a philin A (CypA).Helix fusionieren Studies with proteasome in- www.derma.med.uni-erlangen.de ICPO-specific deletion mutant caused a consi- hibitors in numerous virus systems have been derable minimized CD83 decomposition and continued. The realization that these inhibitors this indicates that ICPO has an important role do not inhibit only release and maturation of Aims and Structure in decomposition of CD83. To analyze this hy- HIV but also block replication of further viru- pothesis there have been made cotransfection ses, demonstrate a central role of UPS in viral The comprehension of the very specific interac- experiments with plasmids, which coded for replication cycles. tion between viral and host cells is a basic pre- CD83 and ICPO. The cotransfection of CD83 condition for the understanding of pathologic and ICPO caused a considerable down regulati- The E3 ubiquitin ligase POSH was identified mechanisms of viral infections. This knowledge on of the CD83 molecule. Contrariwise, the co- by searching further targets in collaborati- provides eventually a decisive assumption for transfection of CD83 with a ICPO deletion mu- on with cooperation partners. It regulates the the development of new antiviral methods of tante, which had no ubiquitin ligase domain, transport of HIV Gag proteins from the trans- treatment as well as improved vaccination stra- did not cause any reduction of CD83. This con- Golgi network to the cell membrane. Essenti- tegies. The genomic structures of many viru- firms the relevance of ICPO at the HSV-1 inter- al is that inactivation of this E3-ligase has only ses are quite simple and extensively explored fered CD83-decomposition and indicates that weak toxic effects on the cell vitality, compa- for the known human pathogen viruses. The the ubiquitin proteasome system (UPS) of the red to the multiple effects of the deactivation bulk of viral gene products have already been host cell is involved in this degradation. Hence, of the proteasom on different aspects of the molecularly characterized. However, there is a as next step we have been carried out infec- cell metabolism. huge discrepancy between detailed knowledge tion experiments with HSV in dendritical cells about the viral genome- and proteom organi- after treatment with specific proteasome inhi- The accessory protein Vpr of HIV-1 represents a sation and the complex virus-host interactions bitors. Interestingly, the CD83-surface expres- virus associated protein which performs a series in the viral replication. sion was unvaried strong, despite HSV infec- of functions during the retroviral replication tion. The hypothesis, that cellular proteasomic cycle. Amongst others Vpr regulates the trans- protein decomposition and the HSV-1-gene port of the pre-intergration complex in the cell Research transcript ICPO have a significant role at CD83 nucleus and induces G2-cell cycle arrest of the decomposition, could be definitely demonstra- infected cell. By means of Biacore spectroscopy, The following sub-projects of the work package ted with these trials. Far Western Blot and Pull down experiments, “viral infections” have been treated: an interaction of Vpr with the cellular PPlase The sub-project of Prof. Alexander Steinkasse- The sub-project NIE-S10T01 of Prof. Schubert could be proven. These studies are based on rer (NIE-S10T02) dealt with the identification of analyzes the interaction of host cell and virus previous structure analyses of small viral prote- new cellular target structures of HSV-1 in dend- proteins on a molecular level. Aim is the deter- ins and their binding partners. Amongst others, ritical cells in order to develop new therapeuti- mination of cellular target structures for the the structure of HIV-1 p6 protein has been de- cal strategies. The HSV infection of mature den- therapy of infections with HIV, HCV and influ- termined which interferes via two so called late dritical cells causes a nearly entire down regula- enza A viruses. Thereby, the UPS and certain (L)-domains with the efficient release of the vi- tion of the surface molecule CD83. As CD83 is folding enzymes take a centre stage. Following rions from the host cell membrane.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 149 DFG Collaborative Research Centres and Research Groups

National Genome Research Network – Mental Retardation Network (MRNET), Erlangen

Logo of the MRNET

Molecular karyotyping reveals genomic aberration. Schematic chromosome representation of a female patient with mental retardation (left). The boxed region on chromo some 9 is enlarged at the right. Red bar indicates a deleted region with reduced signal intensities (green points). Speaker Prof. Dr. med. André Reis

Address Institute of Human Genetics the clinical and scientific expertise of resear- cing of large genomic intervals with next-ge- Schwabachanlage 10 chers and physicians from 7 german universi- neration sequencing technologies. 91054 Erlangen ties (Bonn, Dresden, Erlangen, Essen, Heidel- Candidate genes and their respective signalling Phone: +49 9131 8522318 berg, Muenster and Tuebingen), one institute pathways will be functionally explored in cel- Fax: +49 9131 8523232 of the Max-Planck-Society (Berlin), a research lular assays and in animal models, specially the [email protected] centre of the Helmholtz-Society (Munich) and fruit fly drosophila melanogaster. www.german-mrnet.de the University of Nijmegen (The Netherlands). Finally, genotype-phenotype correlation will An internet webpage (www.german-mrnet. help reveal new clinical entities and to better de) informs physicians as well as patients and describe the natural history of diseases. Fin- Aims and Structure families about aims and achievements of the dings will be transferred into clinical practice in project. a timely manner and made available to affected Mental retardation (MR) has a prevalence of families and thus improve diagnostic options. about 2% in the general population and is one of the most important cost factors in health Research care. During the last years it has become evident that genetic factors play an important role The project combines a medical genetic ap- in the aetiology of MR. The German Mental Re- proach with systematic genome analysis. In a tardation Network (MRNET) is the first natio- multi centre study a total of 3,000 patients will nal network dedicated to the systematic inves- be recruited and receive a standardized clinical tigation of genetic causes of MR. Identification evaluation based on an international phenoty- and characterization of molecular networks in- pe ontology. Patients’ data are collected in a volved should allow identification of targets for specially developed, pseudonymized database. therapeutic intervention. Sporadic as well as familial cases are included. Sporadic ones are subsequently investigated MRNET is funded within the medical genome for submicroscopic aberrations using modern research programme (National Genome Re- micro-array based technologies. We expect to search Network, NGFNplus) of the Federal Mi- detect de novo aberrations in about 10-15% of nistry of Education and Research with a total cases. Patients with similar phenotype to those budget of 5.8 Mio. €. The central coordination with the genomic aberration will be screened located in Erlangen brings together the efforts for point mutations in candidate genes from of 10 centres distributed throughout Germany the respective genomic region. and the Netherlands. The network combines Familial cases will be explored for cosegregati- on of genetic markers with the disease (linkage analysis) to likewise reveal candidate genes from linked regions. Furthermore, some patients will be subject to comprehensive sequen-

150 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Collaborative Research Centres and Research Groups

Project group of the Academy of Science and Literature, Mainz

Speaker Binding of viral glycoproteins does also induce Prof. Dr. med. Bernhard Fleckenstein signal transduction pathways known to be en- volved in the pathogenesis of Kaposi’s sarco- Address ma. Thus, HHV-8 encouters and activates cel- Institute of Virology – Clinical and lular genes contributing to oncogenesis at the Molecular Virology earliest stages of the infection. Schlossgarten 4 91054 Erlangen Section C: Plasmacytoid dentritic cells, the Phone: +49 9131 8523563 Innate immune defense against Human Fax: +49 9131 8522101 Immunodeficiency virus Type 1 (HIV-1) Email: [email protected] and Herpes simplex virus Type 1 (HSV-1) www.adwmainz.de/index infections The research group of PD Dr. med. Barbara Schmidt is investigating the role of the inna- Aims and Structure te immunity for the defense against viral pa- Confocal laser scanning microscopy for demonstration thogens like immunodeficiency and herpesvi- Persistence of pathogens is the pathogenetic of the glycoproteins of the Kaposi sarcoma associated ruses. Hereby the plasmacytoid dendritic cells principle of AIDS and virus induced tumors. human herpesvirus 8 (PDC), which are the main producer of Type 1 The Academy of Sciences and Literature in interferons, contribute substantially to the con- Mainz supports a research program together trol of viral pathogens. There is a direct corre- with the State of Bavaria, which is devoted to process. Indeed, using human polyclonal anti- lation between PDC cell counts and helper cell the investigation of persistent and oncogenic GBV-C E2 positive sera as well as some specific counts and clinical status and a inverse corre- viruses of the hematopoetic system. monoclonal anti-GBV-C E2 antibodies, a varie- lation with the virus load. The research group ty of lab adapted or primary HIV strains can be could demonstrate that a PDC depletion during potently neutralized. If these cross reactive an- HIV pathogenesis is not caused by the HIV in- Research tibodies will prove to be broad and potent re- fection accompanied with a cytopathic effect, active against HIV in the animal model, these but by an increased migration of PDC into se- Section A: Mechanism of the viral interfe- findings establish a new perspective for the de- condary lymphatic organs. The PDC-specific rence between GB Virus C and immunode- velopment of HIV vaccine strategies. interferon secretion is mainly induced by HIV ficiency viruses infected cells, whereby this process is critically The research group of Dr. rer. nat. Dr. med. affected by the affinity of the HIV-1 envelope Heide Reil is studying the phenomenon of viral Section B: Oncogenesis induced by the protein to the CD4 receptor. However the in- interference. Persistent HIV can be suppressed Kaposi sarcoma associated human herpes- duction of interferon is ambiguous, since not by a non-pathogenic virus from the flavi-group, virus 8 only the required immune protection is activa- the GB virus C, which delay the prolonged de- The research group of PD Dr. med. Frank Nei- ted, but also the programmed cell death of by- velopment to AIDS. The clarification of the un- pel is analyzing the role of herpes viruses like stander cells that can increase the immune de- derlying mechanism led to the identification the Kaposi sarcoma associated human herpes- ficiency during the HIV infection. Thus, inhibi- of several flaviviral components. It could be virus 8 in carcinogenesis and AIDS. Using RNA tors of the CD4/gp120 interaction will not only demonstrated that the non structural proteins interference, it could be demonstrated that the suppress virus replication, but also reduce the NS3 and NS5A of GBV-C can inhibit HIV after viral Interferon regulatory factor 3 (vIRF-3) is HIV-1 induced immune stimulation. host cell entry, whereas the glycoprotein E2 of involved in HHV-8 induced oncogenesis. The GBV-C specifically interferes with very early re- group could identify the Interferon regulatory plication steps of HIV, like binding, fusion or factor 5 (IRF-5) as the cellular binding partner. uncoating. This so called new Entry-inhibitor is Hereby a domain of 40 amino acids could be active against a wide spectrum of HIV isolates determined in vIRF-3 that binds to IRF-5, and independently of the co-receptor tropism. In prevents the binding of IRF-5 to some respon- accordance with these findings, recent results sive promoters. Using this strategy, HHV-8 cir- suggest that there is an E2-like epitope on the cumvents some aspects of the cellular immu- HIV particle, which is involved in the HIV entry ne response and prevents the programmed cell death. In 2008, novel ligands for two HHV-8 glycoproteins were identified. The high-affinity interaction of the glycoprotein H/L complex with a tyrosin-kinase receptor is particularly noteworthy. This new receptor is not only relevant for attachment and entry into target cells.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 151 DFG Research Training Groups

Research Training Group 516: Cultural Transfer in the European Middle Ages

Speaker The Research Training Group comprises an in- Prof. Dr. phil. Hartmut Kugler terdisciplinary research and study program in which the Medical Faculty collaborates with Address: the Philosophical Faculty and the Division of Department of German Philology, Theology as well as the Faculty of Engineering Chair of Germanic and German Philology Sciences. In the centre of this program lays the Bismarckstrasse 1 european cultural transfer during the middle 91054 Erlangen ages. The main focus is on the identification of Phone: +49 9131 8522418 the process itself in terms of the persons, the Fax: +49 9131 8526997 ways, methods and aims of transfer. On the [email protected] other hand research is directed to the changes www.germanistik.phil.uni-erlangen.de which knowledge or human artefacts undergo by being assimilated within a different culture. The project of the Chair of the History of Medi- cine concentrates on the impact of the Arabian medicine on western medicine from the 11th century onwards and the 16th century restau- rative efforts in occidental science. Funding period: 1999 – 2008.

152 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Research Training Groups

Research Training Group 592: Lymphocytes – Differentiation, Activation and Deviation

Speaker ker: Prof. Huenig) and Tübingen (speaker: Prof. Prof. Dr. rer. nat. Hans-Martin Jäck H.-G. Rammensee) that take place in an annual rhythm, as well as the 1st and 2nd International Address: GK Symposium on Regulators of Adaptive Im- Division of Molecular Immunology munity initiated by GK 592 doctoral students. Nikolaus-Fiebiger-Centre Twenty high-calibre immunologists from all Glückstrasse 6 over the world were involved as speakers in the 91054 Erlangen 2nd GK Symposium, which also had more than Phone: +49 9131 8535913 400 registered participants. (See http://www. Fax: +49 9131 8539343 lymphozyten.de/symposium2008; Kroczek, C., [email protected] Thiele, S. and Winkelmann, R. (2009). Docto- www.lymphozyten.de ral Students in the Limelight at the 2nd Erlan- gen International Immunology Symposium. Eur J Immunol. 39, 339-341). Aims and Structure

Since 1st May 2000, the German Research Research Foundation (DFG) and Bavaria have sponsored the first ResearchT raining Group (GK) 592 As in the first two funding periods, the topics of on Lymphocytes: Differentiation, Activation & the research projects concentrated on the cel- Deviation at the Erlangen University Hospital. lular, molecular and functional aspects of the Sixteen university lecturers from the Medical differentiation, activation and deviation of lym- Faculty and the Natural Sciences Faculty par- phocytes and their role in autoimmunity, aller- Day of Immunology 2008 ticipate in the program as mentors. In order gy and leukaemia. This also includes immuno- to both the doctoral students and the project therapeutic approaches for the treatment of leaders to participate in the important decisi- tumors. The research programme of the GK on-making processes of the research training 592 has set the goal of clarifying the molecular graduate degree programme for molecular me- group, a research training group commissi- and cellular processes and signal cascades that dicine (Medical Faculty), all of the project lea- on consisting of four elected project leaders are involved in the development of both phy- ders also participate in a methods seminar or- and three representatives of the doctoral stu- siologically desired and pathological lympho- ganised by one of the doctoral students. Fur- dents has been formed. The research training cyte populations in autoimmune, allergic and thermore, the project leaders are directly and group commission decides on the acceptance leukaemic diseases. Research-oriented and cli- actively integrated into the supervision of the of scholarship recipients and associated stu- nical aspects of lymphocyte biology are integ- respective doctoral students as members of dents to the research training group and the rated within this research programme. The in- the doctoral supervisory commissions. All of annual sponsoring of scholarship recipients, as tention is for students to be trained as highly the members of the research training group well as the annual budget. The research focus qualified immunologists who are capable of are also actively participating in the public re- of the research training group is concentrated independently developing scientific hypothe lations work of the research training group on the study of the development and activation ses, verifying them through experiments, cri- (such as the 2008 “International Day of Immu- of lymphocytes, their derailment in autoimmu- tically interpreting the experimental findings nology”) and projects conducted with the Er- ne diseases and chronic processes of inflamma- and discussing them under consideration of langen grammar schools (Gymnasium). A de- tion, as well as the development of tumors of published data. This means that the GK 592 is finite highlight of this was the cooperation of the immune system. Within this research field, designed in an interdisciplinary approach with the GK 592 in a pilot project called W-Seminar doctoral students and university lecturers are regard to the expertise of the project leaders; in Immunobiology within the scope of the G8 offered an interactive and professionally orien- and it concentrates on the biology and patho- Secondary School Reform. This was initiated by ted training program. The core elements are a physiology of lymphocytes in relation to the the Ministry of Education and Cultural Affairs supervisory commission for each doctoral can- research topics. and organised at the Emmy-Noether-Gymnasi- didate, a trainee programme at European and um in Erlangen by Ms. Brigitte Kraml. The fin- North American institutions that has been es- dings of this project, which was coordinated for tablished and financed by the research training Teaching 1.5 years, were presented by members of the group, as well as one- to two-day workshops at research training group during a symposium which topics such as the requirements of the In addition to the classic lectures (such as con- in Munich that was organised by the Ministry industry, elements of the rhetoric and the wri- cepts of immunology, literature seminars, etc.) of Education and Research and was met with a ting of scientific manuscripts and proposals are and practical courses within the scope of the considerable response. taught. Highlights of the current period were Bachelor’s degree (biology and molecular me- the joint network meetings with our partner re- dicine), Master’s degree (cell and molecular search training groups from Würzburg (spea- biology in the Department of Biology) and the

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 153 DFG Research Training Groups

Research Training Group 1071: Viruses of the Immune System

Speaker Prof. Dr. med. Bernhard Fleckenstein

Address Institute of Virology – Clinical and Molecular Virology Schlossgarten 4 91054 Erlangen Phone: +49 9131 8523563 Fax: +49 9131 8522101 [email protected] www.grk1071.uni-erlangen.de

Aims and Structure Network of Research Training Group 1071

The Research Training Group “Viruses of the Immune System” provides an internationally oriented, structured training mainly for PhD, but also for MD students. It is based on established interdisciplinary cooperation among tes to the research focus on infectiology/immu- mandatory research reports at the retreats and scientists of the Medical Faculty and the Fa- nology at the Medical Faculty. by student travel funds that allow for participa- culty of Natural Science at the Friedrich-Alex- tion in scientific conferences. Personal develop- ander-University (FAU). The special feature of Section A: Viral immunodeficiency ment is further boosted by activities mediating the Research Training Group 1071 is an inte- Projects in this field investigate the interactions complementary skills for a career in science or grated exchange program with Harvard Me- of Human Immunodeficiency Virus (HIV) with industry. Among these are autonomous stu- dical School (HMS). Students holding a diplo- its host cells as well as with other viruses. They dent seminar, workshops on presentation and ma or master degree in life sciences or mole- aim at the definition of mechanisms relevant to writing techniques as well as the organization cular medicine from Erlangen join the labora- pathogenesis and at potential targets for thera- of public-oriented and scientific events. Parti- tory of a participating Harvard faculty member peutic intervention. cularly, the International GK Symposium in Er- and, upon completion of their thesis, graduate langen (http://www.lymphozyten.de/sympo- as Dr. rer. nat. from FAU. Joint retreats provide Section B: Basis of Prevention and sium.html), realized for the second time in Oc- an intense exchange between students and fa- Therapy tober 2008 together with students of Research culty members from Erlangen and Boston. This Humoral, cellular and innate immune respon- Training Group 592 and Research Unit 832, was direct interaction enforces the mentoring pro- ses to viruses are the main topic of projects again a great success. gram and enables the students to gain insight in this section. Understanding immunologi- into the everyday life at one of the leading re- cal processes controlling infection may lead search institutions. The resulting internationa- to novel strategies for specific prevention and lization should promote the PhD projects and therapy. the professional perspectives of the students. First funding period: 2005 – 2009. Section C: Lymphotropic tumor viruses This research field covers various aspects of viral oncogenesis. The viruses investigated in- Research duce various forms of lymphoma, which are relevant as human diseases or as model systems The scientific focus of the research training for lymphocyte growth transformation. group 1071 is at the interface of virology and immunology. Current projects mainly concentrate on two groups of persisting lymphotropic Teaching viruses, herpesviruses and retroviruses. They are clinically relevant as causative agents of Our program strives for a comprehensive, in- human tumors and AIDS. Research topics internationally oriented graduate training that clude the basis of AIDS pathogenesis and viral fosters both scientific and personal skills of the oncology as well as therapy and prophylaxis of PhD students. To this end, their research pro- viral infections. Thereby, this network contribu- jects are accompanied by a mentoring program. An early independence is supported by

154 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) DFG Research Training Groups

BioMedTec International Graduate School of Science (BIGSS): Lead structures of Cell Function

Speaker Prof. Dr. rer. nat. Paul Rösch

Address Department of Biopolymers University of Bayreuth 95440 Bayreuth Phone: +49 921 553540/1 Fax: +49 921 553544 [email protected] www.bigss.de

Aims and Structure

Involved universities are Bayreuth, Erlangen- Nürnberg and Würzburg. Participants from the Medical Faculty Erlan- gen-Nürnberg: Prof. Dr. Cord-Michael Becker, Announcement poster of the Bayreuther Strukturtage Chair of Biochemistry and Molecular Medicine, Prof. Dr. Bernhard Fleckenstein, Institute of Cli- nical and Molecular Virology, Prof. Dr. Michael Hensel, Institute of Clinical Microbiology, Im- munology and Hygiene, Prof. Dr. Ulrich Schu- bert, Institute of Clinical and Molecular Virolo- Network of Bavaria” (ENB), which in turn was chanisms and a first-rate selection of students gy, Prof. Dr. Thomas Stamminger, Institute of founded in Bavaria in 2004. The fundamental guarantee a high degree of interdisciplinarity, a Clinical and Molecular Virology, Prof. Dr. Hein- idea of the ENB is to provide the best possible vivid scientific exchange, and high quality dis- rich Sticht, Institute of Biochemistry, Prof. Dr. framework for the scientific careers of students sertations. The success of the graduate school Michael Wegner, Institute of Biochemistry and with excellent background. That needs prima- is reflected by 14 publications within the last Pathobiochemistry. rily a best possible supervision of the projects. two years in important journals. In 2008, the Funding period: since 2004. Consequently, the PhD students are suppor- first five students finished their PhD and mean- ted by their two local supervisors plus an addi- while have changed in carrying on positions in tional external supervisor from a foreign coun- research and industry. Research try. The privileges of the PhD students include numerous offers to acquire soft skills and a ge- The International Graduate School BIGSS (Bio- nerous travel budget that ensures the possibi- MedTec International Graduate School of Sci- lity to participate at international scientific con- ence) is themed “Lead Structures of Cell Func- gresses and workshops. There are, however, tion”, indicating that the focus of interest is in also several obligatory yearly events like writ- the area of biological macromolecular struc- ten yearly progress report, summer school, se- tures. The graduate school applies molecu- minars and evaluation by independent interna- lar biology, molecular modeling, bioinforma- tional reviewers. tics, X-ray crystallography, and spectroscopic Together with the international summer school methods such as nuclear magnetic resonance of Bavaria California Technology Centre, the (NMR) to understand the structure and func- University of San Francisco (UCSF, Prof. Dr. tion of biomolecules. The duration of the indi- Thomas James) and the degree programm vidual grants is limited to three years and offers Macromolecular Science the summer school optimal conditions for currently 17 PhD stu- Structure in Biology – Key to Understanding dents. These eight female and nine male PhD (October 2008) was organized. In addition, in students have been selected out of 600 natio- cooperation with the research centre for Bio- nal and international applicants. The gradua- macromolecules of the university of Bayreuth, te school resulted from an initiative of the Bio- a symposium named Bayreuther Strukturtage MedTec Franken e.V., which forms a network of was established for the first time under the the Universities of Bayreuth, Würzburg and Er- participation of international researchers. This langen. It constitutes one out of the ten gradu- meeting become the main annual meeting of ate schools which are embedded into the “Elite the graduate school. Taken together, these me-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 155 DFG Research Training Groups

Erlangen Graduate School in Advanced Optical Technologies (SAOT)

Speaker Prof. Dr.-Ing. Alfred Leipertz

Address Paul Gordan Strasse 6 91052 Erlangen Phone:+49 9131 8525858 Fax.: +49 9131 8525851 E-mail:[email protected] www.aot.uni-erlangen.de www.exzellenz-initiative.de/erlangen-optical- technologies Fig. 1: Measurements on biotissue phantom: proof of Fig. 2: Development of surgery navigation technology for principle phase of the Epithelium Capillary Grid Real Time laser ablation cancer resection Monitoring project Aims and Structure

In November 2006, the SAOT was established at the Friedrich-Alexander University Erlangen- Nürnberg (FAU) within the framework of the excellence initiative of the German federal and light and tissue promote the development of tions contributing with a talk to a major subject state governments to promote science and re- improved diagnostics, therapy and surgery usually last up to three days. This has already search at German universities. SAOT offers a techniques. Moreover technical specifications been done with the mentioned workshops on structured, internationally oriented (working are defined which will serve as the basis for fu- “Retina image processing“ and “Advanced Op- language English) and interdisciplinary educa- ture development and engineering of bio-optical Methods for Diagnostics, Assessment and tion programme to doctoral candidates. It is tical sensors and apparatuses for medical appli- Monitoring of Clinical Therapy and Surgery“. hosted by the Faculties of Engineering, of Na- cations. To realize these objectives, the Clinical During the one week lasting academies which tural Science and of Medicine and is embedded Photonics Laboratory (CPL) which is headed by take place outside Erlangen once in the winter into an international network of distinguished guest professor Dr. Sasha Douplik was establis- and once in the summer, the doctoral candida- experts in their respective fields of optical tech- hed inside SAOT. The CPL is equipped with a tes are in charge to contribute to the success nologies. The scientific topicsS AOT focuses on worldwide unique apparatus pool for the com- of the formed group work on a specific focus optical metrology, optical material processing, prehensive characterization of optical proper- or have to give short presentations on the ac- optics in medicine, optics in communication ties of biological tissues. CPL runs several col- tivities in their own field. Additionally the suc- and information technologies, optical materials laborations with international institutes spread cessful participation in the entrance academy, and systems and computational optics. all over the world and inside FAU with several which is organized once a year, is mandatory medical and clinics research institutes. To inten- for all SAOT doctoral candidates. In the end sify the interdisciplinary and international colla- of this academy they have to pass the entran- Research borations, SAOT organizes international work- ce examination which comprises problems co- shops routinely. In the topic “Optics in Medici- vering all scientific topics of SAOT. Intensive research work is carried out in each ne” two workshops have been organized so far, of the different SAOT topics which are in their “Retina image processing“ and “Advanced Op- activities partly overlapped with other topics. tical Methods for Diagnostics, Assessment and This in particular is true for the topic “Optics in Monitoring of Clinical Therapy and Surgery“. Medicine” which can be considered to form an application field of the other topics. Thus it is inherently interdisciplinary covering, e.g., op- Teaching tical diagnostics as well as optical therapy and surgery. Thus, the further development of op- During the semester terms SAOT offers stan- tical techniques in medicine demands an in- dard lectures which are related to the applica- tensive and comprehensive exchange and col- tion of optical technologies in medicine. Spe- laboration between the different schools invol- cial SAOT activities related to the educational ved. The topic “Optics in Medicine” deals with programme comprise seminars, workshops and the fundamental functioning principles of the academies. Outstanding scientists from inter- human body, its organs and tissues under the national leading institutions are invited to give exposure of optical radiation covering a broad an one hour talk on specialised themes at the field of frequencies and light strength. These SAOT seminar. Workshops with several spea- detailed investigations of the interaction of kers of leading international research institu-

156 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Interdisciplinary Centres

Interdisciplinary Centre for Clinical Research (IZKF)

funding. Exceptionally, projects can receive additional funding for another 2 years. Support and development of young scientists continues to be a main goal of the IZKF. The IZKF supports two junior research groups, housed in the Nikolaus-Fiebiger-Center for Mo- lecular Medicine. In the reporting period two Logo of the IZKF very successful junior research groups are supported by the IZKF - junior group 2 (PD Dr. med. Reinhard Voll) with the topic „The role of NF-kappaB in the pathogenesis of inflamm- Graphic illustrating the IZKF Speaker atory diseases“ and the junior group 3 (PD Dr. Prof. Dr. med. André Reis med. Michael Wiesener) on „The role of hypoxia-inducible transcription factors in the con- Address text of the development and progression of IZKF- Administrative Office renal cell carcinoma. thus allowing more institutions of the Medical Maximiliansplatz 2 Participation from the IZKF was key to attract Faculty to successfully participate in the IZKF. 91054 Erlangen Prof. Falk Nimmerjahn for a third (associated) Almost half of the projects are so called “tan- Phone: +49 9131 8539223 junior group to Erlangen funded by the Bavari- dem-projects” between clinically and theore- Fax.: +49 9131 8535903 an Genome Research Network. tically working institutions while 2 projects are [email protected] Support of young scientists is also achieved collaborations between different clinical insti- www.izkf.uk-erlangen.de through supporting young clinicians to rotate tutions. The stringent, two-stage peer-review for a certain period of time into the laboratory process (first internal, then external) based so- to follow up their research projects. This pro- lely on scientific criteria, ensures a high scienti- Aims and Structure gramme is also directed to projects not direct- fic quality of the projects with current funding ly funded by the IZKF. The IZKF also supports rates at about 50%. This helped further incre- The Interdisciplinary Centre for Clinical Re- young medical students within IZKF projects ase the acceptance of internal peer-review and search (IZKF) was founded in 1996 under the with grants and a special training program- thus increasing the ability to successfully ap- major topic “Inflammatory Processes: Aetio- me. An annual seminar for MD and PhD stu- plying for extramural funding. In the last years pathogenesis, Diagnostics and Therapy”. Du- dents participating in all the different research both, junior groups and IZKF projects have ring the first 8 years (1996-2004) it recei- programmes at the Medical Faculty is organi- been very successful in this respect. The high ved funding from the Federal Ministry of Re- sed by the IZKF. standard of research done at IZKF also beco- search and Technology within the program- Furthermore, core units represent a strong mes evident through the large number of sci- me “Health related research 2000”. Beginning structuring element. Currently, 3 core units entists appointed to external chairs and pro- with the funding period 2004-2007 the IZKF’s are funded: fessorships. budget of 3.600.000 € was defrayed entirely by the state allowance for education and Z2 – Non-invasive high-resolution imaging of research of the University Hospital Erlangen. small animals (since Oct. 2002) Since several years, the University contributes Z3 – Affymetrix Platform (since Oct. 2007) to the budget - currently 150.000 € yearly - to Z4 – DNA-Extraction Platform (Biobank) support the participation of the institutes out- (since Jan. 2009) side the hospital. Currently 150 scientists from 31 departments, Supporting activities also include the “Visiting institutes and divisions participate in the IZKF Professor Programme” and a triennial interna- in altogether 42 projects from 4 major scientific tional scientific meeting. topics. Through the support of mainly clinically oriented research projects of high quality and through fostering of collaborations between Research clinically and theoretically working groups the IZKF aims to increase the overall quality of cli- The Interdisciplinary Centre for Clinical re- nical research at the Medical Faculty. New pro- search (IZKF) has established itself as a strong jects are established during triennial peer-re- central institution in the research environ- view visits of the scientific advisory board as ment of the Medical Faculty. The initial focus well as at yearly internal and external review on inflammation research could be developed sessions. After a single 3-year funding period further to also accommodate other research projects should be transferred to extramural areas, without sacrificing this distinctive topic,

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 157 Interdisciplinary Centres

Interdisciplinary Centre for Public Health (IZPH)

Speaker Prof. Dr. med. Hans Drexler

Contact PD Dr. med. Peter Kolominsky-Rabas, MBA

Address Schwabachanlage 6 91054 Erlangen Phone: +49 9131 8535855 Fax.: +49 9131 8535854 [email protected] www.public-health.de Successful evaluation of the IZPH by the Governing Body of the University: IZPH Executive Board (Speaker: Prof. Drexler; Managing Director: PD Dr. Kolominsky-Ra- Aims and Structure bas; Prof Gräßel) with the Governing Body of the University of Erlangen-Nürnberg (Vice- President Prof. Steinrück, Dipl.-Ing. Kramp) and the reviewers (Prof. Siebert, Austria, Prof. Röllinghoff, Germany) „Networking across scientific borders” is the unique selling proposition of the Interdiscipli- nary Centre for Public Health (IZPH). The IZPH is a multidisciplinary research centre consisting cer, stroke) as well as assessment of health care of different faculties of the University of Erlan- services funded externally with 2.5 mio. Euro. gen-Nürnberg: the primary objective of the With its emphasis on health promotion/preven- centre is to merge medical, economical and so- tive medicine, health economics/health tech- cial sciences and management in order to ad- nology assessment and federal health monito- vance research in public-health and resolve cur- ring the centre acts as the scientific platform for rent health care challenges of the aging society. outcomes research at the Friedrich-Alexander- Within the Nürnberg Metropolitan Region the University and as the main regional promoter. IZPH bundles all relevant stakeholders of the health care management industry i.e. medical professionals (doctors, hospital trusts, outpati- Teaching ent sectors); the payers (statutory health insu- rances); health technology providers (global Members of the IZPH are providing interdisci- operating companies like Siemens Healthcare plinary lectures and courses in the field of pu- and pharmaceutical manufacturers) as well as blic health, such as health economics, health patients and their family members acting as re- system research, health promotion and preven- search platform for the university. tion. Special focus is also given to lectures on public health issues for students of the Faculty of Economics and to the master program me- Research dical process management (M.Sc.).

The research focus of the centre is driven by its previous interdisciplinary research in the field of public-health, and takes special interest with respect to issues of health promotion/preventive medicine, health technology assessment/health economics and federal health monitoring. During the report period the centre performed a number of large-scale studies addressing research topics as need of care and resource use in chronically ill patients (dementia, can-

158 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Interdisciplinary Centres

Interdisciplinary Centre for Gerontology (ICG)

Speaker regulation of appetite. Hormonal influences (e. Teaching Prof. Dr. phil. Frieder R. Lang g. Ghrelin) seem to be of special importance in this case. The majority of the ICG-members is enga- Address ged in the interdisciplinary course offerings of Naegelsbachstrasse 25 Section: Physical activity the masters program in gerontology (M. Sc.). 91052 Erlangen Targeted activation of physical activity can im- Some courses are realized in close cooperation Phone: +49 9131 8526526 prove physical function and thus help to main- with the associated members of the ICG, es- Fax: +49 9131 8526554 tain independence in older persons (Project pecially those related to gerontological practi- [email protected] “EUNAAPA”). The “PASEO” project intends to ce. A series of lectures (Q7 – medical science of www.izg.uni-erlangen.de improve the implementation of programs for aging) focussing geriatric and ethical topics are the promotion of physical activity among se- organiseded by numerous members of the ICG dentary older people by supporting the deve- at the Medical Faculty of the Friedrich-Alexan- Aims and Structure lopment of new political capacities. Physical der-University. activity also seems to play a major role in the Furthermore, the ICG operates a collective gra- Since the foundation in 2003 the Interdiscip- treatment of mild cognitive impairment (Pro- duate school of gerontology, which provides linary Centre of Gerontology (ICG) is active in ject “Sports and Cognition”). Common un- structured lecturing for PhD students in ge- the fields of biological, medical, psychiatric, derstanding is that multifactorial physical exer- rontology as well as in psychology, psychiatry psychological, behavioral, humanistic, econo- cise helps to prevent falls and increases physical and sport sciences. mical and technological aging research. The ressources like strength and balance. But the centre initiates and supports interdisciplinary process of transfer from research into practi- collaboration on aging research at the Univer- ce still needs to be more investigated (Project sity of Erlangen-Nürnberg. The Centre of Ge- “Stable in old age”). The risk for falls is increa- rontology is also actively collaborating with sing with age, due to physiological and patho- communal institutions of medical care and with logic processes. 50 % of community dwelling nursing homes of the region. Currently the ICG older persons report at least one fall per year in has 27 members coming from four different fa- the age-cohort 80 years and over. To prevent culties and four associated institutions. further falls the first important step is a screening process to identify older persons at risk of falls (Project “Falls in the Nürnberg-Erlangen- Research Fürth-Area”).

Research of the members of the ICG focuses Section: Social relations predominantly on health promoting interven- Beyond dispute the quality of an efficient so- tion and prevention in the domains of nutriti- cial network plays a major role in maintaining on, physical activity and social environment. health and a prolonged time of independent li- Each area of research addresses specific social, ving in old age. For example, positive social re- institutional, technological and environmental lationships substantively contribute to impro- conditions and their effects on physical health, ved health and longevity, as well as to reduced autonomy and personal responsibility. risks of dementia and frailty. There is also some preliminary evidence suggesting that the asso- Section: Nutrition ciation of physical activity and nutrition partly Fully aware of the higher risk for malnutrition depends on the quality of social and family re- and it’s negative consequences for older peo- sources. Research also focuses on the biomedi- ple, different screening instruments of the nu- cal, psychological, and cognitive processes that tritional status were analysed in residents of enhance the quality of social ties in later life acute geriatric hospitals and of homes for the (“RELATE” project). Another research focus is aged (Project “MNA”). A one-year longitudinal on the situation of family caregiver, particular- study in a population of old people home re- ly with respect to caregiver burden, and to the sidents showed a higher survival-rate in obese potentials of psychoeducation of family caregi- persons (BMI > 30 kg/m2) compared to those ver (“GesA” project). Additional projects focus with a low body mass index (< 20 kg/m2) and on quality of caregiving in nursing homes. to those with normal BMI. The outstanding disposition of older people for malnutrition seems to be caused by age-associated changes in the

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 159 Interdisciplinary Centres

Interdisciplinary Centre for Functional Genomics (FUGE)

Speaker Aims and Structure notyping of SNPs. The availability of the Core Prof. Dr. med. André Reis Unit was instrumental in obtaining a large The “Interdisciplinary Centre for Functional Ge- grant from the Federal Ministry of Research Address nomics (FUGE)” was founded in 2001 as an or- within the National Genome Research Net- Institute of Human Genetics ganizational framework to focus and advance work (NGFN) for research on the genetic basis Schwabachanlage 10 activities in all areas of genomics research at of mental retardation. The “German Mental Re- 91054 Erlangen the FAU. Through initiation and fostering of in- tardation Network” (MRNET) aims at systema- Phone: +49 9131 8522318 terfaculty cooperation FUGE integrates the re- tically screening large patient groups for copy Fax: +49 9131 8523232 search field of “genetics and genomics” of the number variation (CNVs) in order to identify [email protected] Faculty of Engineering Sciences into the life novel genes for mental retardation. This natio- www.fuge.uni-erlangen.de/ sciences profile of the university. As a metho- nal network is coordinated by the FUGE-Spea- dological platform, FUGE opens access to the ker A. Reis. A detailed report on the activities complex methodology of genome research for of MRNET is found at page 150. groups working in other focus areas of research Several seminars were held during the re- of the medical faculty, e.g. cancer research, porting period under the auspices of FUGE infectiology and immunology as well as neu- on different topics including Next-Generati- rosciences and strengthens them through in- on-Sequencing technologies. After extensi- teraction. ve discussion of the properties of the different As an university facility FUGE acts so far as a platforms of this important technique, several dislocated centre without having any edificial FUGE members from the Medical and Natural structure of its own. About 15 groups are cur- Science Faculties developed a concept for im- rently involved in the centre. They originate plementation of this technique in Erlangen and from three faculties, the Medical, Natural Sci- prepared a grant application to introduce this ences and Engineering Sciences. Members of method here. FUGE offers an excellent struc- the Medical Faculty come from the Institutes ture to house this interfaculty endeavour. of Biochemistry, Experimental Medicine I and II, Human Genetics, Neuropathology, Micro- biology, Pathology, Pharmacology and Virolo- gy and Department of Gynaecology and that of Medicine 3 as well as the Divisions of Mole- cular and Experimental Surgery and Molecu- lar Immunology. Members from the Natural Sciences Faculty include the chairs of Biotech- nology, Genetics, Microbiology and Molecular Plant Physiology. From the Faculty of Enginee- ring Sciences are involved the Chair of Biopro- cess Engineering and the Computer Science Department 2 (Programming Systems).

The micro array facility started its operation in October 2007 after successful application for a HBFG-grant initiated by several members lead-managed by the speaker. It is operated by the Interdisciplinary Centre for Clinical Re- search (IZKF) which has taken over the interim financing of the personnel until the funds from the Bavarian Innovation Fund become available probably early 2009. These had been previously raised by Prof. A. Reis together with Prof. Sticht (Institute of Biochemistry, Medical Facul- ty). The laboratory is managed by the Institute of Human Genetics. During the reporting period the laboratory performed numerous analyses for many different groups, both in expression profiling as well as genome wide ge-

160 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Programmes and Foundations for Research Support

ELAN programme for supporting clinical research and teaching

Speaker Prof. Dr. rer. nat. Michael Wegner

Address Scientific Office of the Faculty of Medicine Dr. Annette Pfeiffer Oestliche Stadtmauerstrasse 30a 91054 Erlangen Phone: +49 9131 8523708 Fax: +49 9131 8522224 E-mail: [email protected] www.elan.med.uni-erlangen.de

Aims and Structure

The ELAN programme has been designed, according to the guidelines of the National Sci- ence Council and the Conference of Ministers of Cultural Affairs, to support clinical research and teaching. A total of 1.2 Mio € annually are „Spannungsfeld“ by Silvia Stabel devoted to funding projects for limited periods of time taking also into consideration the previous work done by the respective researchers. Decisions on the distribution of funding are made by a committee of faculty members consisting of seven professors from various cli- grant providers. A short term support for per- high ranking or well respected journals. Additi- nical and preclinical departments, the dean of sonnel and running costs for 6 to 12 months onally 74 (8 in 2007, 8 in 2008) grants were ac- the faculty, the clinical director and the chair- appeared best suited for this purpose. From quired from external funding sources (1.1 Mio man of the research advisory board. Main pur- mid 1998 until the end of 2008, a total of 616 € in 2007, 2.8 Mio € in 2008) amounting since poses of the programme are financial support grant applications have been submitted (2007: 1998 to a total of 13.5 Mio €. for research projects, promotion of innovative 63, 2008: 47) coming from virtually all clinical didactic models and internationalization of cli- departments including the IZKF. The numbers In conclusion, the ELAN programme has suc- nical teaching as well as its evaluation. of grant proposals from the respective depart- cessfully stimulated a surge in high quality re- ments reflected both their sizes and research search projects from all clinical departments. activities, though to different extents. The ave- This emphasizes the value of this programme rage requested funding was about 33.000 € for dynamically improving clinical research in Research project support in 2007 and increased in 2008 to 39.000 €, our faculty. at least in part because of rising personnel ex- First of all, funding is provided for projects of penses. The total amount of funding reques- highly qualified young investigators and newly ted ranged from 2.1 Mio € in 2007 to 1.8 Mio established groups. Besides this, pilot projects € in 2008. The total amount of granted money and bridging of financial gaps in ongoing in- oscillated around 1.2 Mio € annually reflecting vestigations are also supported. It is intended the total available resources. External peer re- to enable as many qualified investigators as view of grant proposals is required for funding possible to raise further funding from external requests above 20.000 €. Besides scientific excellence of the project, the committee also con- siders in its funding decisions compliance with other prime goals of the ELAN programme, e. g. start or young investigator support. Since 1998 a total of 405 out of 422 projects were completed, representing a total funding of 9.5 Mio €. From these projects, 223 papers (37 in 2007, 20 in 2008), were produced mostly in

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 161 Programmes and Foundations for Research Support

Johannes and Frieda Marohn-Foundation

Speaker Accepted projects (Time of funding 2007 – 2008) Prof. Dr. med. Dr. med. dent. Friedrich W. Neukam Financial year Budget Number of accepted applications 2007 360,199.- € 12 = 337,375.- € Address Department of Oral and Maxillofacial Surgery 2008 341,194.- € 6 = 150,565.- € Glückstrasse 11 91054 Erlangen Phone: +49 9131 8533601 Fax: +49 9131 8536288 [email protected] Finalized projects (Time of funding 2004 – 2006) www.mkg-chirurgie.uk-erlangen.de Continued funding by Number of projects Number of publications other foundations *

31 50 (from 26 projects) 13 projects Aims and Structure * DFG = 7 projects; other foundations = 6 projects According to the founders’ will, the purpose of 18 projects could not obtain further financial support the J.F.M. Foundation is the promotion of new innovative projects of the Medical Faculty of the Friedrich-Alexander-University Erlangen- Nürnberg, serving diagnosis, prevention and therapy of diseases in general. Projects dealing with diseases in the field of gastroenterology including all liver and pancreatic diseases with diabetes, cancer, and medical data bases shall be supported preferentially. On the other hand, the founders explicitily have stated that the purpose of the foundation can be adapted to other modern developments and needs of medical research taking place at the Medical Faculty of the Friedrich-Alexander-University Erlangen-Nürnberg.

According to the rules of the foundation, 5 members of the faculty have to be elected for a 3 years period to serve on the scientific board of the foundation. Five additional members of the faculty have to be elected to replace members of the scientific board in case of time conflicts or conflict of interests.

Only clearly definde, relevant scientific projects will be granted. Grants can be used for personnel, equipment, consumables as well as for costs of cooperation between scientific and clinical departments.

Grant applications should be sent to the president of the scientific committee. The rules of the foundation itself can be provided by the secretary of the Johannes and Frieda Marohn- Foundation.

162 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Programmes and Foundations for Research Support

Further foundations for research support

In addition to the ELAN programme and the entific achievements in the field of immunopa- donation with base in Nürnberg. Its aim is to Marohn Foundation, a number of foundations thogenesis of hepatitis B and C viral infection. support gifted young physicians who come and endowments are established at the Medi- from the franconian area. To achieve this goal cal Faculty, which support research. There are End of 2007 the Research Foundation of Me- there are awards for extraordinary research re- more than 20 supporting associations, who dicine at the University Hospital Erlangen was sults, benefits for doctorate theses, postdocto- in most cases work closely with an institution. founded at the initiative of the professors of ral qualifications and research projects as well Furthermore, there are donations to the Medi- the University Hospital Erlangen and the Medi- as grantships for a stay in a foreign laboratory. cal Faculty (e.g. Dr. Jahn Donation, Elise Pittroff cal Faculty of the Friedrich-Alexander Universi- The best and most concise postdoctoral qua- Donation). Science supporting foundations are ty Erlangen-Nürnberg. Purposes of the found- lification (Habilitation) is awarded anually by of particular relevance for the research advan- ation are advancement of science and research the Thiersch Prize. Most outstanding doctoral cement. Amongst the foundations that are ad- in all areas of basic and clinical medicine, also theses are awarded by the Staedtler Prize. The ministrated by the university or closely con- the advancement of apprenticeship and further Foundation for Teaching (www.stiftung-lehre. nected to the Medical Faculty, only the most training of scholars as well as physicians and de) was founded to support and improve the important ones are to be mentioned in detail: scientists, the advancement of public health education of young clinicians. The Dr. Fritz Erler Award for a reputed physi- system (particularly with regard to the area of cian engaged in meritorious surgical medici- prevention and early diagnosis of disease) and ne is donated every three years by the Dr. Fritz benevolence within the medical care of pati- Erler Fund. In 2005 the prize was given to Prof. ents in need. Besides, it is planned that prizes Dr. Friedrich Magerl, Switzerland, for his out- for outstanding achievements of scientists as standing contributions to spinal surgery. The well as scholarships and education allowances Dr. Fritz Erler junior prize was newly establis- for gifted learners will be awarded. hed and first given to Prof. Stephan Ensmin- ger, cardiac surgery, to appreciate his results In 2006 the Dr. Kurt and Magarete Groß Do- in the role of CD40-CD154 blockade in the nation was founded for the advancement of pathological mechanisms leading to the de- special achievements in the field of cardiology, velopment of transplant arteriosclerosis. The cardiac-physiology or cardiac surgery. The Ria Gottfried and Lieselotte Naumann Fund make Freifrau von Fritsch Foundation (contact: Mr. V. contributions to ophthalmology, especially to Paul, Ref. F3, ZUV) was established to support clinical ophthalmo-pathology and to micro- cancer research and to finance the Ria Freifrau surgery of the eye. In a four-year rhythm the von Fritsch Prize for an outstanding research prize is given to an extraordinary researcher. achievement. The Sofie Wallner Foundation 2006 the first-time award was donated to Prof. (contact: Mr. H. Riepel, Ref. F3, ZUV) also sup- Thaddeus Dryja, Harvard Medical School, Bos- ports cancer research, especially highly gifted ton, USA, for his fundamental contribution to young researchers interested in oncology by the molecular basics of retinitis pigmentosa, at travel grants to enable a research project in a the World Meeting for Ophthalmology and Vi- guest laboratory in a foreign country. Research sion in Sao Paulo, Brasilia. The Dr. Norbert Hen- projects in environmental medicine can be sup- ning Foundation gives every two years a prize ported by the Adolf Rohrschneider Foundati- for research in the field of gastroenterology. on (contact: Mr. J. Hubert Ref. F3, ZUV). 2007 2007 Prof. Dr. Robert Thimme of the Univer- a project of Prof. Dr. H. Drexler, Institute for sity Hospital Freiburg was awarded for his sci- Occupational, Social and Environmental Medi- cine, to environmental medical lead exposure of hobby shooters via shooting sport was cofi- nanced. The Wilhelm and Helene Dörfler Foun- dation (contact: Prof. Dr. G. Schett, Depart- ment Medicine 3) offers support for projects in clinical immunology (especially rheumatology). The Johanna Prey Foundation (contact: Prof. Dr. J. Kornhuber, Department of Psychi- atry ans Psychotherapy) supports research in the field of Alzheimers disease, especially by giving grants for doctoral theses. The Dr. Ernst and Anita Bauer Foundation is an unaffiliated

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 163 Academic society

Society for Physics and Medicine Erlangen

Speaker 7896-0441-6)). Marco Ritter describes the life Prof. Dr. habil. Dr. med. h. c. Willi A. Kalender of Isidor Rosenthal (1836-1915) who was the first independent physiologist of the Universi- Address ty Erlangen. In this work not only the aspects Institute of Medical Physics of life and work of Isidor Rosenthal but also de- Henkestrasse 91 tailed information on the former circumstan- 91052 Erlangen ces in Poland, Berlin, Erlangen and in the war Phone : +49 9131 8522310 of 1870/1871 between Germany and France Fax: +49 9131 8522824 were given. E-Mail: [email protected] www.imp.uni-erlangen.de/Physicomedica In the year of celebrating the 200th birthday the Medical Society that had been separated in 1958 after the 150th celebration of the Phy- Aims and Structure sico Medica united again with the Society for Physics and Medicine Erlangen. The Erlangen Society for Physics and Medici- sists of four single issues (ISSN 0371-2117). Be- ne, also known as Societas physico-medica Er- side scientific papers the reports contain recent langensis, was founded on March 20, 1808 in outstanding academic speeches, for example order to exchange “ideas, observations and ex- inaugural or farewell speeches, addresses on periences between all the areas of natural sci- the occasion of honorary promotions and of ences and medicine”. These first statutes and the annual graduation ceremony of the Facul- articles, defined in the year 1808, are still valid; ty of Medicine of the University of Erlangen. by amendment of the statutes in 1990 the tech- On June 18th 2008 the Erlangen Society for Phy- nical disciplines have also been admitted. sics and Medicine celebrated its 200th birthday At present, the society has about 490 members in a ceremony at the castle of the University inside and outside Germany, six of them hono- of Erlangen. After the greeting from Prof. Dr. rary and 55 corresponding members. Karl-Dieter Grueske, president of the Universi- ty of Erlangen-Nürnberg, Prof. Dr. Renate Wit- Every semester the society holds three regular tern-Sterzel, head of the Chair of the History of meetings with lectures given by members or in- Medicine, gave a lecture on the early history of vited guests. From 1984 to 2008 nine volumes the Physico-Medica. The invited lecture on “Il- of reports were published, each of them con- luminating Post-Genome Biology with Tomo- graphic Photoning Imaging” was held by Prof. Dr. Vasilis Ntziachristos, Director of the Institute of Biological and Medical Imaging at the GSF- Research Centre on Environment and Health. On the occasion of the 200th birthday the society presented a festschrift (Ritter, Marco: Isi- dor Rosenthal. Forscher - Arzt - Politiker. Fest- schrift zur 200-Jahrfeier der Physikalisch-Me- dizinischen Sozietät zu Erlangen. Verlag Palm & Enke, Jena und Erlangen 2008 (ISBN 978-3-

164 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Degree Programmes

Degree Program in Medicine

Speaker Prof. Dr. med. Hans Drexler Institute and Outpatient Clinic of Occupa- tional, Social and Environmental Medicine, Clinical study section

Prof. Dr. med. Winfried Neuhuber Anatomical Institute I Preclinical study section

Address Institute and Outpatient Clinic of Occupa- tional, Social and Environmental Medicine Schillerstrasse 25/29 91054 Erlangen Phone: +49 9131 8522312 Auscultation on a phantom in the skills lab Fax: +49 9131 8522317 [email protected] www.studiendekanat.med.uni-erlangen.de

Anatomical Institute I Krankenhausstrasse 9 91054 Erlangen many (ZVS). The number of places in the study for Dentistry. The awarded instructor receives Phone: +49 9131 8522265 programs Medicine and Dentistry is reassessed a certificate for good teaching; the grants go Fax: +49 9131 8522863 each semester by the Administrative Court Ans- to the instructor’s clinic or institution and add [email protected] bach due to the fact that applicants for a place to their respective budgets. Instructors in the erlangen.de in the study programs take their cases to court. pre-clinical or theoretical part of the medical www.studiendekanat.med.uni-erlangen.de study program (semester 1-4) receive certifi- cates only; grants cannot be awarded due to Online-Evaluation cameralistic accountancy. Additionally, the de- Aims and Structure partments that offer the top ten classes - ac- Each semester, all courses are evaluated online cording to the student evaluations - are awar- The Medical Department consists of three by the students with the help of the online eva- ded a total of 165,000 Euro. A class can, howe- study programs: Medicine, Dentistry, and Mo- luation system EVALuna (Dr. Ganslandt, Insti- ver, only receive a grant if it has been evaluated lecular Medicine. In the 2007/08 winter term tute for Medical Informatics). The results of the by at least 20% of the students in the respec- 2,680 students were enrolled in these three online evaluation are presented and discussed tive semester. study programs, of which 1,660 were fema- in the central faculty meeting once per semes- le. Thus, the percentage of women studying ter by the Dean of Student Affairs. A major part In the winter term 2007/2008 2015 students in the Medical Department remained constant of the state funds in the university clinics is dis- participated in the online evaluation, 1.414 of at 62 %. According to the statistics of the Uni- tributed according to the results of the online them enrolled in the study program Medicine, versity of Erlangen-Nürnberg for the 2007/08 evaluation. Each semester the students vote for 471 in Dentistry, and 130 in Molecular Medi- winter term, 227 of the students enrolled in the the best lecturers and monetary sums are awar- cine. Thus, the Medical Department evaluates Medical Department were foreigners, which is ded to the clinic or institute that the winners all medical courses in all semesters, thus fulfil- about 8.5 %. Compared to the last year that are employed by. It is noteworthy that teaching ling the requirements of the approbation re- constitutes a rise in the percentage of foreig- awards are financed by the achievement-orien- gulations (ÄAppO). The last year of the study ners enrolled in the Medical Department of ted funds allocation (LOM). Clinics and institu- program medicine, the practical training year about 2.5 percentage points. tions whose instructors do best in the online (PJ), is also evaluated by the students online. evaluation receive grants for good teaching In the 2007/08 winter term, 273 of the students performance. The best three instructors of the began their first semester in the Medical De- clinical part of the study program (semester 5 Skills Lab PERLE partment, 176 in the study program Medicine, – 10) for Medicine receive grants of 30.000, 62 in Dentistry, and 35 in Molecular Medicine. 20.000 and 10.000 Euro. Since fewer profes- Since the introduction of student fees in Ger- Applicants for the study programs Medicine, sorships in the study program for Dentistry many in 2007, the Medical Faculty has had the Dentistry, and Molecular Medicine are chosen participate in the instruction of students, only means to expand the activities in the Skills Lab according to the criteria of the Central Office one grant (10,000 Euro) is awarded to an inst- PERLE. Medical students now take one manda- for the Allocation of university places in Ger- ructor in the clinical part of the study program tory class in the Skills Lab in the fifth semester.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 165 Degree Programmes

Training of surgical suturing in the skills lab

The approbation regulation’s goal for improve- Medical State Examination ment in teaching basic practical medical skills has thus been furthered. The Skills Lab PERLE In 2008 students in Erlangen achieved very offers students an opportunity to practice me- good results in the Medical State Examination dical examination skills while being instructed part one and two. All medical students in Ger- by well-trained student-tutors and doctors. many take the same examination. Therefore, Students can, among other things, practice results are objective and comparable. Accor- auscultation, catheterization, or taking blood ding to the students’ State Examination results, with the help of artificial arm-models. the Medical Faculty in Erlangen belongs to the Skills Lab PERLE is fully funded by student fees top group of Medical Faculties in Germany. and a visible enrichment of the medical education in Erlangen. Courses can be attended by all students during the semester. Additionally, the Skills Lab offers special courses during the lecture free time. In the near future, the Skills Lab will offer special courses for students in the dentistry study program in the field of surgical suturation.

166 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Degree Programmes

Degree Program in Dentistry

Speaker ons for the practice of medicine are already in Our dental clinic is equipped with high-quality Prof. Dr. med. dent. Anselm Petschelt effect has resulted in a clear separation of the technical systems in sufficient numbers so that training we provide in dentistry from the trai- we have no trouble satisfying the demands Address ning we provide in medicine. and needs that arise in connection with den- Department of Operative Dentistry and tistry training. National and international qua- Periodontology As in the first phase of medical school, the lity comparisons show that our standards are Glueckstrasse 11 calculation of admission figures for dentistry very good. All the necessary prerequisites are 91054 Erlangen school is based on a ratio of students to clini- given for our students to receive modern, clini- Phone: +49 9131 8533602 cal academic teaching staff. These parameters cally oriented training in the field of dentistry. Fax: +49 9131 8533603 are considerably less favorable for dentistry stu- The Erlangen School of Dentistry continues to E-mail: [email protected] dents than for medical students (for instance, maintain a leading position in German univer- www.studiendekanat.med.uni-erlangen.de/ in terms of the amount of supervision and sup- sity rankings published by the CHE (Centre for port provided to students during clinical in- University Development). ternships, where they are required to treat patients, there is an average ratio of 6 students Aims and Structure per academic staff member in dentistry school as opposed to somewhere between 3 and 6 The school of dentistry at the University of Er- students per academic staff member in medi- langen-Nürnberg currently admits 110 stu- cal school; academic credit factors for intern- dents per year, despite the fact that our clinical ships are 0.3 for dentistry students as opposed facilities were originally designed to accommo- to 0.5 for medical students). Cases of unexpec- date a maximum enrollment of 100 students. ted rises in enrollment resulting from lawsuits The overall amount of time dedicated to curri- successfully filed against admissions restric- culum teaching and examinations at dentistry tions have become fewer in recent years, so school is quite considerable, given the extensi- that in fact there have been no further unex- ve role played by practical training, compared pected increases in enrollment. Under the con- to what is the case with subjects taught at me- ditions offered by LOM, a performance-based dical school. New licensing regulations for the funding scheme, finances for teaching the den- practice of dentistry have been formulated, but tistry school curriculum have improved. Under are not likely to go into effect for the foreseeab- this scheme the financing of staff positions, le future. The fact that new licensing regulati- whether academic or non-academic (the latter also essential to ensure a good training environment), can be guaranteed on a long-term basis. Teaching evaluation is part and parcel of the training program at our dentistry school. The results are used in the process of updating and restructuring our curriculum with a view to achieving steady improvement in the quality of teaching.

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 167 Degree Programmes

Degree Program in Molecular Medicine

Speaker dicine (M.D.), curricular programs in the basic The freshmen in Molecular Medicine are wel- Prof. Dr. med. Cord-Michael Becker medical sciences (biochemistry, pharmacology, comed by an annual symposium, introducing physiology etc.) are offered leading to M.Sc. them to the program and the Medical Faculty Address or Ph.D. degrees (Master of Science / Doctor of the University of Erlangen-Nürnberg. In re- Institute of Biochemistry of Philosophy). cent years, these symposia have encountered Emil-Fischer-Centre an extraordinary interest among the new stu- Fahrstrasse 17 The B.Sc./M.Sc program in Molecular Medici- dents. Moreover, students are offered support 91054 Erlangen ne in Erlangen addresses these needs and of- by an academic mentoring program. The men- Phone: +49 9131 8524190 fers an interdisciplinary curriculum in the me- tors are recruited among the lecturers involved Fax: +49 9131 8522485 dical basic sciences, which also covers clinical in the B.Sc. program, ensuring a close feedback Email: [email protected] aspects. The B.Sc. program covers 6 semesters, from students to faculty. www.MolMed.de emphasising a solid and thematically diversified education in basic science. The first semesters its syllabus heavily draws on contributions from Applications, development Aims and Structure the science faculties (physics, inorganic/physi- of student numbers and imple- cal/organic chemistry). The second year focu- mentation of the program The degree program in Molecular Medicine ses on preclinical aspects, the curriculum of the combines both, the subjects of experimen- third year will be extended with a focus on pa- Potential applicants are introduced to the pro- tal medicine and the approaches of molecu- thology and experimental therapy. The B.Sc. gram in Molecular Medicine by the Chair of lar biology, biochemistry, and genomics. This program ends with a scientific thesis. Biochemistry and Molecular Medicine, the program acknowledges the fact that bound- Starting in winter semester 2010/11, when first central advisory service of the Friedrich-Alex- aries which traditionally separate biomedical graduate students of Molecular medicine have ander-Universität, as well as by brochures and disciplines have long lost their meaning. The finished, a consecutive master program will the internet homepage www.MolMed.de. The Faculty of Medicine has created a future-ori- be offered to them as well as for applicants program has been registered with internet ser- ented program for medical scientists interes- with similar qualifications. The main training vices (studieren.de) and search engines (Goog- ted in research careers in industry, administ- goal of this four semester program is to acqui- le, Lycos etc.). Indeed, the internet represents ration, and universities. Nationwide, this pro- re a deeper understanding of science by wor- the single most important source of informati- gram in Molecular Medicine has been met by king with original publications and ambitious on among freshman students: about 70 % of an extraordinary interest. Each academic year, practical training. Whereas the B.Sc. focuses on first contacts with Molecular Medicine have 34 students are admitted, as compared to more functional aspects the M.Sc. program mediate been made via the internet. Asking students than 700 applications. The winter semester interdisciplinary themes which are taught to- for their alternative choices in case they would 2007/2008, the first class has been admitted gether by different institutes. This profile is al- not have been admitted to Molecular Medi- to the novel B.Sc./M.Sc program, consistent ready practised in the course of ‘molecular pa- cine, most students listed medicine, bioche- with the declaration of Bologna. Accordingly, thomechanisms’ performed by biochemistry, mistry, or biotechnology. At present, half of the traditional, very successful ‚diploma track‘ pathology and physiology institutes. The M.Sc. the students enrolled in Molecular Medicine program will end. ends with a 6 month master thesis. are in-state students from Bavaria, while the other half originate from other German ‚Län- Compared to the ‘Diploma’ program, the de- der‘ (states) or are international students. This Objectives of the degree gree program will be able to address an additi- situation demonstrates the nationwide attrac- program in Molecular Medicine onal topic by receiving additional support from tiveness of our study program. the Innovation Initiative at the University of Er- Under the influence of molecular and cellular langen-Nürnberg: a newly established profes- Presently, more than 22 applicants compete for methods, medicine has changed fundamen- sorship for molecular medicine will further ex- one admission slot in Molecular Medicine. For tally. Yet, higher education in Germany has tend the curriculum by the new module ‘Mole- the Winter term of 2008/2009, admission re- only begun to reflect these changes. Traditio- cular imaging‘. This module will reflect another quirements for the program had reached the nally, subjects and methods of molecular me- scientific strength of Erlangen, as it will bridge highly selective grade point average of 1.2, re- dicine are distributed over different ‚Fakultä- the gap between the degree program and in- presenting extremely strict criteria. Admissi- ten‘ of our universities. Degree programs in dustrial applications. The Master program Mo- on procedures follow federal and state regu- the biological sciences offer many of the me- lecular Medicine offers 4 groups (A-D) of com- lations (Bayerische Hochschulzulassungsver thods used in molecular medicine, but do so pulsory optional subjects, one of each has to ordnung). Accordingly, 90 % of admissions without a systematic presentation of medical be selected and a single has to be selected for are based on the Gymnasium grade point ave- subjects. In medical programs, on the other specialisation. rage, while another 10 % of admissions are hand, basic science aspects are widely restric- A. Structure and development granted based on a waiting period. Both, the ted to the needs of medical practice. This con- B. Signal cascades and active components admission procedure and the underlying ca- trasts the situation at medical schools in the C. Infection and pathogenesis pacity regulations have been approved by the USA: in addition to the doctoral degree in me- D. Molecular imaging Administrative Court of Bavaria (Bayerischer

168 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Verwaltungsgerichtshof) in Munich. These ru- lings underscore the right of the university to adapt educational programs to current scientific developments.

Since winter term 2007/2008, the new B.Sc. program is offered. It has been our experience that a small number of students drop out of the program before completing the first semester and, again, after the fourth semester when the ‚Vordiplom‘ examinations are due. When asked for their reasons to quit, the students leaving the program frequently attribute their decision to the demanding requirements of basic science studies. We have responded to this drop out rate by intensifying counselling of applicants and offering an online admission test at www.MolMed.de. The number of students leaving, however, is exceeded by the number of applicants trying to enter from medicine, biochemistry or biotechnology. Generally, these Initiative at University of Erlangen-Nürnberg. employment options include research and de- applicants are advised to continue their current The laborious restructuring of the Diploma pro- velopment as well as production and quality academic programs. gram Molecular Medicine to the two-stage Bo- control, marketing or administration. Private The undergraduate phase of the ‘Diploma’ pro- logna schema is currently supported by a half laboratories, hospitals, and authorities depend gram ended with the ‚Vordiplom‘ examinations administration position. on university graduates experienced in mole- taken place for the last time in winter semes- As expected from its interdisciplinary ap- cular diagnostics, DNA and protein diagnostics ter 2008/09. The fraction of students, who suc- proach, the program in Molecular Medicine for medical and biotechnological applications. cessfully passed these examinations in the mi- offers strong interactions with the pure science In a longer perspective, the degree program nimum period of time, has exceeded 80 %. In programs. In particular, the Molecular Science in Molecular Medicine will prove its concepts summer of 2004, the ‚Diplom‘ degree has been program run by the departments of chemistry through successful professional and academic conferred to the first class of the program. In and pharmacy offers complementary topics careers of its graduates. each graduation class, several excellent theses in the life sciences, bio- and nanotechnology. have won prices from the university or exter- Since the Erlangen program in Molecular Medi- nal foundations. cine has been established, similar courses have In contrast to the ‘diploma’ program, the B.Sc. also been introduced by the Universities of Frei- Molecular Medicine according to the declara- burg, Würzburg, Bonn, Göttingen and Ulm. tion of Bologna is characterized by close-mes- hed and course-related exams which are continuously documented in an electronic manage- Perspectives ment system. A lot of students -also high-capacity course participants- feel this situation The degree program in Molecular Medicine incriminating. As the more flexible time sche- has paved the way for a high-quality doctoral dules of Diploma program are no longer availa- program at Friedrich-Alexander-University of ble, the formal specifications and recordings Erlangen-Nürnberg. Graduates may enrol in a have urgently been to liberalise. Otherwise doctoral program (Dr. rer. nat.) offered in col- the number of drop out students will rigorous- laboration with the Faculty of Sciences. At pre- ly increase. sent, the first graduates of Molecular Medicine The core curriculum in Molecular Medicine is program are in a stage of completing their doc- mainly taught by preclinical and theoretical in- toral theses. The degree program in Molecular stitutes, and the Nikolaus-Fiebiger-Centre. In Medicine is intended to enable its students to its first decade, the degree program in Mo- successfully contribute to scientific and practi- lecular Medicine has been implemented in a cal work in medical research, laboratory diag- very efficient way, with no additional universi- nostics, and medical biotechnology. A variety ty budget or outside funding available. In the of occupational fields in industry, private labo- meantime, a new professorship for molecular ratory and public institutions will be open to imaging has been awarded by the Innovation graduates of Molecular Medicine. Industrial

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 169 Degree Programmes

Medical Process Management

Speaker Aims and Structure and 2009/2010. With the master degree in Prof. Dr. med. Dr. h. c. Jürgen Schüttler Medical Process Managemnet an improved The degree programme in Medical Process Ma- understanding of administration and manage- Address nagement is structured as a non-consecutive ment in healthcare systems should provide best Department of Anaesthesiology master programme in order to attract gradua- chances to get employment in diverse fields of Krankenhausstrasse 12 te students of different faculties, primarily na- healthcare management, development of new 91054 Erlangen tural sciences, social and economic sciences, medical technologies, and optimized clinical Phone: +49 9131 8533676 engineering, as well as dentistry and molecular pathway management. Fax: +49 9131 8539191 medicine. The curriculum aims to give insight www.mpm.med.uni-erlangen.de into three major areas: first of all the economical aspects of healthcare are an important subject as well as management and organization of patient care in hospitals and office-based medicine. Finally, much emphasis will be put into the knowledge transfer from clinical medicine into the diverse fields of patient care.T his master programme offers 30 different major topics provided within three faculties of Erlangen Uni- versity. A total of 120 ECS-points are necessary to complete successfully this programme. 20 and 30 students respectively have started with the first and second study years 2008/2009

170 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) APPENDIX

Honorary Doctorate

Honorary Doctorate 2007

Prof. Dr. Hermona Soreq Faculty of Mathematics and Natural Sciences of the Hebrew University Jerusalem, Israel

Honorary Doctorate 2008

Prof. Dr. Dontscho Kerjaschki Medical University of Vienna, Austria

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 171 APPENDIX

A Selection of Awards 2007 – 2008

Ernst Jung-Karriere-Förderpreis für Gerhard-Fürst-Preis des Statistischen Bundesamtes Medizinische Forschung 2007 Dr. rer. nat. Matthias Schmid Dr. med. Jörg Distler Institute of Medical Informatics, Biometry and Epidemiology Department of Medicine 3 – Rheumatology and Immunology Zweiter Preis der Kategorie Grundlagenforschung des Förder- Ferdinand Sauerbruch Forschungspreis der preises für Schmerzforschung Berliner Chirurgischen Gesellschaft Dr. med. Katharina Zimmermann PD Dr. med. Ulrich Kneser Institute of Physiology and Pathophysiology Department of Plastic and Hand Surgery Dr. med. Andreas Leffler Department of Anaesthesiology Innovationspreis der Deutschen Gesellschaft für Arbeits medizin und Umweltmedizin (DGAUM) XVI. International Blindness Prevention Award Prof. Dr. med. Hans Drexler, Prof. Dr. rer. nat. Jürgen Angerer and Prof. emerit. Dr. med. h. c. mult. Gottfried O.H. Naumann Dipl.-Chem. Karl-Heinz Schaller Chair of Ophthalmology Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine Latsis-Preis der Europäischen Wissenschaftsstiftung ESF Prof. Dr. med. Dr. habil. Willi Kalender, Ph.D. BRAHMS-Forschungspreis der Deutschen Gesellschaft für Chair of Medical Physics Nuklearmedizin Herr cand. med. Daniel Bläser Pettenkofer-Preis Department of Nuclear Medicine Prof. Dr. rer. nat. Michael Hensel Institute of Clinical Microbiology, Immunology and Hygiene Helen-Keller-Prize for Vision Research Prof. Dr. med. Elke Lütjen-Drecoll, Chair of Anatomy II Innovationspreis und Wissenschaftlicher Vortragspreis Prof. emerit. Dr. med. Johannes Wilhelm Rohen der Deutschsprachigen Arbeitsgemeinschaft für Chair of Anatomy II Mikrochirurgie (DAM) Dr. med. Justus Beier Innovations-Preis 2007 der Familie-Klee-Stiftung Department of Plastic and Hand Surgery Prof. Dr. med. Georg Michelson Department of Ophthalmology Forschungsförderungspreis der Deutschen Gesellschaft für Geriatrie Wissenschaftspreis 2007 der Deutschen Gesellschaft der Prof. Dr. med. Karl G. Gassmann Plastischen-, Rekonstruktiven- und Ästhetischen Chirurgen Institute of Biomedicine of Aging und der Vereinigung der Deutschen Ästhetischen Plastischen Chirurgen (Habilitationsschrift) Ehrenpreis der Deutschen Gesellschaft für Geriatrie PD Dr. med. Alexander Bach Dr. med. Jürgen Bauer Department of Plastic and Hand Surgery Institute of Biomedicine of Aging

Wissenschaftspreis der Deutschen Gesellschaft der Hans J. Dengler-Preis für Klinische Pharmakologie Plastischen, Rekonstruktiven und Ästhetischen Chirurgen Dr. rer. nat. Hartmut Gläser Prof. Dr. med. Raymund Horch Institute of Experimental and Clinical Pharmacology and Toxicology Department of Plastic and Hand Surgery Wilhelm-Feuerlein-Forschungspreis 2007 Auszeichnung der Habilitationsschrift mit dem Wissenschafts- Prof. Dr. med. Stefan Bleich preis 2007 der Deutschen Gesellschaft für Zahnärztliche Institute of Experimental and Clinical Pharmacology and Toxicology Hypnose (DGZH) e.V. PD Dr. med. dent. Stephan Eitner Sertürner-Preis 2007 Dental Department 2 - Prosthetic Dentistry Prof. Dr. med. Dr. h. c. Kay Brune Doerenkamp-Chair of Innovations in Animal and Consumer Protection Hans-Jörg Weitbrecht-Preis für Klinische Neurowissenschaften Prof. Dr. med. Rolf Schröder Innovationspreis eHealth 2008 Institute of Neuropathology Prof. Dr. med. Georg Michelson Department of Ophthalmology

172 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Ernst-Derra-Preis 2008 Forschungsförderungspreis der Prof. Dr. med. Robert Cesnjevar Deutschen Zöliakie-Gesellschaft e. V. 2008 Department of Cardiac Surgery PD Dr. rer. nat. Walburga Dieterich und Dr. Birgit Esslinger Department of Medicine 1 – Gastroenterology, Lung Diseases and Forschungspreis 2008 der Dr. Geisenhofer-Stiftung Endocrinology Dr. med. Tamme Goecke Department of Obstetrics and Gynaecology Erster Preis der Kategorie Grundlagenforschung des Förder- Dr. med. Udo Reulbach preises für Schmerzforschung 2008 Department of Psychiatry and Psychotherapy PD Dr. rer. nat. Andreas Hess Institute of Experimental and Clinical Pharmacology and Toxicology Ted Stanley Award for Innovation in Anaesthetic Pharmacology Sir Hans Krebs-Preis 2008 Prof. Dr. med. Dr. Dipl.-Phys. Helmut Schwilden Prof. Dr. med. Anita Rauch Department of Anaesthesiology Institute of Human Genetics

Auszeichnung der Diplomarbeit mit dem Kulturpreis Bayern der E.ON Bayern AG Werner von Siemens Excellence Award 2008 Dr. med. Teja W. Groemer Philip Stenner Department of Psychiatry and Psychotherapy Institute of Medical Physics Auszeichnung der Diplomarbeit mit dem Preis für die beste wissenschaftliche Arbeit aller Friedrich-Wingert-Nachwuchspreis Bayerischen Frauenkliniken Herr cand. Dipl. Inf. Andreas Beck Prof. Dr. rer. nat. Ralf Dittrich Institute of Medical Informatics, Biometry and Epidemiology Department of Obstetrics and Gynaecology Förderpreis 2008 der Albert-J.B.-Sturm Stiftung Preis für gute Lehre an Bayerns Universitäten Dr. med. Frank Unglaub Dr. med. Wolfgang Frobenius Department of Plastic and Hand Surgery Department of Obstetrics and Gynaecology Preis der Union of European Neonatal and Forschungspreis für geburtshilfliche Forschung Perinatal Societies (UENPS) in Europa 2008 Prof. Dr. Holm Schneider Dr. med. Tamme W. Goecke Department of Pediatrics Department of Obstetrics and Gynaecology Dr. med. Udo Reulbach Department of Psychiatry and Psychotherapy

Franz Kölsch-Preis 2008 Dr. med. Gintautas Korinth Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine

Georges-Koehler-Preis der Deutschen Gesellschaft für Immunologie Prof. Dr. rer. nat. Diana Dudziak Department of Dermatology

PHOENIX-Phamazie-Wissenschaftspreis 2008 Prof. Dr. med. Torsten Kuwert Chair of Clinical Nuclear Medicine

Hauptpreis 2008 der Stiftung der Deutschen Gesellschaft für Hygiene und Mikrobiologie Prof. Dr. rer. nat. Michael Hensel Institute of Clinical Microbiology, Immunology and Hygiene

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 173 APPENDIX

Doctorate Theses, Board Qualifications, Additional Qualifications, Habilitations

Anatomical Institute mit Hilfe der funktionellen Magnetresonanzto- Institute of Biochemistry – Emil-Fischer- Chair of Anatomy I mographie Centre Lennerz, Jochen, Dipl. Mol. Med. (2007): Elek- Chair of Biochemistry and Molecular Medicine Doctorate Theses trophysiologische Charakterisierung vagaler Afferenzen im oberen Ösophagus der Ratte – Doctorate Theses Ganns, Daniela, Dr. med. (2007): Untersuchung Relevanz für die mukosale Nozizeption allgemeiner und zytoskelettaler Marker zur Grömer, Teja Wolfgang, Dr. med (2007): Vesi- Mayer, Stephanie, Dr. med. (2007): Bradykinin- quantitativen Bestimmung von Neuronenpopu- kel-Populationen bei spontaner und aktivitäts- induzierte Nozizeptorsensibilisierung gegen lationen im menschlichen Darm abhängiger synaptischer Übertragung Hitze hängt ab von COX-1 und COX-2-Aktivi- Kapp, Sonja, Dr. med. (2007): Chemische Ko- Meiselbach, Heike, Dr. rer. nat. (2007): Compu- tät in isolierter Rattenhaut dierung der submukösen Typ V-Neuronen im tergestützte Untersuchung der Struktur, Dyna- Rickeheer, Sebastian, Dr. med. (2007): Signal- Ileum des Schweins mik und Energetik von Proteininteraktionen analyse in der funktionellen Kernspintomo- Lennerz, Jochen, Dr. med. Dipl. Mol. Med. Müller, Wolfgang, Dr. rer. nat. (2007): Struktur- graphie (fMRI): Detektion schmerzinduzierter (2007): Elektrophysiologische Charakterisie- basierte Bewertungsfunktionen zur Vorhersage Aktivität im Gehirn durch Klassifikation von rung vagaler Afferenzen im oberen Ösophagus neuer Protein-Protein-Interaktionen BOLD-Signalen ohne Vorkenntnis des Stimula- der Ratte - Relevanz für die mukosale Nozizep- Braune, Marlen, Dr. rer. nat. (2008): Die hy- tionsmusters tion pertone Bewegungsstörung der Mausmutante Schödel, Andrea, Dr. med. (2007): Der Einfluss Ewald, Philipp, Dr. med. (2008): Immunreakti- spastic von Rating auf BOLD Effekte in verschiedenen vität des vesikulären Glutamattransporter 1 in Dinkel, Holger, Dr. rer. nat. (2008): A computa- Regionen des menschlichen Kortex während der extrinsischen und intrinsischen Innervation tional strategy for the prediction of functional taktiler und schmerzhafter mechanischer Sti- des Rattenösophagus interaction motifs mulation Kallmünzer, Bernd, Dr. med. (2008): Enterische Homeyer , Nadine, Dr. rer. nat. (2008): Unter- Spitzer, Martin, Dr. med. (2007): Mechanismen Co-Innervation von quergestreifter Muskulatur suchung des Einflusses von Phosphorylierung der stimulierten axonalen Neuropeptid-Freiset- im menschlichen Ösophagus auf Struktur, Dynamik und Funktion des HPr- zung aus isolierten Ischiasnerven der Ratte Kraus, Tobias, Dr. med. (2008): Distribution of Proteins Tröltzsch, Markus, Dr. med. (2007): The calci- vesicular glutamate transporter 1 in the mouse tonin gene-related peptide (CGRP) receptor esophagus Habilitation antagonist BIBN4096BS reduces neurogenic Weidmann, Simone, Dr. med. dent. (2008): increases in dural blood flow Schiebel, Katrin, Prof. Dr. rer. nat. (2007): DNA- Quantifizierung des Anteils der mutmaßlichen De Col, Roberto, Dr. med. (2008): Die Leitungs- Polymorphismen und ihre pathobiochemische primär-afferenten Neuronen im Plexus myente- geschwindigkeit unmyelinisierter Nervenfasern Bedeutung (Erweiterung der Lehrbefähigung ricus des menschlichen Dünndarms der Dura mater encephali wird von der Verfüg- für die Fächer Biochemie und Molekularbio- Wolf, Matthias, Dr. med. (2008): Calcitonin ge- barkeit der spannungsgesteuerten Natriumka- logie) ne-related Peptide: Ein Marker für mutmaßliche näle bestimmt primär-afferente Neuronen im Plexus myenteri- Hager, Ulrich, Dr. med. (2008): Die morphologi- cus des Schweinedünndarms sche Charakterisierung des MrgC-Rezeptors der Institute of Biochemistry – Emil-Fischer- Centre Ratte und eine funktionelle Analyse von Rezep- Chair of Biochemistry and Pathobiochemistry Institute of Physiology and toragonisten Pathophysiology Herde, Lina, Dr. med. (2008): Juckreiz, der durch Doctorate Theses Chair of Physiology eine neue Methode induziert wird, führt zur limbischen Deaktivierung - Eine Untersuchung Kosian, Thomas, Dr. rer. nat. (2007): Interaktion Doctorate Theses mit funktionellem Kernspin und Modifikation des HMG-Box Transkriptions- Langhammer, Andreas, Dr. med. (2008): For- faktors Sox10 Denekas, Thomas, Dr. med. (2007): Inhibition ward and Backward Enhancement“ bei bal- Werner, Torsten, Dr. rer. nat. (2007): Untersu- of stimulated meningeal blood flow by a cal- listischer Stoßreizung der Haut – eine taktile chungen zur genregulatorischen Aktivität evo- citonin gene-related peptide binding mirror- Sinnestäuschung? lutionär konservierter, nicht-kodierender regio- image RNA oligonucleotide Rühle, Belinda, Dr. med. (2008): Zentrale Re- nen im Sox10 Locus. Derow, Alexandra, Dr. med. (2007): Prostaglan- präsentation von mechano sensitiven versus Zoubek, Robert, Dr. rer. nat. (2007): Subzellulä- dine steigern die Hitzeantwort von Nozizepto- mechano insensitiven C-Nozizeptoren – funk- re Verteilung von Thymosin-b4 in Abhängigkeit ren, nicht aber deren CGRP-Freisetzung in iso- tionelle Kernspintomographie am menschlichen seiner G-Aktin-Bindungssequenz lierter Rattenhaut Gehirn Hoser, Melanie, Dr. rer. nat. (2008): Entwick- Engel, Matthias, Dr. med. (2007): Cannabinoide lungsbiologische Studien zur Funktion von hemmen und fazilitieren konzentrationsabhän- Habilitation SoxC-Proteinen während der Mausembryoge- gig die reizinduzierte calcitonin gene-related nese. peptide-Freisetzung aus Ratten- und Maushaut Fischer, Michael, Dr. med. habil. (2008): Bei- Schubert, Steffen, Dr. rer. nat. (2008): Identifi- Hullard-Pulstinger, Caroline, Dr. med. dent. träge zur Sensibilität und Sensibilisierbarkeit kation der mit dem Transkriptionsfaktor GCMa (2007): Darstellung und Vergleich der kortika- primärer nozizeptiver Afferenzen mit Fokus auf assoziierten Signalwege und die Herstellung len Repräsentation von sowohl willkürlich- aktiv Calcitonin Gene-Related Peptide eines konditionalen GCMa-Knockout-Mausmo- als auch unwillkürlich-passiv provoziertem Tie- dells fenschmerz mit Hilfe von funktioneller Magne- tresonanztomographie und eines computerge- stützten Hirnatlas Kaschka, Miriam, Dr. med. dent. (2007): Ver- gleich der Lokalisationen der durch Oberflä- chen– und Tiefenschmerz aktivierten Hirnareale

174 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Habilitations Planungs- und OP-Dokumentationssystems in Tyralla, Karin, Dr. med. (2007): Untersuchung einem Universitätsklinikum des regressiven Einflusses einer hochdosierten Stolt, Claus, PD Dr. rer. nat. (2007): Sox-Proteine Sojer, Reinhold, Dr. hum. biol. (2008): Trans- Behandlung mit dem Angiotensin-Converting- in der Entwicklung von Oligodendrozyten formation des Arzneimittelsicherheitsystems Enzym-Hemmer Enalapril auf kardiovaskuläre Schlierf, Beate, PD Dr. rer. nat (2008): Unter- KLASSE in eine standardisierte Wissensreprä- Veränderungen im experimentellen Modell der suchungen zur transkriptionellen Regulation sentation chronischen Niereninsuffizienz durch Sox10 Walcher, Felix, Dr. med. (2007): Einfluß von humanem Endothelin-2 auf die myokardiale Schä- Institute of the History of Medicine and digung bei Diabetes mellitus am Tiermodell der Institute of Medical Informatics, Medical Ethics ET-2 transgenen Ratten Biometry and Epidemiology Chair of the History of Medicine Chair of Biometry and Epidemiology Wernicke, Konstanze, Dr. med. (2007): Der Ein- fluß von nativem und modifiziertem C-reakti- Doctorate Theses Doctorate Theses ven Protein auf die Atherosklerose Entwicklung Krüger, Dorothea Irene Edith, Dr. phil. (2007): in Apolipoprotein E-knockout-Mäusen Adler, Werner, Dr. rer. biol. hum. (2007): De- „Zwangssterilisationen im Nationalsozialis- Bacmann, David, Dr. med. (2008): Die Her- velopment and evaluation of an automated mus: Das „Gesetz zur Verhütung erbkranken unterregulierung des TGF-beta-Rezeptor 2 in classification method for early detection of Nachwuchses“ vom 14. Juli 1933 und seine tumorassoziiertem Stroma verschlechtert die glaucoma Durchführung an der Universitäts-Frauenklinik Prognose und High-grade Tumore zeigen mehr Menezes de Pádua, Cristiane Aparecida, Dr. rer. Erlangen“ tumorassoziierte Makrophagen und geringere biol. hum. (2007): Allergic Contact Dermatitis Schlee, Steffen Dieter, Dr. phil. (2007): Maxi- Expression von TGF-beta 1 in colorektalen Kar- to Topical Drugs - Epidemiological Risk Assess- milian Anton Wintrich (1812-1882) Die Ein- zinomen ment führung der physikalischen Diagnostik an der Casper, Sandra, Dr. med. (2008): Systemische Tartler, Bärbel, Dr. med. (2007): Diagnostik von Universität Erlangen im 19. Jahrhundert Wirkung von Tabak- und Asbestexposition auf Kontaktallergien gegen Inhaltsstoffe von Haar- Niere und Gefäßsystem im Tierversuch kosmetika Habilitation Forster, Christian, Dr. med. (2008): Morpholo- Rabe, Christina, Dr. rer. biol. hum. (2008): Ver- gische und stereologische Untersuchungen der fahren zur Schätzung partieller attributabler Steger, Florian, PD Dr. phil. (2008): „Keine Stoff- Mesangiolyse in der murinen Habutoxin Neph- Risiken bei multifaktoriell bedingten Erkrankun- wechselstörung im Gehirn, sondern eine per- ropathie der Maus gen sönliche Geschichte“ Geschichte und Ethik der Friebel, Daniela, Dr. med. (2008): Prognostische Wolf, Carmen Christine, Dr. med. (2008): Son- Psychiatrie und Psychotherapie im 20. und 21. Bedeutung tumorinfiltrierender T-Zellen beim nenschutz bei Kindern. Die Erlanger Kindergar- Jahrhundert klassischen Hodgkin Lymphom ten-Studie -- aktueller Wissensstand und dar- Koch, Stefan, Dr. med. (2008): Auswirkungen aus resultierende Präventionskampagnen im einer oralen Therapie mit Atorvastatin auf re- weltweiten Kontext Institute of Pathology nale Schäden im Tiermodell der ApoE-/-Knock Chair of General Pathology and Pathological out Maus Institute of Medical Informatics, Anatomy Lang, Katrin, Dr. med. (2008): Einfluss des P2Y1- Biometry and Epidemiology Rezeptors mit und ohne adjuvante Gabe des Endowed Chair of Medical Informatics Doctorate Theses P2Y12 Rezeptorblockers Clopidogrel auf den Krankheitsverlauf im anti-GBM-Glomerulone- Doctorate Theses Frangou, Phroso, Dr. med. (2007): Epstein-Barr phritis-Mausmodell Virus-Replikation in Epithelzellen in vivo Lill, Maria, Dr. med. (2008): Auswirkungen einer Dumitru, Corina, Dr. med. (2007): A systematic Greiner, Axel, Dr. med. (2007): Expression von oralen Therapie mit Perindopril, Candesartan approach for the evaluation of Web-based per- B-Zell-Differenzierungsantigenen in Hodgkin und S 18886 auf renale Schäden im Tiermodell sonal health records in Germany Lymphomen der unilateral nephrektomierten obese Zucker Gerdsen, Frederic, Dr. hum. biol. (2007): Ent- Grimm, Roland, Dr. med. (2007): Auswirkun- Ratte (OZR) wicklung eines Referenzmodells zur Unterstüt- gen von Anämie und Urämie auf das Myokard: Sachs, Albrecht, Dr. med. (2008): Die Butyrat- zung von integrierter Glaukomversorgung und Strukturelle und hämodynamische Veränderun- induzierte Expression des Zellzyklusinhibitors -forschung durch standardisierte Kommunikati- gen im Modell der subtotal nephrektomierten p21 Cip1/Waf1 erfolgt unabhängig von CDX2 on auf Basis der Clinical Document Architecture Ratte Jantsch, Stefan, Dr. med. (2008): Evaluation Kolb, Jochen, Dr. med. (2007): Reduktion der von Pathifier. Ein zeitstrahlbasiertes Präsenta- Cdx2-Expression in kolorektalen Karzinomen Institute of Neuropathology tionsprogramm integrierter Patientendaten als durch ß1-Integrin Stimulation Chair of Neuropathology Basis für vielseitige klinische Anwendungen Lange, Oliver, Dr. med. (2007): Morphometri- Klein, Andreas, Dr. hum. biol. (2008): Ein ge- sche Veränderunge in der Frühphase der STZ- Doctorate Theses nerischer Ansatz zur Realisierung verteilter induzierten experimentellen Diabetischen Ne- Siebzehnrübl, Florian A., Dr. rer. nat (2007): Datenerfassung in der vernetzten klinischen phropathie nach 5 und 15 Tagen Therapeutic applicability of adult brain stem Verbundforschung Porzner, Marc, Dr. med. (2007): Die Bedeutung cells Lang, Martin, Dr. hum. biol. (2008): Prozessmi- von Mutationen im APC-Gen für die subzellulä- Coras, Roland, Dr. med. (2008): The peroxisome ning und Prozessoptimierung zur Verbesserung re Lokalisation von APC und ß-Catenin in hu- proliferator-activated receptor-y agonist trogli- klinischer Workflows im Umfeld bilderzeugen- manen kolorektalen Karzinomen tazone inhibits transforming growth factor-ß– der Fächer Päzolt, Doreen, Dr. med. (2007): Expression von mediated glioma cell cell migration and brain Pálffy, Péter, Dr. hum. biol. (2008): Konzep- TH2 Zytokinen und Chemokinen beim Hodgkin invasion tion und Einführung eines DV-basierten OP- Lymphom und beim Nasopharynxkarzinom

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 175 APPENDIX

Institute of Microbiology – Clinical Marzi, Andrea, Dr. rer. nat. (2007): Die Bedeu- Vogel, Eva-Maria, Dr. rer. nat. (2008): Bedeu- Microbiology, Immunology and Hygiene tung zellulärer Anheftungsfaktoren für die Filo- tung der autonomen renalen Innervation für Chair of Microbiology and Immunology of virus-Infektion Entzündungsvorgänge bei experimentellen Ne- Infection Tschochner, Monika, Dr. rer. nat. (2007): Korre- phritiden lation von Replikationskapazität und Pathoge- Doctorate Theses nität zum Resistenzmuster von HIV-1-Varianten Wucherpfennig, Frank, Dr. rer. nat. (2007): Institute of Experimental and Clinical Eckert, Melanie, Dr. rer. nat. (2007): Unter- Pharmacology and Toxicology Transfer und Freisetzung von Episomen für die suchungen zur Expression und Funktion von Chair of Clinical Pharmacology and Clinical murinem bactericidal/permeability increasing somatische Gentherapie durch einen Herpesvi- Toxicology protein (BPI) rus/Adenovirus-Hybridvektor Gerlach, Roman, Dr. rer. nat. (2007): Characte- Alberter, Barbara, Dr. rer. nat. (2008): Die Epige- Doctorate Theses rization of Virulence Genes in Salmonella Pa- netik des Herpesvirus saimiri-Genoms thogenicity Island 4 Berndt, Anja, Dr. rer. nat. (2008): Characteriza- Gradhand, Ulrike, Dr. rer. nat. (2007): Expres- Halici, Serkan, Dr. rer. nat. (2007): Molekulare tion of covalent and non-covalent interactions sion, Lokalisation und Regulation der ABC- Mechanismen der Interferenz von intrazellulä- of the cellular ubiquitin-homologous protein Transporter Multidrug Resistance Protein 3 und ren Salmonellen mit der Antigen-Präsentation SUMO with the major immediate-early tran- Multidrug Resistance Protein 4 in der humanen von murinen Dendritischen Zellen sactivator IE2p86 of human cytomegalovirus Leber Aichele, Diana, Dr. rer. nat. (2008): Analysis of Gack, Michaela , Dr. rer. nat. (2008): Regulation Neuwald, Sebastian, Dr. med. (2007): Pharma- the function of human bacteridical/permeabili- of RIG-I-mediated anti-viral innate immunity kokinetische und pharmakodynamische Effekte ty-increasing protein (BPI) and of the expressi- Glanz, Anja, Dr. rer. nat. (2008): Wechselwir- von Etoricoxib und Valdecoxib im experimentel- on of selected BPI-family members kungen von StpC mit Signalwegen der T-Zell- len Schmerzmodell Braun, Tobias, Dr. med. (2008): Charakterisie- Aktivierung Stadelmann, Alexander, Dr. med. (2007): In- rung Lipid-reaktiver T-Zell-Subpopulationen Kaiser, Nina, Dr. rer. nat. (2008): Selektion und teraktion von Geruch und Geschmack unter beim Menschen Charakterisierung von pUL84-bindenden Pep- besonderer Berücksichtigung des Sättigungs- Braun, Joachim, Dr. med. (2008): Untersuchun- tid-Aptameren zur Hemmung der Cytomegalo- zustands gen zur Expression und Regulation zytotoxi- virus-Replikation Eberl, Sonja, Dr. rer. nat. (2008): Die Inhibition scher Effektormoleküle in Lymphozyten Kittan, Nicolai, Dr. med. (2008): Native Immu- des OATP1B3- und P-Glykoprotein-vermittelten Groer, Gerhard, Dr. rer. nat. (2008): Immuno- nabwehr plasmazytoider dendritischer Zellen Arzneimitteltransports: Untersuchungen zur tagmine (IMTAGs)-Struktur, calciumabhängige (PDC) bei Patienten mit akuter retinaler Nekro- Relevanz bei Arzneimittelinteraktionen Lipidbindung und Expression in Lymphozyten se (ARN) durch Herpesviren Krajcik, Rastislav, Dr. rer. nat. (2008): Funktio- Henning, Dorothée, Dr. med. (2008): Die Knöpfel, Stefanie, Dr. rer. nat. (2008): Einfluss nalisierte Kohlenstoffnanoröhren als neuartiges entzündungshemmende Wirkung einer nied- der Prozessivität der Reversen Transkriptase des Transfektionsmittel für effizientes gene silenci- rigdosierten Strahlentherapie beinhaltet eine humanen Immundefizienzvirus Typ I auf die G- ng in Rattenkardiomyozyten verminderte CCL20-Chemokin-Expression und zu-A Mutationsrate induziert durch APOBEC3- Seithel, Annick, Dr. rer. nat. (2008): Der huma- Adhäsion von Granulozyten an Endothel Proteine ne Aufnahmetransporter OATP1B1: Bedeutung Saake, Marc, Dr. med. (2008): Analyse der Ex- Silbermann, Katrin, Dr. rer. nat. (2008): Antia- für Arzneimittelinteraktionen und funktionelle pression der Komponenten des Prostaglan- poptose durch das Onkoprotein Tax menschli- Charakterisierung von Sequenzvariationen dinsystems bei der Mukoviszidose und der cher T-Zell-Leukämieviren experimentellen Pseudomonas aeruginosa- Tavalai, Nina, Dr. rer. nat. (2008): Analysis of the Board Qualifications “Klinische Pharmakologie“ Pneumonie role of the cellular subnuclear structure ND10 for human cytomegalovirus replication Zolk, Oliver, Dr. med. (2007) Board Qualification Bachmakov, Iouri, Dr. med. (2008) Habilitation Lang, Roland, PD Dr. med. (2007): Mikrobiolo- Habilitation gie, Virologie und Infektionsepidemiologie Metzner, Karin, PD Dr. med. (2007): Genomic diversity and population dynamics of simian Zolk, Oliver, PD Dr. med. (2007): Bedeutung der and human immunodeficiency viruses (SIV/ humoralen Faktoren Endothelin-1 und Cardio- Institute of Virology – Clinical and HIV) Molecular Virology trophin-1 für die Entwicklung der Herzinsuffi- Chair of Clinical Virology zienz Institute of Experimental and Clinical Doctorate Theses Pharmacology and Toxicology Chair of Pharmacology and Toxicology Institute of Experimental and Clinical Gramberg, Thomas, Dr. rer. nat. (2007): Analy- Pharmacology and Toxicology Doerenkamp-Chair of Innovations in Animal se der Interaktion viraler Hüllproteine mit zellu- Doctorate Theses and Consumer Protection lären Anheftungsfaktoren Hochstein, Norbert, Dr. rer. nat. (2007): Der Blaich, Anna, Dr. rer. nat. (2008): Untersuchung Doctorate Theses epigenetische Status eines Transgenoms in der Rolle des Schrittmacherkanals HCN4 im Ge- Hamsterzellen hirn adulter Mäuse Eichele, Karin, Dr. rer. nat. (2007): Decisive role Hülsmann, Peter, Dr. rer. nat. (2007): RNA-Inter- Erhardt, Annette, Dr. rer. nat. (2008): Toleran- of cyclooxygenase-2 and lipocalin-type prosta- ferenz und das Suizidgen tBid als neue Ansätze zinduktion in der Leber nach T- und NKT-Zel- glandin D synthase in R(+)-methanandamide- gentherapeutischer Strategien gegen HIV-1 laktivierung and chemotherapeutics-induced apoptosis of Klinger, Patricia, Dr. rer. nat. (2007): Rolle des Hoesl, Evelyn, Dr. rer. nat. (2008): Konditionelle human cancer cells. UPS in der HIV-1-Virusassemblierung Gendeletion im Reizleitungssystem der Maus

176 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Hille, Sandra, Dr. rer. nat. (2007): Die Rolle von Förster, Katrin, Dr. rer. nat. (2008): Entwicklung Nikolaus-Fiebiger-Centre of Molecular Caspasen bei der T-Zell-Aktivierung und der Pa- und Anwendung analytischer Verfahren für ein Medicine thogenese des Asthma Human-Biomonitoring von Naphtalin im Rah- Chair of Experimental Medicine II Puljic, Ruzica, Dr. rer. nat. (2007): Anti-Zytokin men arbeits -und umweltmedizinischer Frage- (Molecular Oncology) Strategien zur Therapie von COPD stellungen Amon, Annette, Dr. rer. nat. (2008): Die Rolle Jacobs, Stephanie Elisabeth, Dr. med. (2008): Doctorate Theses des MAP-Kinase-Signalwegs bei der antient- Bestimmung der Herzfrequenzvariabilität mit Bauer, Katja, Dr. rer. nat. (2007): Untersuchung zündlichen Wirkung von Glucocorticoiden und dem Prototyp eines „stand-alone“-Plethysmo- molekularer Mechanismen der transendothelia- PDE4-Inhibitoren graphen: Validierung der implementierten Al- len Migration von Tumorzellen: Bedeutung von Besz, Dominika, Dr. med. (2008): Untersuchung gorithmen mit einem „gold-standard“. Integrin ß3 und EVA1 der Zyklooxygenasehemmwirkungen von Nap- Korinth, Gintautas, Dr. med. (2008): Vergleich Stemmer, Volker, Dr. rer. nat. (2007): Interak- roxen: Kardioprotektion im Gegensatz zu gast- von in-vivo- und in-vitro-Methoden zur Erfas- tion von Snail mit beta-Catenin und deren Be- rointestinaler Toxizität sung der dermalen Penetration von Arbeits- deutung für den Wnt-Signalweg stoffen durch exzidierte Humanhaut und bei Wacker, Ingrid, Dr. rer. nat. (2007): Activin B der Ratte am Beispiel von 2-Butoxyethanol und - ein Schlüsselmolekül in der zellulären Trans- Institute of Human Genetics Toluol. Chair of Human Genetics formation infolge Inaktivierung des von Hippel- Lindau Tumorsuppressors Board Qualifications “Arbeitsmedizin” Doctorate Theses Dehner, Manuel, Dr. rer.nat. (2008): Identifizie- Zöbelein, Petra, Dr. med. (2007) rung und funktionelle Charakterisierung von Chavarria Soley, Gabriela, Dr. rer. nat. (2008): Ochsmann, Elke, Dr. med. (2008) SGK1 als neues Zielgen der Wnt-Signaltrans- Genome-wide identification and characterisati- duktion on of well-defined genes involved in glaucoma Kohler, Eva Maria, Dr. rer. nat. (2008): A gene- and pterygioum corneae Institute of Medical Physics ral model that explains the complex pattern of Lascorz Puertolas, Jesús, Dr. hum. biol. (2008): Chair of Medical Physics biallelic APC mutations in colorectal carcinoma, Systematic association studies and functional duodenal and desmoid tumours characterization of positional and functional Doctorate Theses candidate genes for psoriatic arthritis and psoriasis vulgaris Henke , Maria, Dr. rer. biol. hum. (2008): Multi- Institute of Biomedicine of Aging dimensionale adaptive Filterung zur Rauschre- Chair of Internal Medicine - Geriatrics duktion in der Computertomographie: Vergleich Institute of Forensic Medicine und Kombination faltungs- und splinebasierter Board Qualification Chair of Forensic Medicine Verfahren Niebler, Christine, Dr. rer. biol. hum. (2008): Singler, Katrin, Dr. med. (2007): Innere Medizin Doctorate Theses Vermessung und Korrektur des Misalignments und Endokrinologie und Diabetologie robotergeführter C-Bogen-Systeme Eckardt, Gerlinde, Dr. rer. biol. hum. (2008): Reinhart, Christian, Dr. rer. biol. hum. (2008): Additional Qualifications “Notfallmedizin” Quantifizierung von Betäubungsmitteln in Bild- versus rohdatenbasierte Zwei-Spektren- Haaren – Praktische Untersuchungen zur Auf- Heppner, Hans-Jürgen, Dr. med. (2007) Computertomographie nahme von Betäubungsmitteln in Haare bei Singler, Katrin, Dr. med. (2007) Vollmar, Sabrina, Dr. rer. biol. hum. (2008): Do- beruflich exponierten Personen im Vergleich zu sisreduktion in der weiblichen Brust bei Thorax Drogenkonsumenten CT Department of Orthopaedics in the Meier, Maria, Dr. med. (2008): Entwicklung und Waldkrankenhaus Validierung eines Short Tandem Repeat Multi- Chair of Orthopaedics and Orthopaedic plex Systems für die Typisierung degradierter Nikolaus-Fiebiger-Centre of Molecular Surgery DNA-Proben Medicine Chair of Experimental Medicine I Doctorate Theses Board Qualification (Connective Tissue Research) Betz, Tobias Oliver, Dr. med. (2007): Langzeit- Bock, Horst, Dr. med. (2007): Rechtsmedizin Doctorate Theses untersuchungen zur knöchernen Reaktion auf einen zementfreien Hüftendoprothesenschaft Surmann-Schmitt, Cordula, Dr. rer. nat. (2007): mittels CT-gestützter Osteodensitometrie Institute and Outpatient Clinic of Struktur, Funktion und Expression von UCMA, Böhm, Roland Alexander, Dr. med. (2007): Occupational, Social and Environmental einem neuen Knorpelspezifischen Protein Langzeitergebnisse mit der Wagner Metall- Medicine Mühle, Christiane, Dr. rer. nat. (2008): Molecu- Chair of Occupational and Social Medicine Metall Schalenprothese lar basis and characteristics of the polyclonal Forster, Silvia Irene Maria, Dr. med. (2007): antibody response to exogenous coagulation Doctorate Theses Morphologische Veränderungen des Tractus- factor VIII in patients with hemophilia A iliotibialis und des Septum intermusculare fe- Krückert, Kerstin, Dr. med. (2007): Frühdiag- moris laterale bei Jungen mit Duchenne-Mus- nostik asbestbedingter Bronchialkarzinome mit keldystrophie Hilfe der low - dose Spiral-CT Wertigkeit einer Kandemir, Bahadir, Dr. med. (2007): Später- 3 D-Software zur Detektion kleiner pulmonaler gebnisse knöcherner Eingriffe am Hüftgelenk Rundherde in einem ehemals Asbest-exponier- des Zerebralparetischen Kindes Beschreibung ten Hochrisikokollektiv. der Behandlungsmethoden und Analyse der Er- gebnisse von knöcherner Eingriffe, funktioneller

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 177 APPENDIX

Behandlung und Hilfsmittelversorgung von 73 erkennung einer Atemwegsobstruktion unter Otto, Patrick, Dr. med. (2007): Das Eosiniphile Patienten nasaler nCPAP-Überdruckbehandlung des obs- Kationische Protein im Serum als Aktivitäts- Nowak, Tobias Eckhard, Dr. med. (2007): truktiven Schlafapnoesyndroms parameter bei Morbus Crohn nach resektiver Computertomographie-gestützte Osteodensi- Batz, Hans-Bernd, Dr. med. (2007): Schlafbezo- Operation tometrie nach Implantation eines zementfreien gene Atmungsstörungen und diastolische Dys- Peter, Gisela, Dr. med. (2007): Beeinflussung des Hüftendoprothesenschaftes - Untersuchungen funktion - Hat die nächtliche Beatmung bei Pa- Wachstumshepatozellulärer Karzinomzellen 3 Jahre postoperativ - tienten mit schlafbezogener Atmungsstörung durch Inhibitoren der Angiogenese, der Histo- Peykan-Sepahi, Nilufar, Dr. med. (2007): MRT- einen Effekt auf die diastolische linksventrikulä- ndeazetylase und zyklin-abhängiger Kinasen basierte Darstellung der Knorpelverteilung im re Funktion des Herzens? in vitro Hüftgelenk bei Patienten nach sphärischer Brückner-Schmutt, Kerstin, Dr. med. (2007): Premm, Wolfgang, Dr. med. (2007): Untersu- Hüftpfannenosteotomie nach WAGNER Effekte einer continuous positive airway pressu- chungen zur mittleren Apnoedauer beim obs- Vornlachner, Michael Paul, Dr. med. (2007): re-Therapie auf die sekundäre Insulinresistenz truktiven Schlafapnoesyndrom Das Beschwerdebild nach Halswirbelsäulendis- bei Patienten mit obstruktivem Schlafapnoe- Rößner, Elke, Dr. med. (2007): Diagnostische torsion Zeitliche Dynamik und Einflussfaktoren Syndrom und Diabetes mellitus Typ 2 Bedeutung von Natürlichen Killer-Zellen in der Pfitzner, Tilman, Dr. med. (2008): Die operative Bölükbas, Servet, Dr. med. (2007): Untersu- Bronchoalveolären Lavage Rekonstruktion der rupturierten Rotatorenman- chung zur Pharmakokinetik von Ceftazidim Seegara Heenen, Luisa, Dr. med. (2007): Der Ef- schette - klinische, radiologische und magnetre- (Fortum i.v.(R)) bei Intensivpatienten mit aku- fekt von zusätzlichem Unterricht in einem Me- sonanztomographische Analyse tem Nierenversagen unter kontinuierlicher ve- dizischen Trainings- und Prüfungszentrum im Röhr, Markus, Dr. med. (2008): Ergebnisse der nöser Hämofiltration (CVHF) und hämofiltrati- internistischen, chirurgischen und urologischen operativen Therapie der juvenilen Knochenzys- onsfreien Intervall Blockpraktikum auf die Ergebenisse in Objekti- te unter Berücksichtigung der Rezidivrate Döltz, Stefanie, Dr. med. (2007): Häufigkeit und ven Strukturierten Klinischen Examina Prognose von ambulant erworbenen Pneumo- Steinebrunner, Niels, Dr. med. (2007): Hepa- Board Qualification nien 2002 tische Transitzeit bei benignen und malignen Döltz, Thomas, Dr. med. (2007): Retrospektive Leberraumforderungen kontrastverstärkten Ul- Müller, Lutz Arne, PD Dr. med. (2007): Ortho- Erfassung von Prädiktoren für das Überleben traschall pädie und Unfallchirurgie nach PEG-Anlage Walter, Benjamin, Dr. med. (2007): Mukosap- Frank, Michael, Dr. med. (2007): Untersuchun- rotektive Eigenschaften von Ghrelin bei durch Habilitation gen zur Induktion von Arousalreaktionen durch Ischämie und Reperfusion verursachten Ma- Müller, Lutz Arne, PD Dr. med. (2007): Die Variationen des Therapiedruckes während einer genläsionen im Rattenmodell femorale und periacetabuläre Knochendichte APAP-Therapie bei obstruktivem Schlafapnoe- Wasmeier, Alexandra, Dr. med. (2007): Eine nach Hüfttotalendoprothesen - Implantation: Syndrom prospektive Untersuchung zur Lebensqualität Validität der Methodik, Reproduzierbarkeit der Freiin Marschall von Bieberstein, Kerstin, Dr. von Patienten einer internistischen Intensiv- Messung und in-vivo Langzeitergebnisse mit- med. (2007): Einführung eines Behandlungs- station im zeitlichen Verlauf unter Berücksich- tels CT-gestützter Osteodensitometrie pfades für ambulant erworbene Pneumonie. tigung des Alters Bedeutung für die Dauer der intravenösen und Wiesnet, Johannes, Dr. med. (2007): Europäi- oralen Antibiose sches Pilotprojekt: Prospektive Evaluation des Department of Orthopaedics in the Karakurt, Zeynep, Dr. med. (2007): Auswirkun- Wertes von zusätzlichen intensivierten prakti- Waldkrankenhaus gen der Einführung eines klinischen Behand- schen Trainingskursen an einem Simulations- Division of Orthopaedic Rheumatology lungspfads für ambulant erworbene Pneumonie modell (ComacptEASIE(R)) im Vergleich zur unter besonderer Berücksichtigung der Effekte herkömmlichen Ausbildung für die endoskopi- Additional Qualification auf die Wahl und Dauer der initialen Antibio- sche Blutstillung Eichinger, Stephan, Dr. med. (2008): Orthopä- tikatherapie und der Häufigkeit peroraler Se- Baumbach, Christina, Dr. med. (2008): Hämo- dische Rheumatologie quenztherapie dynamische Effektivität eine neuartigen Hämo- Kleinecke, Caroline, Dr. med. (2007): Vaskula- clips im Vergleich zur Injektionstherapie bei der Habilitation risationsmuster hepatozellulärer Karzinome in Versorgung von Blutungen im oberen Gastro- der dynamischen Kontrastmittelsonographie in intestinaltrakt Carl, Hans-Dieter, PD Dr. med. (2007): Untersu- Korrelation zum Goldstandard Histologie Bermbach, Daniela, Dr. med. (2008): Koagulo- chungen zur Effizienz orthopädisch-rheumato- Ludwig, Rayk, Dr. med. (2007): Identifikation pathien bei Intensivpatienten logischer Interventionen von Helicobacter spezies in Leberbiopsaten Busch, Ekaterina, Dr. med. (2008): Klinische ägyptischer Patienten mit chronischer Hepati- Bedeutung der lymphatischen Hyperplasie am tis C Infektion mit und ohne hepatozellulärem unteren Gastrointestinaltrakt Department of Medicine 1 – Gastroenterology, Lung Diseases and Karzinom Dorlaque, Laure, Dr. med. dent. (2008): Die Be- Endocrinology Matthes, Kai, Dr. med. (2007): Prospektive Eva- deutung der Genexpression von Matrix-Metal- Chair of Internal Medicine I luation von zusätzlichen praktischen Trainings- loproteinasen bei metastasierten kolorektalen kursen an einem Simulationsmodell (Com- Karzinomen Doctorate Theses pactEASIE) im Vergleich zur rein klinischen Fritsche, Berit, Dr. med. (2008): Nachsorgever- Ausbildung in endoskopischer Blutstillung - Ein halten nach Resektion relevanter (<10mm) ko- Ackermann, Andreas, Dr. med. (2007): Compu- Pilotprojekt an neun New Yorker Kliniken lorektaler Adenome tergestützte Detektion unerwünschter Arznei- Neukirchner, Claudia, Dr. med. (2007): Objek- Geyer, Dietmar, Dr. med. (2008): Evaluierung mittelwirkungen auf der Basis von Laborwerten, tive und subjektive Effektivität einer oszillomet- klinischer und laborchemischer Parameter so- Medikation und Diagnosen risch gesteuerten Auto-CPAP-Therapie des ob- wie Befunden der apparativen Diagnostik be- Asshoff, Gerald, Dr. med. (2007): Oszillomet- struktiven Schlafapnoe-Syndroms während der züglich ihrer Aussagekraft für die Etablierung rie versus Ösophagusdruckmessung zur Früh- Therapieeinleitung im Schlaflabor

178 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) der Diagnose gastrointestinal vermittelte Aller- lypektomie: Retrospektive Analyse klinikopatho- Board Qualifications gie logischer- und Verlaufsdaten von Erffa, Johannes, Dr. med. (2007): Innere Grimm, Verena, Dr. med. (2008): Untersuchun- Zimmermann, Annette, Dr. med. (2008): Medi- Medizin und Kardiologie gen zur Mortalität bei akuten Blutungen am kamentöse Kombinationstherapie des HCC mit Zimmermann, Stefan, Dr. med. (2007): Innere oberen Gastrointestinaltrakt Biomodulatoren an einem syngenen Hepatom- Medizin Herbst, Alexandra, Dr. med. (2008): Analyse der modell Schneider, Reinhard, Dr. med. (2008): Innere prädiktiven und prognostischen Faktoren beim Medizin und Kardiologie kleinzelligen Bronchialkarzinom unter palliati- Board Qualifications “Innere Medizin” Wolf, Tobias, Dr. med. (2008): Innere Medizin ver Erstlinien-Therapie mit ACE - eine retrospek- und Kardiologie tive Analyse von 16 Jahren Geise, Arnim, Dr. med. (2007) Hiemer, Eva, Dr. med. (2008): Untersuchungen Krauss, Norbert, Dr. med. (2007) zur Bedeutung von Spirometrie und Bodyple- Ganslmayer, Marion, Dr. med. (2008) Additional Qualifications Zopf, Steffen, Dr. med. (2008) thysmographie bei der Diagnostik des obstruk- Ropers, Dieter, PD Dr. med. (2007): Intensivme- tiven Schlafapnoe-Syndroms dizin Additional Qualifications Kimpel, Silke, Dr. med. (2008): Langzeitverlauf Schneider, Reinhard, Dr. med. (2007): Sportme- der Methylhistamin- und Leukotrien-Ausschei- Bernatik, Thomas, PD Dr. med. (2007): Gastro- dizin dung im Urin bei Morbus Crohn Patienten enterologie Achenbach, Stephan, Prof. Dr. med. (2008): unter Medikation mit Omega-3-Fettsäuren im Boxberger, Frank, Dr. med. (2007): Medikamen- Intensivmedizin Vergleich mit Mastozytose Patienten töse Tumortherapie Garlichs, Christoph, Prof. Dr. med. (2008): In- Kollmann, Sylvia, Dr. med. (2008): Untersu- Brückl, Wolfgang, PD Dr. med. (2007): Pneu- tensivmedizin chung von Geschmack und Ernährung bei Pati- monologie Stumpf, Christian, PD Dr. med. (2008): Inten- enten mit Morbus Crohn Fuchs, Florian, Dr. med. (2007): Pneumonologie sivmedizin Korn, Corinna, Dr. med. dent. (2008): Kompli- Riel, Rosina, Dr. med. (2007): Endokrinologie kationen der endoskopisch-retrograten Cholan- Brückl, Wolfgang, PD Dr. med. (2008): Schlaf- Department of Medicine 3 – gio-pankreatikographie (ERCP) von 1990-2000 medizin in einem norddeutschen Krankenhaus der Re- Rheumatology and Immunology Geise, Arnim, Dr. med. (2008): Pneumonologie Chair of Internal Medicine III gelversorgung Kölln, Sandra, Dr. med. (2008): Untersuchungen der Adipozytokine Leptin und Adiponektin, so- Department of Medicine 2 – Cardiology Doctorate Theses and Angiology wie Resistin bei Zystischer Fibrose Franz, Sandra, Dr. rer. nat. (2007): Fingerprin- Chair of Internal Medicine II Lampel, Emilia, Dr. med. (2008): Biochemische ting Apoptotic Cell Surfaces: Alterations of Gly- Evaluation des Effektes von Pankreasenzymen cocalyx and Membrane Composition Doctorate Theses auf die Allergenstruktur von wichtigen Nah- Munoz, Luis, Dr. med. (2007): The influence on rungsmittelallergenen Becker, Clemens Franz Maria, Dr. med. (2007): the immunomodulatory effects of dying and Lechler, Annette, Dr. med. (2008): Toxizität/ Dreidimensionale Echokardiographie: Algorith- dead cells of Annexin V Nebenwirkungen der ACE-Chemotherapie beim menvergleich der „average - rotation - method“ Neubert, Kirsten, Dr. rer. nat. (2007): Eliminie- kleinzelligen Bronchialkarzinom - eine retros- und Scheibchensummationsmethode in der rung autoreaktiver Plasmazellen durch Prote- pektive Analyse über 16 Jahre linksventrikulären Volumetrie aneurysmatisch asominhibition in Lupus-Mausmodellen Leu, Thorsten, Dr. med. (2008): Beeinflussung nachempfundener pulsierender Herzmodelle Barbara, Fürnrohr, Dr. rer. nat. (2008): Hitze- von Apoptose, Proliferation und Differenzie- Derlien, Hans-Joachim, Dr. med. (2007): Kli- schockproteine bei der Pathogenede des syste- rungs-Mustern durch Zebularine und SAHA in nische Evaluation der nichtinvasiven Darstel- mischen Lupus erythematodes Pankreaskarzinom-Modellen lung von Koronararterien und aorto-koronaren Mösch, Christian, Dr. med. (2008): Prognosti- Bypassgefäßen mittels kontrastverstärktem Department of Medicine 3 – sche Bedeutung der Mikrosatelliteninstabilität Mehrzeilen-Spiral-CT und retrospektivem EKG- (MSI) bei metastasierten sporadiscehn kolorek- Rheumatology and Immunology Gating Division of Molecular Immunology talen Karzinomen unter palliativer Chemothe- Frimmel, Sonja Alexandra Frizzi, Dr. med. rapie (2007): Langzeitverlauf der Progression koro- Doctorate Theses Nürnberger, Andreas, Dr. med. (2008): Lokale narer Kalzifizierungen peristomale Infektion nach PEG-Anlage - eine Marquart, Andreas, Dr. med. (2007): Überprü- Herrmann, Kai-Uwe, Dr. rer. nat. (2007): Unter- prospektive Studie zur Erfassung von Risikofak- fung der Abbildungsgenauigkeit bei der Koro- suchungen zur Transport- und Signalkompe- toren nararteriendarstellung durch 16-Zeilen-Spiral- tenz von schweren IgM-Ketten Rienecker, Helmut, Dr. med. (2008): Protektiver Computertomographie mittels Vergleich zur Vettermann, Christian, Dr. rer. nat. (2007): Effekt von H. pylori auf die Entstehung einer quantitativen Koronarangiographie Funktion der Unique-Region von Lambda-5 für gastro-intestinal vermittelten Allergie Ruthrof, Susanne Margarete Rose, Dr. med. die Entwicklung von B-Lymphozyten Scheibner, Claudia, Dr. med. (2008): Pharma- (2008): Interventionelle Therapie und 30-Ta- kologische Interventionen bei experimenteller ge-Prognose des akuten ST-Streckenelevations- Department of Medicine 4 – Nephrology Entzündung des Darmes im Mausmodell Myokardinfarktes (STEMI) bei Frauen im Ver- Stegemann, Tanja, Dr. med. (2008): Die Auswir- and Hypertensiology gleich zu männlichen Patienten -Erfahrungen Chair of Internal Medicine IV kungen von Alkohol- und Nikotinabusus auf die an der Universitätsklinik Erlangen 1999-2005- Rate von unerwünschten Arzneimittelwirkun- gen während der stationären Behandlung Doctorate Theses Vogler, Marcus, Dr. med. (2008): Entwicklung Friedrich, Chris, Dr. med. (2007): Antiproteinu- metachroner kolorektaler Karzinome nach Po- rische Wirksamkeit von Angiotensin-Rezeptor-

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 179 APPENDIX

Blockern bei diabetischen und nicht-diabeti- Habilitations Deoxyglukose-Positronenemissionsstomogra- schen Patienten: Systematischer Review mit phie (FDG-PET) Hohenstein, Bernd, PD Dr. med. (2008): Modu- Meta-Analyse lators of microvascular endothelial injury and Handtrack, Claudia, Dr. med. (2007): Einfluss Board Qualification repair in the kidney des Angiotensinogen-Genotyps auf Hypertonie Jacobi, Johannes, PD Dr. med. (2008): Rolle von und Nephrosklerose in der Maus Reiermann, Jung, PD Dr. med. (2007): Nukle- ADMA bei entzündlichen Gefäßschäden Porstner, Martin, Dr. med. (2007): Plasminogen- armedizin Lindner, Tom Herbert, Dr. med. (2008): Typ- Aktivierung und die Nierenschädigung beim Di- 2 Diabetes und arterielle Hypertonie: ein ge- abetes mellitus Habilitation meinsamer genetischer Lokus auf Chromosom Segitz, Verena, Dr. med. (2007): Induktion von 1 (Erweiterung der Lehrbefähigung Innere Prante, Olaf, PD Dr. rer. nat. (2008): Entwicklung CTGF durch Aldosteron in Mesangiumzellen der Medizin) Subtyp-selektiver Dopamin-D4-Radioliganden Ratte für die Positronen-Emissions-Tomographie Özcan, Zehra, Dr. med. (2007): Einfluss von In- tegrin alpha 8 auf die Zytoskelettorganisation Department of Medicine 5 – Lechler, Philipp, Dr. med. (2008): Expression des Haematology and Oncology Institute of Radiology antiapoptotischen Faktors Survivin in der Niere Chair of Haematology and Oncology Chair of Diagnostic Radiology Oehmer, Sebastian, Dr. med. (2008): Nachweis u. Untersuchung erythropoietin-bedingter Än- Doctorate Theses Doctorate Theses derung auf den Vasotonus der Unterarmarterie Fierl, Andrea Marita, Dr. med. dent. (2008): Brand, Martin, Dr. med. (2008): Dosisreduktion bei Hypertertonikern und Normotonikern Hemmung des Ras-Raf-MAPK-Signalweges in der pädiatrischen Computertomographie un- Ott, Christian, Dr. med. (2008): Einfluss von beim Multiplen Myelom durch neuartige spezi- ter Anwendung einer Dosisautomatik Veränderungen des Zytoskeletts auf die CTGF fische Inhibitoren Kerl, Josef, Dr. med. (2008): Split-Bolus Contrast Expression Rolbetzki, Stefan, Dr. med. (2008): Assoziation Medium Injection with Diluted Contrast Mate- Schafflhuber, Markus, Dr. med. (2008): Bedeu- von MHC Klasse II und CTLA-4 Polymorphis- rial for Visualization of The Right Heart at Co- tung extrazellulärer Matrix für die Speicherung men mit Wespengiftallergie ronary CT Angiography von Natrium in osmotisch inaktiver Form Unger, Martina, Dr. med. (2008): Die Bedeutung Klemm, Christine, Dr. med. (2008): Stereotak- Schneider, Andreas, Dr. med. (2008): Spirono- der Biographie für die Ausbildung salutogener tische Vakuumbiopsie - Erfolg, Korrelation von lacton in nicht bludruckwirksamer Dosierung Ressourcen im Umgang mit chronischer Krank- Histologie und BI-RADS™-Klassifikation, Pati- reduziert die linksventrikuläre Masse heit. Eine biographie-analytische und fallver- entenakzeptanz gleichende Untersuchung Runck, Frank, Dr. med. (2008): Magnetic reso- Board Qualifications Völkl, Simon, Dr. rer. nat. (2008): Immunregula- nance imaging: Influence of imaging modality Forster, Christian, Dr. med. (2007): Innere Me- torische Funktion humaner TCRab+ CD4- CD8- and post processing on measurement dizin T-Lymphozyten Rüdel, Christina, Dr. med. (2008): Mehrzeilen- Griesbach, Daniela, Dr. med. (2007): Innere Spiral CT (MSCT) der Halsregion: Dosisoptimie- Medizin und Nephrologie Board Qualifications “Innere Medizin” rung unter Berücksichtigung der Bildqualität Heider, Annette, Dr. med. (2007): Innere Medi- Spörl, Markus, Dr. med. (2008): PEDBONE: Kallert, Stefan, Dr. med. (2007) zin und Nephrologie Online-Referenzdatenbank für Standardrönt- Ferstl, Barbara, Dr. med. (2008) Jacobi, Johannes, Dr. med. (2007): Innere Medi- genaufnahmen in der Pädiatrie zin und Nephrologie Board Qualifications “Diagnostische Jank, Sabine, Dr. med. (2007): Innere Medizin Department of Nuclear Medicine Radiologie” und Nephrologie Chair of Clinical Nuclear Medicine Kueri, Nadia, Dr. med. (2007): Innere Medizin Anders, Katharina, Dr. med. (2008) Radtke, Steffen, Dr. med (2007): Innere Medizin Doctorate Theses Küfner, Michael, Dr. med. (2008) und Nephrologie Radkow, Tanja, Dr. med. (2008) Raff, Ulrike, Dr. med. (2007): Innere Medizin Ketelsen, Dominik, Dr. med. (2007): Arten der Informationsvermittlung im radiologisch-ana- Stein, Holger, Dr. med. (2007): Innere Medizin Habilitations und Nephrologie tomischen Studentenunterricht - Auswirkungen Zapf, Arnd-Oliver, Dr. med. (2007): Innere Me- auf die Leistungen der Studenten Janka, Rolf, PD Dr. med. (2007): Magnetreso- dizin und Nephrologie Knickenberg, Ines, Dr. med. (2007): www.HNO- nanzangiographie der Becken- und Beingefäße: Zeltner, Raoul, Dr. med. (2007): Innere Medizin Rad.de Eine interdisziplinäre interaktive Fall- Untersuchungstechnik und klinische Bewertung und Nephrologie sammlung in HNO-Radiologie im Internet Engelhard, Karl, PD Dr. (2008): Wertigkeit der Kraß, Christine, Dr. med. (2008): Innere Medizin Spörl, Markus, Dr. med. (2007): PEDBONE: Magnetresonanz-Tomographie in der Primärdi- Schneider, Markus, Dr. med. (2008): Innere Me- Online-Referenzdatenbank für Standardrönt- agnostik und der Stadieneinteilung des Prosta- dizin genaufnahmen in der Pädiatrie takarzinoms Seitz, Randolf, Dr. med. (2008): Innere Medizin Bläser, Daniel, Dr. med. (2008): In vitro Studi- en zur Signaltransduktion der Aufnahme von 2 Institute of Radiology Additional Qualification [18F]Fluor-2-desoxy-D-glucose und [131I]Jodid in die Schilddrüse Division of Neuroradiology Willam, Carsten, PD Dr. med. (2008): Intensiv- Wolz, Gabriele, Dr. med. (2008): Vergleich der medizin anatomischen Genauigkeit interaktiver ma- Doctorate Theses nueller und automatischer, Software-basierter Thek-Ling , Eddy, Dr. med. (2007): Diffusionsge- starrer und nicht-starrer Registrierung von wichtete MRT in der Akutphase des experimen- Röntgencomputertomographie (CT) und F-18-

180 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) tellen generalisierten Status epilepticus. Prädik- Eine retrospektive Verlaufsbeobachtung an 27 mit Teratom-Anteilen männlicher Patienten. tion von neuronalem Zelluntergang operierten, übergewichtigen Patientinnen 221 Fälle (1969–2007) und Literaturübersicht Okorn, Christine, Dr. med. (2008): Effekte des Gugger, Christine Yoko, Dr. med. (2008): Nar- Pfrang, Sven, Dr. med. (2008): Besonderheiten AT1-Rezeptor-Blockers Candesartan auf den benhernienentstehung nach Laparotomie Eva- des Morbus Crohn im Kindes- und Jugendalter zerebralen Blutfluß, Infarktgröße und neurolo- luation der Tensiometrie und weiterer poten- aus kinderchirurgischer Sicht. Erlanger Kran- gischen Status bei fokaler zerebraler Ischämie. zieller Prognosefaktoren kengut 1987–2005 Experimentelle Untersuchungen am Tiermodell Langenbach, Andreas, Dr. med. (2008): Im- munhistochemische und molekulargenetische Schöll, Petra Hannelore, Dr. med. (2008): Additional Qualifications “Röntgen Untersuchungen von Mannose-bindendem Laparoskopische und konventionelle Appendek- diagnostik” Lektin (MBL) in gesundem und entzündlich ver- tomie in der Kinderchirurgie. Ein retrospektiver ändertem Darmgewebe bei Morbus Crohn Gölitz, Philipp, Dr. med. (2007) Vergleich (Erlanger Patienten 2000–2004) Perrakis, Aristotelis, Dr. med. (2008): Integrier- Schulz-Heise, Susanne, Dr. med. (2007) te Operationssysteme in der minimal invasiven Engelhorn, Tobias, PD Dr. med. (2008) Chirurgie - Bedeutung der Sprachsteuerung Board Qualification Kloska, Stephan, PD Dr. med. (2008) Rosenbauer, Siegfried Ulf, Dr. med. (2008): Chi- Richter, Gregor, Dr. med. (2008) Knorr, Christian, Dr. med. (2007): Chirurgie rurgische Therapie des Rektumprolaps an der Frankenwaldklinik Kronach von 1999 bis 2004 Habilitation Spiegel, Astrid, Dr. med. (2008): Bedeutung der Department of Surgery Engelhorn, Tobias, PD Dr. med. (2007): Neue Lymphangiogenese bei der Lymphknotenmeta- Division of Trauma Surgery Therapieansätze beim Schlaganfall. Pathophy- stasierung des Kolonkarzinoms siologische und magnetresonanztomographi- Votteler, Birgit, Dr. med. (2008): Chronische Doctorate Theses Pankreatitis und Duodenumerhaltende Pankre- sche Untersuchungen am tierexperimentellen Bogsch, Heike, Dr. med. (2007): Nichtoperative askopfresektion an der Chirurgischen Klinik der Ischämiemodell Behandlung von Verletzungen der Brust- und Friedrich-Alexander-Universität Erlangen-Nürn- Lendenwirbelsäule berg: Operatives Risiko und Follow up Fischer, Stefan Erwin, Dr. med. (2007): Die Department of Surgery Wanninger, Sebastian, Dr. med. (2008): Evalua- winkelstabile Plattenosteosynthese bei Mehr- Chair of Surgery tion des postoperativen Verlaufs bei parastoma- fragmentfrakturen und Pseudarthrosen der len Hernien - eine Analayse des Patientenguts Klavikula Doctorate Theses der Chirurgischen Klinik des Universitätsklini- Keller, Kristin, Dr. med. (2007): Prospektiv ran- kums Erlangen Klug, Eva Maria, Dr. med. (2007): Effizienz und domisierte Studie zur Untersuchung der Aus- Wetzler, Dirk-Andreas, Dr. med. (2008): Mittel- Tolerabilität der Hämorrhoidopexie nach Longo wirkung des Wunddrainagesystems auf die fristige Ergebnisse nach vorderer Kreuzbander- Melling, Nathaniel Timon, Dr. med. (2007): Entstehung eine postoperativen Seroms in der satzplastik mit dem mittleren Patellarsehnend- Dreidimensionale Ganganalyse vor und nach Hüftendoprothetik rittel als bone-tendon-bone-Transplantat unter Anschlussheilbehandlung bei hüftendoprothe- Kolvenbach, Carl Paul, Dr. med. (2007): Ret- besonderer Berücksichtigung des Operations- tisch versorgten Patienten rospektive Untersuchung nach operativer Kor- zeitpunktes Pross, Annette, Dr. med. (2007): Die volare Plat- rektur des Hallux valgus durch subkapitale Me- Yildirim, Ümit, Dr. med. (2008): Mammakar- tenosteosynthese als Standardverfahren bei tatarsalosteotomie nach Stoffella zinom beim Mann Retrospektive Analyse des handgelenksnahen Frakturen Ergebnisse am Schindler, Andreas Christoph, Dr. med. (2007): Patientengutes des Klinikums Nürnberg-Nord Klinikum Bayreuth Der internationale militärisch-medizinische Ein- 1988-2003 Richter, Norbert Rudolf, Dr. med. (2007): Die satz am Beispiel des Schiffsarztes von heute Zimmermann, Patrick, Dr. med. (2008): Risi- Operation nach Graner II zur Therapie der Lu- Grimm, Andreas Hilmar, Dr. med. (2008): Bio- koabschätzung für septische Komplikationen natumnekrose mechanische Push-out-Überprüfung der Osseo- nach großen abdominalchirurgischen Eingriffen Schürger, Irina-Doris, Dr. med. (2007): Pseudar- integration von laserstrukturierten TiA16V4- anhand der Zytokine IL-6 und TNF-a throsenbehandlung durch extrakorporale Stoß- Titan-Endoprothesenoberflächen wellentherapie (ESWT) - Klinische Ergebnisse - Haferkamp, Ines, Dr. med. (2008): Ganganaly- Ziegler, Christian Björn, Dr. med. (2007): Ein tische Funktionsprüfungen nach Hüftendopro- Vergleich verschiedener Rekonstruktionsmetho- Board Qualifications thesen - Implantation im Verlauf eines halben den nach Fingerkuppenamputationen bezüg- Dürsch, Markus, Dr. med. (2007): Chiurgie Jahres lich Sensibilität, Funktionalität und kosmeti- Förtsch, Thomas, Dr. med. (2007): Chirurgie schem Ergebnis Schildberg, Claus, Dr. med. (2007): Chirurgie Board Qualifications “Orthopädie und Bialecki, Diana, Dr. med. (2008): Prä- und post- Croner, Roland, PD Dr. med. (2008): Gefäß Unfallchirurgie” therapeutische Schätzung der Prognose bei chirurgie Resektion kolorektaler Lebermetastasen am Blanke, Matthias, Dr. med. (2007) Herrmann, Olaf, Dr. med. (2008): Gefäßchirurgie Gusinde, Johannes, Dr. med. (2007) Krankengut der Chirurgischen Klinik am Uni- Hoffmann, Martin, Dr. med. (2008): Chirurgie versitätsklinikum Erlangen im Zeitraum 1995- 2006 Additional Qualifications Decker, Martin Georg, Dr. med. (2008): Der Department of Surgery Brem, Matthias, Dr. med. (2007): Sportmedizin Division of Pediatric Surgery Einfluss der hyperthermen intraperitonealen Gelse, Kolja, Dr. med. (2007): Sportmedizin Chemoperfusion (HIPEC) auf die Heilung kolo- Müller, Olaf, Dr. med. (2007): Spezielle Unfall- rektaler Anastomosen im Tiermodell Doctorate Theses chirurgie Engert, Alexandra Barbara Elisabeth, Dr. med. Kolbeck, Michael, Dr. med. (2007): Prä- und Blanke, Matthias, Dr. med. (2008): Manuelle (2008): Gastroplastik nach Mason und Law: postpubertäre Teratome und Keimzelltumore Medizin/Chirotherapie

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 181 APPENDIX

Olk, Alexander, Dr. med. (2008): Spezielle Un- Cevikel, Ufuk, Dr. med. (2007): Die stadienab- Helm, Stephanie Nadine, Dr. med. (2008): Die fallchirurgie hängige Expression von TGFß1-spezifischen Rolle des Chemokinrezeptors CCR 7 bei der Pa- Olk, Alexander, Dr. med. (2008): Ärztliches Signalproteinen beim Morbus Dupuytren – Eine thogenese der Transplantatarteriosklerose Qualitätsmanagement immunhistochemische Studie an Resektions- Schulz-Drost, Stefan, Dr. med. (2008): Notfall- präparaten medizin Euler, Simon, Dr. med. (2007): Früh- und Spät- Department of Urology Chair of Urology angiogenetische Ereignisse der Gefäßinduktion, Habilitation -adaptation und –reifung in einem Isolations- Doctorate Theses kammermodell durch den Einsatz einer arterio- Schöffl, Volker, PD Dr. med. (2007): Sport- venösen Gefäßschleife Strasser, Hans, Dr. med. (2007): DNA double- artspezifische Verletzungen der Hand und Fin- Heidner, Kristina, Dr. med. (2007): Osteoblast- strand break induction and repair in irradiated ger im Klettersport entransplantation in axial prävaskularisierte lymphoblastoid, fibroblast cell lines and white Hartmatrizes: Untersuchungen im Modell der blood cells from ATM, NBS and radiosensitive Department of Surgery arterio-venösen Gefäßschleife patients Division of Transfusion Medicine and Lippert, Marion, Dr. med. (2007): Zur Effekti- Bogner, geb. Goeb, Katja, Dr. med. (2008): Haemostaseology vität der Keratinozytentransplantation bei der MRI-Spectroscopy in screening for prostate Behandlung von Brandwunden, im Vergleich cancer Doctorate Theses zur Spalthauttransplantation – eine Metaana- Landsmann, Dr. med. (2008): Treatment of lyse advanced transitional cell carcinoma of the Frank, Maren, Dr. med. dent. (2007): Diagno- Konzi, Melanie, Dr. med. (2008): Evaluation von bladder (TCC) by irinotecan in an experimental sestatistik für Empfänger von Plasmaderivaten Wirkung und Effizienz verschiedener Transplan- animal model aus dem Blutdepot der Transfusionsmedizini- tationstechniken autolog und allogen gewon- schen und Hämostaseologischen Abteilung des nener Keratinozyten bei chronischen, therapie- Board Qualifications “Urologie” Universitätsklinikums Erlangen refraktären Wunden unterschiedlicher Genese: Friedrich, Iris, Dr. med. (2007): Ist es nicht Eine Metaanalyse Rith, Torsten, Dr. med. (2008) höchste Zeit, die Blutspender gegen Hepatitis Lanczak, Johanna, Dr. med. (2008): Aktivierung Strasser, Hans, Dr. med. (2008) B zu impfen? des Jak1-Stat1-Cross-Talks hzur Blockade des Hendelmeier, Martin, Dr. med. (2007): Gewin- profibrotischen TGFß1-Signalweges – Adenovi- Additional Qualifications “Medikamentöse nung CD14-positiver Zellen und Rekrutierung ral codiertes IFNy agiert via Überexpression von Tumortherapie” monozytärer Subpopulationen durch Apherese Smad 7 Strobel, Julian, Dr. med. (2007): Einfluss von Krause, Frens Steffen, PD Dr. med (2008) Gammastrahlung auf die Gerinnungsaktivie- Walter, Bernhard, Dr. med. (2008) Board Qualifications “Plastische und rung in Gefrorenem Frischplasma Ästhetische Chirurgie” Helmer-Krex, Martina, Dr. med. (2008): Der Habilitation Einfluss der Veränderung des Azetat- und Zit- Kneser, Ulrich, Dr. med. (2007) Zugor, Vahudin, PD Dr. med (2008): Solide re- ratanteils auf die in-vitro Qualität von in addi- Loos, Bernd, Dr. med. (2007) nale Raumforderungen: Therapie, Klinik und tiver Lösung gelagerten Thrombozytapherese- Dragu, Adrian, Dr. med. (2008) Prognose unter besonderer Berücksichtigung konzentraten Polykandriotis, Elias, Dr. med. (2008) des Kindes- und Jugendalters König, Julia, Dr. med. (2008): Die Wirkung der Antikoagulation von Proben auf die Messung Additional Qualification von zirkulierenden Wachstumsfaktoren, die aus Department of Anaesthesiology Bach, Alexander, PD Dr. med. (2007): Handchi- Thrombozyten freigesetzt werden Chair of Anaesthesiology rurgie Wintzheimer, Simone, Dr. med. (2008): In-vitro-Qualitätskontrollen von mit verschiedenen Doctorate Theses Habilitation Methoden leukozytendepletierten und teilweise Donhauser, Andreas, Dr. med. (2007): Simula- mit 30 Gray bestrahlten Erythrozytenkonzen- Kneser, Ulrich, PD Dr. med. (2008): Tissue En- tion eines Mehrwellenpulsoximeters zur Bestim- traten gineering von Knochen: von der zellbesiedelten mung der technischen Spezifikationen für eine Hartmatrix zum axial vaskularisierten bioartifi- nicht-invasive Messung der Carboxyhämoglo- Additional Qualifications ziellen Knochenhgewebe binfraktion Achenbach, Susanne, Dr. med. (2008): Hämo- Frötsch, Katrin, Dr. med. (2007): Renale Ne- staseologie Department of Cardiac Surgery benwirkungen von Paracetamol oder Parecoxib Ringwald, Jürgen, PD Dr. med. (2008): Ärztli- Chair of Cardiac Surgery nach orthopädischen Operationen bei älteren ches Qualitätsmanagement Patienten Doctorate Theses Herrndobler, Franz, Dr. med. (2007): Modula- tion der kortikalen Schmerzverarbeitung durch Department of Plastic and Hand Surgery Heckel, Matthias Karl, Dr. med. (2008): Früh- Cyclooxygenase-Hemmung in einem UV-B in- postinterventionelle Stentkomplikationen und duzierten Hyperalgesiemodell: eine funktionelle Doctorate Theses operative Myokardrevaskularisation bei koro- Kernspintomographie-Studie narer Herzerkrankung - eine Situationsanalyse Koch, Yvonne, Dr. med. (2007): In vitro Unter- Brockmann, Silke, Dr. med. (2007): Vergleichen- unter Berücksichtigung der aktuellen Versor- suchung der Auswirkungen von neuen Volu- de Betrachtung des distal gestielten Suralis- gungsleitlinien menersatzmitteln auf die Gerinnung und Peroneuslappens zur Rekonstruktion des Meyer, Verena, Dr. med. (2007): Zuverlässig- distalen Unterschenkels und Fußes keit von Pulsoximetern der dritten und vierten

182 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Generation bei raschen Änderungen von Herz- Patienten kontrollierter Periduralanalgesie ver- Schreiner, Stefanie, Dr. med. (2007): Der Kon- frequenz und Sauerstoffsättigung während der sus intravenöser/peroraler Schmerztherapie zentrationsabhängige Einfluss von 17ß-Estradi- Elektrokrampftherapie Wilderer, Jürgen, Dr. med. (2008): Diskrimi- ol und Progesteron auf das Kontaktionsverhal- Reindl, Michael, Dr. med. (2007): Die Ärztliche nanzanalyse des spontanen und evozierten ten des Myometriums Übergabe als wichtige Schnittstelle zwischen EEG zur Unterscheidung und Vorhersage ver- Geiler, Sonja, Dr. med. (2008): Polymorphismen Intensivstation und Normalstation schiedener klinischer Narkosestadien im Aromatasegen (CYP19A1) und deren Asso- Singler, Boris, Dr. med. (2007): Modulation der Zapke, Tobias, Dr. med. (2008): Alcuronium ziation mit dem histopathologischen Phänotyp Remifentanil-induzierten Hyperalgesie durch und Atracurium im Vergleich hinsichtlich ihrer beim Mammakarzinom Propofol in einem experimentellen Schmerzmo- lytischen Wirkung auf Succinylcholin-induzierte Heusinger, Katharina, Dr. med. (2008): Genau- dell am Menschen Muskelfaszikulationen igkeit der Tumorgrößenbestimmung im Rah- Sittl, Ruth, Dr. med. (2007): Modulation der Re- men des klinischen Stagings von Brustkrebspa- mifentanil-induzierten Analgesie und Hyperal- Board Qualifications “Anästhesiologie” tientinnen – eine vergleichende, prospektive gesie durch Parecoxib in einem experimentellen klinische Studie Schmerzmodell am Menschen Klein, Carsten, Dr. med. (2007) Kollmannsberger, Bettina, Dr. med. (2008): Wick, Stefanie, Dr. med. (2007): Studie zur Er- Lang, Anna-Katharina, Dr. med. (2007) Polymorphismen in den 5-Hydroxytryptamin- fassung der Anschlagszeit und Dauer einer Schwalb, Rebecca, Dr. med. (2007) rezeptorgenen HTR3B und HTR3C und deren neuromuskulären Blockade durch Rocuronium Strube, Marion, Dr. med. (2007) Bedeutung für chemotherapieinduziertes Erbre- bei Patienten mit Duchenne Muskeldystrophie Tzabazis, Alexander, Dr. med. (2007) chen Arlt, Verena, Dr. med. (2008): Wirkungsprofil des Aumiller, Thomas, Dr. med. (2008) Kusuma Widjaja, Widya, Dr. med. (2008): Eta- Muskelrelaxans Mivacurium bei Patienten mit Jeleazcov, Christian, Dr. med. (2008) blierung eines Mikrochip-Präzisionsdruckkathe- Muskeldystrophie Typ Duchenne Müller, Susanne, Dr. med. (2008) ters zur Messung intrauteriner Druckverläufen Feuchter, Sonja, Dr. med. (2008): Wirksamkeit Rieß, Simon, Dr. med. (2008) sowie Einführung der Perfusionsdruckmessung und Verträglichkeit von transdermalem Bu- Schmidt, Astrid, Dr. med. (2008) mit einem digitalen Transducer im ex vivo prenorphin bei einer Applikationsdauer von 4 Schön, Christoph, Dr. med. (2008) Schweineuterusperfusionsmodell Tagen im Vergleich zu 3 Tagen Strembski, Dieter, Dr. med. (2008) Kösztner, Heike, Dr. med. (2008): Die Kryokon- Göhring, Markus, Dr. med. (2008): Effekte einer Wilhelm, Ilca-Ricarda, Dr. med. (2008) servierung von Geweben und Organen am Bei- oralen Gabe von Pregabalin und Aprepitant spiel des Schweineuterus auf Schmerz und zentrale Sensibilisierung in Habilitations Langbein, Manuela, Dr. rer. nat. (2008): Die einem experimentellen Schmerzmodell beim Münster, Tino, PD Dr. med. (2007): Muskelre- Rolle des PPARγ Signalweges für die Tropho- Menschen laxation bei Patienten mit neuromuskulären blasten-Differenzierung im Verlauf normaler Günther, Werner, Dr. med. (2008): Supra-addi- Erkrankungen: Wirkprofil von Mivacurium und und pathologischer humaner Plazentogenese tive Effekte von Tramadol und Paracetamol in Rocuronium Rauh, Claudia, Dr. med. (2008): Einfluss von einem Schmerzmodell am Menschen Schmidt, Joachim, PD Dr. med. (2007): Peri- hormonellen und reproduktiven Faktoren auf Heinl, Kathrin, Dr. med. (2008): Einfluss einer operativer Einsatz moderner nicht-depolarisie- die Entstehung und Prognose eines Mamma- multimodalen Gruppentherapie auf Medika- render Muskelrelaxanzien: Untersuchungen zu karzinoms mentenverhalten und Symptomatik bei chroni- Anwendungsgewohnheiten, Monitoring, Phar- schen Kopfschmerzpatienten makodynamik an verschiedenen Muskelgrup- Board Qualifications “Frauenheilkunde Körber, Nicole, Dr. med. (2008): Unterschied- pen sowie zur Pharmakodynamik bei Patienten und Geburtshilfe” liche Profile von Analgesie und Antihyperalge- mit neuromuskulären Erkrankungen Fasching, Peter, Dr. med. (2007) sie nach Buprenorphin in einem menschlichen Jeleazcov, Christian, PD Dr. med. (2008): Para- Schmerzmodell Mehlhorn, Grit, Dr. med. (2007) metrization and pharmacodynamic modelling Meurer, Britta, Dr. med. (2007) Leuthold, Christian, Dr. med. (2008): Entwick- of spontaneous and evoked EEG to optimize lung eines neuen Tiermodells für Reanimation Siemer, Christian, Dr. med. (2007) anaesthetic drug therapy by simultaneous Allali, Faouz, (2008) bei akutem Myocardinfarkt und Evaluation trend monitoring in children and adults der Hämodynamik nach Wiederkehr des Spon- Hart, Nicola, Dr. med. (2008) Schiessl, Christine, PD Dr. med. (2008): Patien- Lux, Michael Patrick, Dr. med. (2008) tankreislaufes am Hausschwein tenkontrollierte Analgesie (PCA) in der Tumor- Plettke, Regina, Dr. med. (2008): Pharmakody- Oppelt, Patricia, Dr. med. (2008) schmerztherapie: Indikation, Management und Reißmann, Christine, Dr. med. (2008) namische Modellbildung anästhesieassoziierter Behandlungsergebnisse Veränderungen quantitativer EEG-Variablen während Sevofluranapplikation bei der Ratte Additional Qualifications Priller, Michael, Dr. med. (2008): Pharmakody- Department of Obstetrics and Goecke, Tamme, Dr. med. (2007): Spezielle Ge- Gynaecology namische Modellbildung anästhesieassoziierter burtshilfe und Perinatalmedizin Chair of Obstetrics and Gynaecology Veränderungen quantitativer EEG-Variablen Oppelt, Peter, Dr. med. (2007): Gynäkologische während Isofluranapplikation bei der Ratte Onkologie Doctorate Theses Radünz, Sonia, Dr. med. (2008): Totale intra- Cupisti, Susanne, Dr. med. (2008): Spezielle Ge- venöse Anästhesie mit Fospropofol (Aquavan Grabbert, Martina, Dr. med. (2007): Fetal out- burtshilfe und Perinatalmedizin Injection) - einem wasserlöslichen Prodrug von come bei Sectio caesarea in Spinalanästhesie, Cupisti, Susanne, Dr. med. (2008): Gynäkologi- Propofol - während koronarchirurgischer Ope- Periduralanästhesie und Intubationsnarkose sche Exfoliativ-Zytologie rationen Hoffmann, Frederike, Dr. med. (2007): Einfluss Frobenius, Wolfgang, Dr. med. (2008): Spezielle Schulte, Klaus, Dr. med. (2008): Klinische An- von Maillard-Produkten vom Typ Chelatbildner Geburtshilfe und Perinatalmedizin wendungsbeobachtung zum Vergleich der auf die kupferkatalysierte Oxidation von Low Thiel, Falk, Dr. med. (2008): Gynäkologische postoperativen Schmerztherapie nach endo- Density Lipoprotein Onkologie prothetischer Versorgung des Kniegelenkes mit

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 183 APPENDIX

Habilitations Lymphozyten im Plattenepithelkarzinom des Falkenberg, Christian, Dr. med. (2007): Todes- Oropharynx ist abhängig von der Art der Be- ursachen der juvenilen chronischen Arthritis Fasching, Peter, PD Dr. med. (2007): Risikoein- handlung Graml, Michael, Dr. med. dent. (2007): Pros- schätzung für das Mammakarzinom in Präven- Gebel, Philipp, Dr. med. (2008): Gemcitabine pektive Erfassung von endokrinen Spätschäden tion und Früherkennung aktiviert H2AX über blockierte Replikationsga- bei Kindern und Jugendlichen nach Hirntumort- Binder, Helge, PD Dr. med. (2008): Untersu- bel herapie im Rahmen der GPOH-Studie HIT 2000 chungen zur Genetik, Klinik und Kostenana- Hofmann, Anne, Dr. med. (2008): Unterschie- Klaffenbach, Daniela, Dr. med. (2007): Regula- lyse des ovariellen Überstimulationssyndroms de in der Signaltransduktion einer normalen tion und Signaltransduktion der Toll-like-Rezep- (OHSS) in der Sterilitätstherapie menschlichen Zelllinie im Vergleich zu einer toren in humanen Plazentazellen Cupisti, Susanne, PD Dr. med. (2008): Endokri- Zelllinie mit Nijmegen Breakage Syndrom Krauß, Alexander, Dr. med. dent. (2007): Pro- ne und metabolische Evaluation der klinischen Kühn, Leonhard, Dr. med. (2008): Bildung der laktin-Konzentrationen im Serum von Kindern Kriterien des Polyzystischen Ovar-Syndroms Nuklear Bodies in Abhängigkeit von der p53- und Jugendlichen und Einfluß des Body-mass-Index Posphorylierung in bestrahlten lymphoblastoi- Kunz, Katharina, Dr. med. dent. (2007): Pulmo- den Zellen und Fibroblasten von einem Gesun- nalatresie mit intaktem Ventrikelseptum: ope- Department of Radiation den und einem NBS-Patienten rative Therapie und mittelfristige Ergebnisse Chair of Radiation Therapy Lettmaier, Sebastian, Dr. med. (2008): Lang- Mahfoud, Suleiman, Dr. med. (2007): Inhalati- zeitergebnisse zur Wirksamkeit von Amifostin ve Anwendung von Adrenomedullin im Modell Doctorate Theses in der Prävention der chronischen radiogenen surfactantdepletierter neonataler Ferkel mit Xerostomie pulmonaler Hypertension Baierlein, Sammy, Dr. med. (2007): Kombinier- Mese, Mesut, Dr. med. (2008): Einfluss der Ope- Neuner, Andrea, Dr. med. (2007): Evaluierung ter Effekt von Tumor Nekrose Faktor alpha und rationstechnik auf die Rezidivhäufigkeit beim einer pränatalen Gentherapiestrategie für die ionisierender Strahlung auf die Induktion von Rektumkarzinom nach standardisierter Radio- Behandlung des Morbus Herlitz Apoptose in 5637 Harnblasenkarzinomzellen chemotherapie Eine retrospektive Analyse des Pickel, Naemi, Dr. med. (2007): Unterschiedli- Lahmer, Godehard, Dr. med. (2007): Der Ein- Krankenguts einer fränkischen Klinik im Zeit- che ontogenetische Regulation der mRNA-Ex- fluss immunkompetenter Zellen auf die Progno- raum 01.04.1993 bis 30.04.2002 pression konstitutiver und induzierbarer pepti- se des Analkarzinoms nach einer Radiochemo- Schendel, Roy, Dr. med. (2008): Tumor und derger und nitriderger Systeme in der Plazenta therapie Stroma beim lokal fortgeschrittenem duktalen Popp, Karolin, Dr. med. (2007): Hemmung der Metz, Anja, Dr. med. (2007): Resultate der neo- Pankreaskarzinom: Die Expression von moleku- pulmonalen Fibroseinduktion durch inhalatives adjuvanten Radiochemotherapie bei Patienten laren Markern und deren Korrelation mit dem Adrenomedullin im Modell surfactantdepletier- mit fortgeschrittenen Mundhöhlenkarzinomen Überleben bei Patienten mit definitiver, simulta- ter neonataler Ferkel Schilcher, Florian, Dr. med. (2007): Radiothe- ner Radiochemotherapie Tell, Kai, Dr. med. dent. (2007): Der Diabetes-Si- rapie der medialen Lymphabflusswege gleicht Ullmann, Christian, Dr. med. (2008): Der Ein- tuations-Test: Statistische Evaluierung von Ob- die ungünstigere Prognose eines medialen fluss tumorinfiltrierender Lymphozyten auf die jektivität, Reliabilität, Validität und Testscore- und zentralen Primärtumorsitzes beim kleinen Prognose des Oropharynxkarzinoms veränderungen im Rahmen des „Projekt D“ Mammakarzinom aus Wolze, Carolin, Dr. med. (2008): Die organer- Todoric, Teofil, Dr. med. (2007): Die diagnosti- Strasser, Hans, Dr. med. (2007): DNA-Dop- haltende Therapie des Harnblasenkarzinoms sche Aussagekraft visuell evozierter Potentiale pelstrangbruch-Induktion und Reparatur in durch transurethrale Resektion und kombinierte nach Blitz- und Musterreizung bei Säuglingen bestrahlten Lymphoblastoiden Zellen, Fibro- Radiochemotherapie und Kleinkindern mit Mehrfachbehinderung blasten und Leukozyten von ATM-, NBS- und und permanenter kortikaler Blindheit strahlensensiblen Patienten Board Qualifications “Strahlentherapie” Weigel, Corina, Dr. med. (2007): Einfluss expe- Uhl, Matthias, Dr. med. (2007): Veränderungen rimenteller Hypoxie auf die Expression von Syn- der NBS-Phosphorylierung nach Bestrahlung Melzner, Winfrid, Dr. med. (2007) cytin und dessen Rezeptor ASCT2 von Säugerzellen im zeitlichen Verlauf Windschall, Andrea, Dr. med. (2007) Albert, Christian, Dr. med. (2008): Untersuchun- Waas, Alexandra, Dr. med. (2007): Kann mit gen zur intrakapillären Hämoglobinoxygenie- Hilfe des G2/M-Arrests die individuelle Strah- Habilitations rung bei Kindern mit Wachstumshormonman- lenempfindlichkeit von Patienten vorhergesagt Fahrig, Antje, PD Dr. med. (2007): Innovative gel unter Wachstumshormontherapie mit dem werden? Techniken in der Hochpräzisions-Strahlenthe- Erlanger Mikrolichtleiter-Spektrophotometer Wittlinger, Michael, Dr. med. (2007): Zeit- und rapie: experimentelle Grundlagen und klinische Berzl, Gabriele, Dr. med. (2008): Veränderungen dosisabhängige Phosphorylierung von p53 Ergebnisse endokriner Parameter in der Plazenta bei hypo- an Serin 15 in Zelllinien mit unterschiedlicher Gaipl, Udo, PD Dr. rer. nat. (2008): Dying and trophen Früh- und Neugeborenen Strahlensensibilität dead cells as inducer of chronic autoimmunity Bosselmann, Stephan, Dr. med. (2008): Thera- Albrecht, Christine, Dr. med. (2008): Expression and as tool for immune intervention pie des akuten Lungenversagens mit aerosoli- und Modulation von p53 und Mdm2 in Kopf- siertem Perfluorcarbon im tierexperimentellen Hals-Tumoren Modell des neonatalen ARDS: Vergleich der Brandl, Isabella, Dr. med. (2008): Die Bedeutung Department of Pediatrics Wirkung von kontinuierlich und atemphasen- von p53-Mutationen für die Wirksamkeit einer Chair of Pediatrics abhängig appliziertem Perfluorcarbon in unter- adjuvanten Radiotherapie bei Plattenepithel- schiedlichen Testdosen karzinomen des Oropharynx Doctorate Theses Bäcker, Silke, Dr. med. (2008): Bakterielle Trans- Dietel, Katrin, Dr. med. (2008): Der Einfluss tu- Eitel, Annelie-Beate, Dr. med. (2007): Immun- migration an Darmepithelzellinien unter dem morinfiltrierender Lymphozyten auf die Progno- Einfluss verschiedener Ingredienzien se des Oropharynxkarzinoms globulin-G-Subklassen-Verteilung und Erkran- kungsmuster bei Kindern mit rezidivierenden Denekas, Anja, Dr. med. dent. (2008): Parodon- Fickenscher, Rainer, Dr. med. dent. (2008): Der titis – eine Frage der körpereigenen Abwehr? prognostische Einfluss von tumorinfiltrierenden Infekten

184 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Fischer, Barbara, Dr. med. (2008): HLA-DRal- Department of Pediatrics Habilitations pha- und DRbeta-spezifische Antikörper zur Division of Pediatric Cardiology Nettelbeck, Dirk Manfred, PD Dr. rer. physiol. Lyse maligner B-Zellen (2007): Engineering of Oncolytic Adenoviruses Klingmüller, Karin, Dr. med. (2008): Expression Doctorate Thesis for Targeted Treatment of Malignant Melano- Hypoxie-induzierbarer metabolischer Faktoren Spicher, Janna-Kristin, Dr. med. (2008): Bal- ma in der humanen Plazenta in vivo unter akuter londilatation der valvulären Aortenstenose: und chronischer Hypoxie Prädiktoren für den unmittelbaren Erfolg und Marek, Ines, Dr. med. (2008): Molekulare Un- Langzeitergebnisse Department of Ear, Nose and Throat – terschiede im Ablauf der experimentellen me- Head and Neck Surgery sangioproliferativen Glomerulonephritis nach Chair of Otorhinolaryngology intrauteriner Wachstumsrestrikton in der Ratte Department of Dermatology Otto, Stephanie Johanna , Dr. med. (2008): Chair of Skin and Venereal Diseases Doctorate Theses Kombinierte ösophageale pH- und Impedanz- Brase, Christopher, Dr. med. (2007): Antwort- messung nach operierter Ösophagusatresie Doctorate Theses profile individueller olfaktorischer Glomeruli Rückel, Aline, Dr. med. (2008): Reduktion der im Bulbus olfactorius principalis von Xenopus- pulmonalen Hypertonie sowie der Expression Bekou, Vassiliki, Dr. med. (2007): Entwicklung laevis-Larven. der proinflammatorischen Interleukine 1beta eines ELISA zum Nachweis von Autoantikörpern Gill, Sandra, Dr. med. (2007): Sonographische und 8 im Rahmen eines Großtiermodells des gegen Laminin 5 beim Schleimhautpemphigoid Kontrastmittelkinetikanalyse in der Dignitäts- neonatalen Atemnotsyndroms durch den Inter- Eisemann, Jutta, Dr. rer. nat. (2007): Untersu- bestimmung von Lypmphknoten im Kopf-Hals leukin-1-Rezeptorantagonisten Anakinra chungen zur Interaktion von HSV-1 mit reifen Bereich Schrey, Dominik, Dr. med. (2008): Findung der dendritischen Zellen Göderer, Lisa, Dr. med. (2007): Das CRPS (= Dosis und der Applikationsart für die aerosoli- Busch, Marion, Dr. med. (2008): Surrogatprote- komplex regionales Schmerzsyndrom) - eine sierte Perfluorcarbon-Beatmung an surfactant- ine in Latexhandschuhen induzieren allergen- Langzeit Follow-up-Studie depletierten Ferkeln mit ARDS spezifische IgE-Antikörper im Mausmodel: Eta- Miller, Ludwig Andreas, Dr. med. dent. (2007): Walther, Julia, Dr. med. (2008): Verbesserung blierung einer Microarray-basierten Diagnostik Der Erfolg der adaptiven Desaktivierung gegen von Gasaustausch und Lungenmechanik, Re- muriner Antikörper Acetylsalicylsäure bei Patienten mit Polyposis duktion der pulmonalen Hypertonie durch ae- Erfurt-Berge, Cornelia Susanne, Dr. med. nasi und Analgetika-Intoleranz gemessen am rosolisiertes Perfluorcarbon am surfactantde- (2008): Erstmaliger Nachweis einer CD4+ postoperativen Beschwerdebild pletierten Ferkel mit ARDS T-Zell-vermittelten Immunantwort auf das Müller, Oliver, Dr. med. dent. (2007): Ergebnis- Wich, Christina, Dr. med. (2008): Genexpression Tumorantigen „Melanom-assoziiertes Chond- se der chirurgischen Therapie des Zenker Diver- des plazentaren Fusionsproteins Syncytin und roitinsulfat-Proteoglykan (MCSP)“ und Identifi- tikels: Endoskopische Schwellendurchtrennung dessen Transkriptionsfaktors GCMa, des Syncy- zierung des immunogenen Epitopes versus transzervikale Methoden tin-Rezeptors ASCT2 und des Effektormoleküls Gagg, Tina Brigitte, Dr. med. (2008): Epidemio- Nguyen, Danny Tho, Dr. med. (2007): Stape- Connexin 43 unter Normoxie und Hypoxie in logische Untersuchungen zur chronischen Ur- dotomie - Stapedektomie Eine Langzeitstudie humanen trophoblastären Zellen tikaria unter besonderer Berücksichtigung des zweier Operationsmethoden unter Betracht des Wolst, Andreas, Dr. med. (2008): Chylothorax Krankheitsverlaufes und der Abheilung Innenohr- und Mittelohrbereiches nach Herzoperation im Kindesalter Horstmann, Brigitte, Dr. med. vet. (2008): Im- munmodulation Dendritischer Zellen durch Reißenweber, Christian Matthias, Dr. med. niedrigmolekulare, makrozyklische Inhibitoren dent. (2007): Langzeitergebnisse zur adap- Board Qualifications “Kinder- und Jugend- medizin” in vivo und in vitro tiven Desaktivierung gegen Acetylsalicylsäure Knippertz, Ilka, Dr. rer. nat. (2008): Genetic and (ASS) bei Patienten mit Polyposis nasi et sinu- Karle, Stephanie, Dr. med. (2007) physical modification of human DC in order to um und Analgetika-Intoleranz-Syndrom Eine Metzler, Markus, Dr. med. (2007) improve vaccination protocols retrospektive Krankengutanalyse von 1986 bis Richter, Markus, Dr. med. (2007) Kosmides, Daniela, Dr. rer. nat. (2008): Modula- 2004 der Hals-Nasen-Ohrenklinik Sauerstein, Katja, Dr. med. (2007) tion of Viral Gene Expression and Capsid Com- Schmidt, Manfred Georg, Dr. med. (2007): Topf, Hans-Georg, Dr. med. (2007) ponents to Engineer Oncolytic Adenoviruses for Parotidektomien der Jahre 1990-2001 an der Galiano, Matthias, Dr. med. (2008) Virotherapy of Cancer Hals-Nasen-Ohren-Klinik, Kopf- und Hals-Chir- Gratzki, Nils, Dr. med. (2008) Schierer, Stefan, Dr. rer. nat. (2008): Modulation urgie des Universitätsklinikums Erlangen Melichar, Volker, Dr. med. (2008) Of Dendritic Cell Biology By Oncolytic Adenovi- Zeidelhack, Nicole Florentine Inge Hilde, Dr. Zapke, Maren, Dr. med. (2008) ruses And By Melanoma Cells Lysed By Onco- med. dent. (2007): Komplikationen akuter von Goessel, Heiko, Dr. med. (2008) lytic Adenoviruses Rhinosinusitiden Eine Analyse stationärer Auf- Seidel, Helmut Andreas, Dr. med. dent. (2008): enthalte Habilitations Prognose von Berufsdermatosen - Eine Follow- Birk, Stephanie, Dr. med. (2008): Genetische up Untersuchung des Berufskrankheitenregis- Markierung von humanen mesenchymalen Rauh, Manfred, PD Dr. rer. nat. (2007): LC-Tan- ters Haut Nordbayern (BKH-N) Stammzellen mittels enhanced green fluores- dem-Massenspektrometrie. Neue analytische cent protein. Möglichkeiten für das klinische Labor Board Qualifications “Haut- und Gaitzsch, Christian, Dr. med. dent. (2008): Utsch, Boris, PD Dr. med. (2008): Hand-Fuß- Geschlechtskrankheiten” Hörverlauf nach transtemporaler mikrochirur- Genitalsyndrom – Polyalanin-Expansionen gischer Entfernung von Vestibularisschwanno- Hezel, Svea, Dr. med. (2008) men Zajitschek, Jörg, Dr. med. (2008) Hechtel, Christina, Dr. med. (2008): Mediane Halszysten und Halsfisteln Untersuchung am Patientengut der Hals-Nasen-Ohren-Klinik,

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 185 APPENDIX

Kopf- und Halschirurgie Erlangen von 1992 bis Weigl, Veronika, Dr. med (2007): Ängstlichkeit, Steinhäuser, Maike, Dr. med. (2008): OCT ge- 2002 Depressivität und gesundheitsbezogene Le- stützte Referenzebene für das HRT-eine neue Häusler, Marcus Alexander, Dr. med. (2008): bensqualität der Mütter von Kindern mit Lip- Option? Analyse der Immunogenität von Plattenepithel- pen-Kiefer-Gaumenspalten karzinomen des Kopf-Hals-Bereiches mit der Wurzbacher, Tobias, Dr.-Ing. (2007): Vocal Fold Serex-Methode Dynamics - Quantification and Model-based Department of Neurology Chair of Neurology Kapsreiter, Markus, Dr. med. (2008): Über die Classification Innervation der Arteria centralis retinae des Bößenecker, Arno, Dr. med. (2008): Analyse der Doctorate Theses Menschen. Dreidimensionalen Stimmlippendynamik Kluge, Sonja Elisabeth, Dr. med. dent. (2008): Preclik, Markus , Dr. med (2008): Anamnesebo- Breuer, Lorenz, Dr. med. (2007): Megaphen- die Identifizierung immunogener Strukturen eines gen für Auditive Verarbeitungs- und Wahrneh- Rolle der Universitäts-Nervenklinik Erlangen bei Cholesteatoms mungsstörungen – Psychometrische Korrelation der klinischen Einführung der ersten Neurolep- Prillwitz, Heino Torsten, Dr. med. (2008): An- im Vorschulalter tika in Deutschland wendung und Versuch der Validierung der Schmitt, Claudia, Dr. med (2008): Screening der Kiphuth, Ines-Christine, Dr. med. (2007): Ent- Funktionellen Eicosanoid-Typisierung (FET- kognitiven Entwicklung von Vorschulkindern wicklung einer Methode zur molekularen Ha- AIT®) bei Patienten mit Polyposis nasi – Bewertung der essentiellen Grenzsteine der plotypisierung: allelspezifische Bestimmung Rogler, Katrin, Dr. med. (2008): Einfluss von kindlichen Entwicklung nach Michaelis von Mutationen und genetischen Markern im Phosphatase- und Kinase- Inhibitoren auf die Vogt, Beate, Dr. med (2008): Numerische Quan- PAH-Gen Phosphorylierung und Aggregation des Tau- tifizierung der Verständlichkeit von Schulkin- Porsche, Christian, Dr. rer. nat. (2007): Neuro- Proteins in Zellkulturen. dern mit isolierter und kombinierter Gaumen- nale Plastizität im Hippocampus der Maus: Die Schardt, Katharina, Dr. med. (2008): Untersu- spalte Rolle von Neurotrophinen und Cytokinen chungen zu Tumorantigenen an einem Adeno- Pohle, Rebecca, Dr. med. (2008): Zusammen- karzinom der Nasennebenhöhle mittels „SER- Board Qualifications “Sprach-, Stimm- und hang zwischen Schlaganfallentitäen gemäß EX“ kindliche Hörstörungen” den Diagnosekriterien der TOAST Klassifikation Schnell, Jennifer-Lisa, Dr. med. (2008): Retros- Toy, Hikmet, Dr. med. (2007) und dem Auftreten von funktioneller Behin- pektive Analyse von operativen Defektdeckun- Schützenberger, Anne, Dr. med. (2008) derung nach einem Schlaganfall im Erlanger gen im Bereich der Rhinobasis unter besonderer Schlaganfall Projekt Berücksichtigung von intraoperativ verursach- Racz, Attila, Dr. rer. nat. (2008): Molecular de- Habilitation ten Schädelbasisdefekten bei endoskopischen terminants of hippocampal oscillatory activity Nasennebenhöhlenoperationen der Jahre 1990 Lohscheller, Jörg, PD Dr.-Ing. (2007): Analyse, - 2004 Visualisierung und Klassifikation stimmerzeu- Board Qualifications “Neurologie” Tziridis, Konstantin, Dr. rer. nat. (2008): The role gender Strukturen basierend auf endoskopi- of the pontine nuclei in visually guided hand schen Hochgeschwindigkeitsaufnahmen Kollmar, Rainer, Dr. med. (2007) and eye movements Ulrich, Kathrin, Dr. med. (2007) Bardutzky, Jürgen, Dr. med. (2008) Board Qualifications “Hals-Nasen-Ohren- Department of Ophthalmology Schramm, Axel, Dr. med. (2008) heilkunde” Chair of Ophthalmology Habilitations Bumm, Klaus, Dr. med. (2007) Doctorate Theses Bohr, Christopher, Dr. med. (2008) Bardutzky , Jürgen, PD Dr. med. (2008): Ma- Link, Barbara, Dr. med (2007): Einfluss des spon- gnetresonaztomographische Untersuchungen tanen Venenpulses auf morphometrischen Pa- zur Entwicklung und Dynamik der Perfusions/ Department of Ear, Nose and Throat – pillenmessungen mit dem HRT Diffusions Mismatches am tierexperimentellen Head and Neck Surgery Raum, Christoph, Dr. med (2007): Planimetri- Ischämiemodell Division of Phoniatrics and Pediatric Audiology sche Langzeitbeobachtung von Patienten mit Huttner, Hagen, PD Dr. med. (2008): Neue in- stabilem und progressivem Glaukom tensivmedizinische Behandlungsaspekte bei der Doctorate Theses Rödl, Johannes, Dr. med (2007): Glaukomatö- intrazerebralen Blutung Brauner, Kristof, Dr. med. (2007): Früherken- se Neurodegeneration - Homocystein als neuer Kollmar, Rainer, PD Dr. med. (2008): Experimen- nung von Sprachentwicklungsstörungen – Be- Risikofaktor telle Untersuchungen zu induzierter Hypother- wertung des Screenings anhand der Grenzstei- Schröder, Sabine, Dr. med (2007): Planimetri- mie als Therapieverfahren nach akutem ischä- ne der kindlichen Entwicklung nach Michaelis sche Langzeitbeobachtung von Normalen und mischen Schlaganfall Burger, Martin, Dr.-Ing. (2007): Assessment of Patienten mit okulärer Hypertension Schäuble, Barbara, PD Dr. med. (2008): Diag- the Individual Auditory Perception via Evoked Düz, Melek, Dr. med (2008): Semiautomatische nose und Therapie der Epilepsie Potentials Messung parapapillärer Autofluoreszenz bei Stemper, Brigitte, PD Dr. med. (2008): Störun- Haderlein, Tino, Dr.-Ing. (2007): Automatic eva- Normalen, Patienten mit Glaukomverdacht gen der kardiovaskulären und zerebrovaskulä- luation of tracheoesophageal substitute voices und Glaukom ren Regulation bei Erkrankungen des periphe- Paal, Sonja-Gerda, Dr. med (2007): Evaluation Hösel, Laura, Dr. med (2008): Wertigkeit unter- ren und zentralen Nervensystems of speech disorder in children with cleft lip and schiedlicher Methoden zur semi-automatischen palate Diagnosestellung bei Glaukomen mit dem HRT Rasp, Oliver, Dr. med (2007): The pitch raise pa- Schrems, Wolfgang, Dr. med (2008): Diagnosti- radigm: a new task for real-time endoscopy of sche Wertigkeit von GDxVCC und Stratus-OCT non-stationary phonation bei Glaukomen Schwarz, Raphael, Dr.-Ing. (2007): Model-Based Quantification of Pathological Voice Production

186 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) Department of Neurosurgery Rischer, Angela, Dr. phil. (2007): Sorgen und sowohl im Blut als auch im Sperma nach akuter Chair of Neurosurgery Grübeln: Zwei Seiten derselben Medaille? Ein Alkoholintoxikation Konzeptvergleich von Worry und Rumination Mertens, Florian, Dr. med. (2008): Verordnung Board Qualifications “Neurochirurgie” in einer multizentrischen Studie an Patienten von Benzodiazepinen bei der Behandlung von mit Depression und einer nichtklinischen Ver- depressiven Erkrankungen Nestler, Dirk, Dr. med. (2007) gleichsstichprobe. Mertens, Andreas, Dr. med. (2008): Kombina- Weigel, Daniel, Dr. med. (2007) Scheer, Raimund, Dr. med. (2007): Saisonale tions- und Augmentationsstrategien bei der Eyüpoglu, Ilker, Dr. med. (2008) Auffälligkeiten bei Patienten mit Schizophrenie Behandlung depressiver Störungen hinsichtlich Zeitpunkt der Geburt und stationä- Rauh, Johannes, Dr. med. (2008): Genetische Habilitations rer Aufnahme Variationen des Serotonin-Transporter-Gens im Stadlbauer, Andreas, PD Dr. techn. (2008): Ma- Struck, Ingo, Dr. med. (2007): Vorhersage von Zusammenhang mit Craving bei Patienten mit gnetresonanzspektroskopie und Diffusionsten- pharmakologisch induzierten Gewichtsverän- Alkoholabhängigkeit sor-Bildgebung bei hirneigenen Tumoren derungen durch Körpergewicht, Body Mass In- Rogler, Katrin, Dr. med. (2008): Einfluss von dex (BMI), Körperfettmasse und Alter Phosphatase- und Kinase-Inhibitoren auf die Stößel, Christina, Dr. med. (2007): Geschmacks- Phosphorylierung und Aggregation von Tau in Department of Psychiatry and störungen bei Patienten mit akutem Schlagan- Zellkulturzellen Psychotherapy fall Rotter, Andrea, Dr. med. (2008): Der Effekt von Chair of Psychiatry and Psychotherapy Summ, Elisabeth, Dr. rer. nat. (2007): Psycho- Antidepressiva auf die Expression von Wachs- edukation Angst bei stationären Patienten – tumsfaktoren am Zellmodell von differenzierten Doctorate Theses PASTA Neuroblastomzellen SH-SY5Y Bartl, Christina, Dr. med. (2007): Optische Visu- Tripal, Philipp, Dr. rer. nat. (2007): Gemeinsam- Scholz, Sarah, Dr. med. (2008): Die Rolle epige- alisierung und Analyse der Exozytose singulärer keiten und Unterschiede der humanen Gua- netischer Faktoren bei der Kontrolle des dopa- Vesikel in Phaeochromozytoma – Zellen mittels nylatbindeproteine minergen Systems bei Essstörungen Total-Reflexions-Mikroskopie (TIRF) Bock, Eva, Dr. med. (2008): Körperliche Be- Schütz, Patricia, Dr. med. (2008): Untersuchung Bauer, Christiane, Dr. med. (2007): Die Border- schwerden bei Müttern von Kindern mit von Biomarkern der neuronalen Zellschädigung line-Störung: aktuelle Konzepte, therapeutische Sprachentwicklungsstörungen bei der Elektrokonvulsionsbehandlung von Pati- Ansätze und erste Ergebnisse des Nürnberger Carl, Marco, Dr. med. (2008): Alkoholismus- enten mit Depression Kriseninterventionsprogramms assoziierte Hyperhomocysteinämie und deren Sieling, Swantje, Dr. med. dent. (2008): Früher- Breuer, Lorenz, Dr. med. (2007): Megaphen®: Verlauf im Alkoholentzug kennung qualitativ hoch stehender Forscher der Die Rolle der Universitäts-Nervenklinik Erlangen Cimmino, Natalie, Dr. med. (2008): Einfluss mo- deutschen Neurologie durch global zugängli- bei der klinischen Einführung der ersten Neuro- derner Antidepressiva auf Körperzusammenset- che bibliometrische Indikatoren leptika in Deutschland zung, Körpergewicht, Tumor-Nektrose-Faktor, Zimmermann, Rüdiger, Dr. med. (2008): Der Bruckmoser, Ralf, Dr. med. (2007): Die Rolle der Leptin und Psychopathologie Stellenwert der ß-Amyloid-Quotienten Aßx-42/ präanalytischen Probenbehandlung in der neu- Degirmenci, Ümüt, Dr. med. (2008): Homocy- Aß1-42/Aßx-40 für die Neurochemische De- rochemischen Demenzdiagnostik stein, ApoE4 und akute postoperative neuro- menzdiagnostik Dütsch, Carmen, Dr. med. (2007): Dantrolen psychologische Defizite nach aorto-coronaren und das Maligne Neuroleptische Syndrom: ein Bypassoperationen Board Qualifications “Psychiatrie und meta-analytischer Ansatz zur Evidenzprüfung Freiberger, Verena, Dr. med. (2008): Einfluss der Psychotherapie” Antipsychotika Quetiapin und Ziprasidon auf der therapeutischen Effektivität Maler, Juan Manuel, Dr. med. (2007) Gewicht, Leptin, TNF-alpha System und Psy- Greiner, Annette, Dr. med. (2007): Verände- Nowak, Magdalena, Dr. med. (2007) chopathologie rungen der Serumaktivität der Semicarbazid- Weih, Markus, Dr. med. (2007) Hoeß, Uta, Dr. med. (2008): Versorgung von sensitiven Aminooxidasen bei verschiedenen Bayerlein, Kristina, Dr. med. (2008) Schlaganfallpatienten mit ambulanten Heil- psychiatrischen Erkrankungen Biermann, Teresa, Dr. med. (2008) Hauenstein, Tobias, Dr. med. (2007): Der Ein- und Hilfsmitteln im Langzeitverlauf nach stati- fluss des Homocystein-Serumspiegels auf die onärer neurologischer Rehabilitation Additional Qualifications Kurzspeicherkapazität – die HomEMed-Studie Koch, Marlene, Dr. med. (2008): Der Plasma- an Medizinstudenten homocysteinspiegel: Circadianer Rhythmus und Hillemacher, Thomas, PD Dr. med. (2008): Ger- Jacob, Harald, Dr. med. (2007): Früherkennung Zusammenhang mit der geistigen Leistungsfä- iatrie qualitativ hochstehender Forscher der deut- higkeit Maler, Juan Manuel, Dr. med. (2008): Geriatrie schen Psychiatrie durch global zugängliche bi- Koloschin, Tatjana, Dr. med. (2008): Vergleich Nowak, Magdalena, Dr. med. (2008): Schlaf- bliometrische Indikatoren der in den Zitationsindizes erfassten und zi- medizin Jacobi, Andrea, Dr. med. (2007): Der Einfluss der tierten Publikationen in Nachautorenschaft Vagusstimulation auf trigeminale Schmerzreize mit denen in Allein-/Erstautorenschaft – eine Krieglstein, Christian, Dr. med. dent. (2007): Verlaufsstudie am Beispiel der Ordinarien der Der Einfluss des Plasma-Homocysteinspiegels deutschen Psychiatrie und des Alkoholkonsums auf die (epigeneti- Krauß, Katharina, Dr. med. dent. (2008): Circa- sche) DNA-Methylierung bei Gesunden. Ge- dianer Rhythmus der Reaktionszeit bei Depres- nomische und Gen-spezifische Analysen unter siven verglichen mit gesunden Kontrollpersonen Berücksichtigung des circadianen Rhythmus Löwe, Nadine, Dr. med. (2008): Verminderte Lenz, Bernd, Dr. med. (2007): Homocystein- Methylierung der DNA im Sperma und Ände- assoziierte epigenetische Veränderungen von rungen in der Expression der Methyltransfe- DNA-Methylierung bei Alkoholabhängigkeit. rasen DNMTs und alkoholgesteuerten Genen In-vitro- und in-vivo- Untersuchungen

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 187 APPENDIX

Department of Psychiatry and Berger, Susanne, Dr. med. dent. (2008): Die Be- Karl, Christina, Dr. med. dent. (2007): Adhä- Psychotherapy urteilung unterschiedlicher Materialien bei der siver Verschluss von Wurzelkanalfüllung nach Division of Child and Adolescent Mental Sinusaugmentation Eine retrospektive Studie unterschiedlicher Versäuberung der Trepanati- Health Beyer, Kathrin, Dr. med. dent. (2008): In vivo onsöffnung Modell zur Analyse der CD105-Expression im Kentsch, Caroline, Dr. med. dent. (2007): Mi- Board Qualification ersatzschwachen Wundheilungsgebiet nach kroleakage-Untersuchung von Wurzelkanalfül- Fehn, Thomas, Dr. med. (2008): Kinder- und Ju- mikrovaskulärem freien Weichgewebetransfer lungen nach unterschiedlichen Abschluss- Spü- gendpsychiatrie und -psychotherapie im Rahmen ablativer Tumorchirurgie im Kopf- lungen - zwei klassische Wurzelkanalsealer im und Halsbereich Vergleich zu einem selbstadhäsiven Zement Bilwatsch, Stefanie, Dr. med. dent. (2008): Löffler, Christian, Dr. med. dent. (2007): Ad- Department of Psychiatry and Dreidimensionale Analyse des Einflusses des häsiver Verschluss direkt nach endodontischer Psychotherapy Verschlusses einer einseitigen Lippen-Kiefer- Behandlung: Dichtigkeit vor und nach Kausi- Division of Psychosomatics and Psychotherapy Gaumenspalte nach Tennison-Randall auf die mulation Gesichtssymmetrie des Spaltpatienten Medelnik, Jürgen, Dr. med. dent. (2007): Wur- Doctorate Theses Bloch-Birkholz, Alexandra Ellen, Dr. med. dent. zelkanalsauberkeit nach Aufbereitung und Krajinovic, Ljubica, Dr. med. (2007): Erfassung (2008): Lebensqualität von Patienten mit Plat- Revision mit modernen rotierenden Nickel-Ti- der Psychopathologie von Essstörungen bei tenepithelkarzinomen der Mundhöhle unter tan-Instrumenten: Eine zweiteilige rasterelekt- adipösen Patienten vor Magenbandoperation: Vergleich zweier Therapiestrategien ronenmikroskopische Studie Interview oder Selbstbeurteilungsverfahren? Geidl, Achim, Dr. med. dent. (2008): Immun- Meier, Bettina, Dr. med. dent. (2007): Sekun- Doll, Michael, Dr. med. (2008): Dissoziative histologische Untersuchung der ossären Hei- därkaries - Möglichkeiten der Frühdiagnostik Symptomausprägung einer psychosomatischen lung am Modell des „critical-size-defects“ unter mit Clinpro Cario Diagnosis Stichprobe im Verlauf der Psychotherapie Verwendung von autologem Knochen als Füll- Meißner, Thomas, Dr. med. dent. (2007): Oumard, Daniela Gabriela, Dr. med. (2008): material Bruchzähigkeit von modernen Füllungskompo- Geschlechtsspezifische Unterschiede in Psycho- Kramer, Manuel Rolf, Dr. med. dent. (2008): siten in Abhängigkeit von der Füllstoffstruktur pathologie, Lebensqualität und Essverhalten Intraoperative noncontact, nonionizing, optical Onczul, Christian, Dr. med. dent. (2007): Ein- vor chirurgischer Adipositastherapie 3D exophthalmometry during repositioning of fluss optimierter Applikationsstrategien auf die Postler, Peter, Dr. med. (2008): Beschreibung dislocated globes: first results marginale Adaptation von Kompositfüllungen und Prä-Post-Vergleich der vollstationären und Lederer, Jean Wolfgang, Dr. med. dent. (2008): im Seitenzahnbereich tagesklinischen Behandlung des Psychosoma- Tierexperimentelle Untersuchung der knöcher- Radon, Claudia, Dr. med. dent. (2007): Opti- tischen und Psychotherapeutischen Abteilung nen Regeneration um enossale Implantate mit mierung der Randqualität von Klasse V Kom- des Universitätsklinikums Erlangen Vakuum-Titanplasma-Spray oder Calciumphos- positfüllungen bei Verwendung simplifizierter phat-Beschichtung Adhäsive Stauber, Irene, Dr. med. dent. (2008): Dreidi- Schiller, Thomas, Dr. med. dent. (2007): Zur Department of Oral and Maxillofacial mensionale Analyse der Gesichtssymmetrie von Dentinhaftung verschiedener Adhäsivsysteme Surgery Patienten mit einseitiger Lippen-Kiefer-Gau- an Milchzähnen Chair of Dental, Oral and Maxillofacial menspalte anhand optischer Oberflächendaten Schußmüller, Marc, Dr. med. dent. (2007): Ein- Medicine – especially Oral and Maxillofacial fluss von Applikation und Polymerisation auf die Surgery Board Qualification Randqualität von Klasse-II-Kompositfüllungen Seltmann, Thomas, Dr. med. dent. (2007): Doctorate Theses Kühnel, Thomas, Dr. Dr. (2008): Mund-Kiefer- Microtensile-Untersuchungen zu einem selbst- Gesichtschirurgie Bieth, Anna Silke Caroline, Dr. med. dent. adhäsiven Universalzement (2007): Entstehung von Osteoradionekrosen Stein, Julia, Dr. med. dent. (2007): Randverhal- als Folge kurativ-intendierter Radio- bzw. Ra- Dental Department 1 - Operative ten ästetisch optimierter Komposite in Klasse- diochemotherapie bei Karzinomen des Oberen Dentistry and Periodontology II-Kavitäten Aerodigestivtraktes - Einfluss auf Funktion und Chair of Dental, Oral and Maxillofacial Teubner, Alexander, Dr. med. dent. (2007): Re- Lebensqualität Medicine – especially Operative Dentistry, tentionsstärke von Goldinlays in Abhängigkeit Gadner, Klaus, Dr. med. dent. (2007): Der klini- Periodontology and Pediatric Dentistry vom Befestigungszement sche Einsatz von periostalen osteoblastenähn- Weise, Miriam, Dr. med. dent. (2007): Effekti- lichen Zellen für „Bone tissue engineering“ am Doctorate Theses vität verschiedener Wurzelkanalreinigungsme- thoden in gekrümmten Wurzelkanälen - Eine Beispiel des Sinuslift Aly, Tarek, Dr. med. dent. (2007): Polymerisa- rasterelektronenmikroskopische Studie - Jehle, Marc, Dr. med. (2007): MAGE-A-, p53- tionsleistungen von LED- und Halogenlampen Zwerger, Stefan, Dr. med. dent. (2007): Flow- und p21-Expression als prognostischer Marker Back, Michael, Dr. med. dent. (2007): Einfluss able Komposite in extendierten Kavitäten- eine bei oralen Plattenepithelkarzinomen verschiedener Befestigungstechniken auf die in- Langzeitstudie - Kamm, Tobias, Dr. med. dent. (2007): Mikrora- terne Dentinhaftung von Kompositinlays Aßmann , Irene, Dr. med. dent. (2008): Ver- diographische - und immunhistologische Unter- Basel, Miriam, Dr. med. dent. (2007): Polymeri- gleich von Geräten zur Kinetischen Kavitäten- suchung zweier knochenersatzmaterialien sationsbedingte Stressentwicklung in zahnärzt- präparation untereinander und zu einem rotie- Schinhammer, Martin, Dr. med. dent. (2007): lichen Kompositwerkstoffen renden Instrument Expression der Proliferationsmarker Repp86, Boos, Melanie, Dr. med. dent. (2007): Polymeri- Beck, Philipp, Dr. med. dent. (2008): Einfluss Ki- 67 und Topoisomerase IIα beim Plattenepi- sationsstress von Kompositen bei konventionel- der Schmelzabschrägung auf das Dentinrand- thelkarzinom der Mundhöhle - eine immunhis- ler und gepulster Polymerisation verhalten zervikaler Kompositfüllungen tochemische Analyse El-Komi, Samira, Dr. med. dent. (2007): Zur Bienert, Karin, Dr. med. dent. (2008): Einfluss Schmelzhaftung selbstätzender Adhäsivsyste- des Sauerstoffgehalts der Umgebungsluft auf me im Kavitätendesign

188 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) die Festigkeit des Komposit-Dentinverbunds im unter dem Einfluss endodontischer Spüllösun- Rill, Ulrich, Dr. med. dent. (2008): Vergleichen- Microtensile-Verfahren gen de klinische Studie zur Wirksamkeit von Aku- Brügel, Philip, Dr. med. dent. (2008): Haft- Schultes, Camilla, Dr. med. dent. (2008): Haft- punktur beim CMD in Zusammenwirken mit verbund zweier selbstätzender und selbstad- verbund zweier adhäsiver Sealer am Wurzelka- progressiver Entspannung mittels Stützstiftre- häsiver Befestigungszemente am Wurzelka- naldentin unter dem Einfluss unterschiedlicher gistrat naldentin unter dem Einfluss endodontischer Spüllösungen Schlaupe, Alexander, Dr. med. dent. (2008): Spüllösungen Taranu, Ramona, Dr. med. dent. (2008): Lang- Präzision in der Meistermodellherstellung für Deines, Irene, Dr. med. dent. (2008): Der Ein- zeitpenetrationsuntersuchung zur Dichtigkeits- implantatgetragene Restaurationen – der Ein- fluss verschiedener Wurzelkanalsealer auf das überprüfung von Wurzelkanalfüllungen mit drei fluss unterschiedlicher Abformmaterialien auf Wachstum unterschiedlicher Bakterien modernen Sealer die Präzision Dennerlein, Michael, Dr. med. dent. (2008): Todorova, Milena, Dr. med. dent. (2008): Ko- Untersuchung der apikalen und koronalen Un- ronale Dichtigkeit von Wurzelkanalfüllungen Habilitation dichtigkeit von adhäsiven und nicht-adhäsiven nach Präparation einer Stiftkavität in vitro Wurzelkanalsealern Ungvári, Stefan, Dr. med. dent. (2008): Bakte- Karl, Matthias, PD Dr. med. dent. (2008): Bio- Fereidouni, Amir, Dr. med. dent. (2008): Scher- riendichtigkeit von Wurzelkanalfüllungen unter mechanische und materialkundliche Unter- festigkeit von verschiedenen Befestigungsze- Verwendung verschiedener Wurzelkanalsealer - suchungen zur Passgenauigkeit festsitzenden menten am Wurzelkanaldentin Eine In-vitro Studie implantatgetragenen Zahnersatzes Fink, Martin, Dr. med. dent. (2008): Experi- Welz-Reitinger, Fabian, Dr. med. dent. (2008): mentelle Untersuchung zu Prüfparametern des Einfluss unterschiedlicher Verarbeitungsmodi Dental Department 3 - Orthodontics and Farbstoffpenetrationstestverfahrens an bovi- moderner Adhäsivsysteme auf die Dentinhaf- Orofacial Orthopedics nem Zahngut tung Chair of Dental, Oral and Maxillofacial Flassig, Thomas, Dr. med. dent. (2008): Detai- Medicine – especially Orofacial Orthopedics lerkennbarkeit von Lufteinschlüssen im Wurzel- Habilitation kanalfüllmaterial AH Plus™ bei Zahnfilmauf- Doctorate Theses nahmen Lohbauer, Ulrich, PD Dr.-Ing. (2007): Long-term Hilbert, Tanja, Dr. med. dent. (2007): In-vitro Freiberger, Hannes, Dr. med. dent. (2008): performance of the tooth-restoration compart- Untersuchung zur Scherfestigkeit von Keramik- Einfluss von C-Faktoren und Vorbehandlung ment - dynamic fatigue simulation brackets auf humanem Zahnschmelz und Be- auf die Haftung eines selbstadhäsiven Befesti- wertung der Schmelzoberfläche gungszements Dental Department 2 - Prosthetic Knorr, Kristin, Dr. med. dent. (2007): Vergleich Freyberger, Sina, Dr. med. dent. (2008): Inhibi- Dentistry des Korrosionsverhaltens von Metallbrackets tion des Bakterienwachstums durch verschiede- Chair of Dental, Oral and Maxillofacial der Firma 3M Unitek und Forestadent und des- ne Wurzelkanalsealer - eine In-vitro-Studie Medicine – especially Prosthetic Dentistry sen Einfluss auf die Haftfestigkeit Grötsch, Marisa, Dr. med. dent. (2008): Ein- Lorenz, Stefan, Dr. med. dent. (2007): Zur Ent- fluss eines Kalziumhydroxidpräparats auf die Doctorate Theses wicklung der vertikalen und sagittalen Relation Dentinhaftung unterschiedlicher Adhäsivsyste- Göllner, Matthias, Dr. med. dent. (2007): Un- bei Patienten mit ein- und beidseitigen Lippen- me tersuchung zur Evaluierung und Etablierung Kiefer-Gaumenspalten Herbstleb, Edith, Dr. med. dent. (2008): Mi- photogrammetrischer Messtechnik in der Neuroth, Jeannette, Dr. med. dent. (2007): Be- kroleakage-Untersuchungen von Wurzelka- Zahnmedizin wertung der Verbundfestigkeit von verschiede- nalfüllungen nach unterschiedlichen Abschluss- Helbig, Isabella, Dr. med. dent. (2007): Riss- nen Bracket-Adhäsiv-Befestigungssystemen in Spülungen - zwei neue Wurzelkanalsealer im bildung und Rissverhinderung bei keramisch der Kieferorthopädie Vergleich zu AH Plus- verblendeten Implantatbrücken - eine in vitro Rodich, Melanie, Dr. med. dent. (2007): Topo- Hock, Katrin, Dr. med. dent. (2008): Vergleich Studie an zementierbaren und verschraubba- graphie von Oberkiefer-Eckzahnverlagerungen. der Schmelzhaftung von vier selbstätzenden ren Implantatbrücken Eine metrische Analyse im dreidimensionalen Adhäsivsystemen unter Anwendung unter- Krug, Florian, Dr. med. dent. (2007): Einfluss Computertomogramm mit vergleichender Ein- schiedlicher Applikationsmodi statischer und dynamischer Belastung auf die schätzung im Orthopantomogramm Keller, Michael, Dr. med. dent. (2008): Einfluss Stabilität keramisch verblendeter Implantatre- Roesel, Nina, Dr. med. dent. (2007): Quantita- der Etch-and-rinse-Technik auf die Dauerhaf- staurationen tive systemische Bestimmung von Legierungs- tigkeit des Komposit-Dentinverbundes selbstät- Scholz, Nicola, Dr. med. dent. (2007): Neuro- bestandteilen im Zusammenhang mit der Ein- zender Adhäsive physiologische Effekte bei mund-, kiefer-, ge- gliederung festsitzender kieferorthopädischer Kent, Hamdi, Dr. med. dent. (2008): Klinische sichtschirurgischen Eingriffen unter Hypnose Mulitbracketapparaturen - eine prospektive Überprüfung eines ionenaktiven Komposits im – Eine vergleichende klinische Studie zur Evalu- klinische Studie Milchgebiss -Ergebnisse einer 2-Jahres-Prospek- ation kardiopulmonaler Parameterveränderun- Schirm, Harald, Dr. med. dent. (2007): Einfluss- tivstudie im Vergleich zu einem Kompomer- gen unter Hypnose faktoren auf die Entwicklung des retromolaren Kägi, Ute, Dr. med. dent. (2008): Quantitative Zillmann, Elke, Dr. med. dent. (2007): Neuro- Raumes hinsichtlich der Prognose des Weis- Randspaltanalyse von Hytac/Dyract AP nach 4 physiologische Effekte bei mund-, kiefer-, ge- heitszahndurchbruchs Jahren - in vivo sichtschirurgischen Eingriffen unter Hypnose Siegmund Teixeira Soares, Verena, Dr. med. Ritzmann, Claus, Dr. med. dent. (2008): Ein – Eine vergleichende klinische Studie zur Be- dent. (2007): Dreidimensionale CT-basierte automatisiertes Kariesmodell zur Erzeugung urteilung subjektiver Parameter und von EEG- Evaluation der Spaltmorphologie einschließlich sekundärkariöser Läsionen Veränderungen unter Hypnose der Nase bei Lippen-Kiefer-Gaumenspalten Rödl, Stefanie, Dr. med. dent. (2008): Haftver- Kirchner, Elena, Dr. med. dent. (2008): Lexikali- Slotta, Regina, Dr. med. dent. (2007): Differen- bund eines kunstharzbasierten und metharc- sche Analyse des implantologischen Wortschat- zialdiagnostische Bewertung und Klassifikation rylatbasierten Sealers am Wurzelkanaldentin zes der russischen Sprache der Angle-Klasse II,1 nach morphologischen Kriterien

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 189 APPENDIX

Münch, Susanne, Dr. med. dent. (2008): Multi- zentrischer Ringversuch zur Scherhaftfestigkeit von Adhäsiven für kieferorthopädische Befesti- gungselemente nach Normvorlage DIN Schaubmayr, Martin, Dr. med. dent. (2008): Untersuchung der Haftfestigkeit von Kompo- sitzylindern und Brackets auf bovinem Schmelz bei Einsatz neuartiger Adhäsivsysteme Siegel, Peggy Dr. med. dent. (2008): Testung der Scherfestigkeit und des Bruchlinienverlaufs verschiedener Adhäsive in Verbindung mit Ke- ramikbrackets Weinelt, Thorsten Dr. med. dent. (2008): Un- tersuchung des Musculus masseter in Ruhe und Funktion mittels Sonographie, Elektromyogra- phie und Bisskraft

Board Qualifications “Kieferorthopädie” Holzmeier, Marcus, Dr. med. dent. (2007) Meurer, Annika, Dr. med. dent. (2007) Forster, Hedwig, Dr. med. dent. (2008) Lovrov, Sylvia, Dr. med. dent. (2008)

190 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) APPENDIX

In Memoriam

2007 – Deceased Person

Prof. Dr. med. Erich Rügheimer Professor emeritus of the Department of Anaesthesiology Dean 1974 – 1979

2008 – Deceased Persons

Dr. med. Heinrich Baust Medical researcher in the Department of Radiology

Prof. Dr. med. Werner Bautz Chair of Diagnostic Radiology 1996 – 2008 Medical Director 2006 – 2008

Prof. Dr. med. Volker Becker Professor emeritus of the Chair of General Pathology and Pathological Anatomy Dean 1981 – 1983

Prof. Dr. rer. nat. Ralph Grassmann Scientist in the Institute of Clinical and Molecular Virology

Walburga Forster General duty nurse in the University Hospital Erlangen

Thomas Holz Radiographer in the Department of Medicine 2 – Cardiology and Angiology

Petra Kandler Housemaid in the Department of Obstetrics and Gynaecology

Dr. med. h. c. Kurt Köhler Syndikus and Chancellor of the Friedrich-Alexander-University Erlangen-Nürnberg 1966-1988 Honorary Doctorate of the Medical School

Hannelore Macher Administration secretary in the University Hospital Erlangen

Andreas Stark Former male nurse and member of the Employee Committee of the University

Prof. Dr. med. Helmut Valentin Professor emeritus of the Chair of Occupational and Social Medicine Dean 1969 – 1970

Marcus Voigtmann Laboratory technician in the Division of Neuroradiology of the Institute of Radiology

Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 191 Publisher Faculty of Medicine of the Friedrich-Alexander-University Erlangen-Nürnberg

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192 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008)