Werner Hoffmann

Otto-von-Guericke-Universität Magdeburg, Magdeburg, Saxony-Anhalt, Germany

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Publications (39)133.01 Total impact

  • W Hoffmann
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    ABSTRACT: The gastric mucosa and its glands represent a close interactive barrier to the outside world. This delicate surface is protected by a multilayered mucus barrier which contains among others the mucins MUC5AC and MUC6 and the trefoil factor family peptide TFF2. Furthermore, two types of gastric glands form delicate homeostatic systems, i.e. the fundic and antral glands, which show continual bidirectional self-renewal via differentiation from stem and progenitor cells. It was the aim of this study to analyze the self-renewal of these gastric units.
    Der Pathologe 11/2014; 35 Suppl 2:202-6. · 0.62 Impact Factor
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    ABSTRACT: Background/Aims: TFF2 is a secretory peptide (106 amino acid residues) of the gastric mucosa, the porcine exocrine pancreas as well as immune cells and the CNS. It was the aim of this study to compare gastric and pancreatic TFF2. Methods: TFF2 was purified from the porcine stomach and pancreas, respectively, by size-exclusion and anion-exchange chromatography and then analyzed by Western blots as well as mass spectrometry. Results: Gastric and pancreatic TFF2 differed markedly, i.e. gastric TFF2 was exclusively associated with the high molecular mass mucus fraction, whereas pancreatic TFF2 appeared as a low molecular mass product. Unexpectedly, the latter predominantly formed a non-covalently linked homodimer resistant to boiling SDS. In contrast, gastric TFF2 is an integral mucus constituent predominantly binding to the mucin MUC6 in a non-covalent fashion. Conclusion: The non-covalent interaction of TFF2 with the mucin MUC6 is typical of a "link peptide" which is perfectly suited to assemble and stabilize the laminated structure of gastric mucus and to modulate its rheological properties. © 2014 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 03/2014; 33(4):895-904. · 3.42 Impact Factor
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    Ting Fu, Hubert Kalbacher, Werner Hoffmann
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    ABSTRACT: Background/Aims: The trefoil factor family (TFF) peptide TFF1 is typically secreted by gastric surface mucous cells. These cells are also the major players in gastric restitution, i.e., repair of the stomach mucosa by cell migration after injury. Methods: An established in vitro model of gastric restitution, i.e., migration of the non-transformed rat gastric cell line RGM-1 after scratch wounding, was investigated by expression profiling of selected genes from separated stationary and migratory cells. Also semi-quantitative immunocytochemistry was performed. Furthermore, RGM-1 cells were transfected with stealth RNAi™ duplexes targeting Tff1 and relative cell migration rates were analyzed. Results: Surprisingly, Tff1 expression was up-regulated in migratory cells. No unequivocal signs of the epithelial-mesenchymal transition were detectable in migratory cells. Transfection of RGM-1 cells with Tff1-siRNAi duplexes negatively influenced migration of these cells. Conclusion: This clearly points to a function of Tff1 as a motogen. A possible up-regulation of TFF1 synthesis in migratory surface mucous cells also in vivo would be an ideal mechanism to specifically enhance gastric restitution only where topologically needed and to minimize eventual negative side effects of TFF1 such as cell scattering and invasiveness. © 2013 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 10/2013; 32(4):997-1010. · 3.42 Impact Factor
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    ABSTRACT: In the human stomach, the peptide TFF2 is secreted together with the mucin MUC6 by mucous neck cells and antral gland cells. TFF2 is strongly associated with the gastric mucus and promotes gastric restitution. Here, TFF2 was purified from the human corpus and antrum, respectively, by size exclusion chromatography, and the N-linked glycan structure at N-15 of the mature peptide determined. As a hallmark, the unusual monofucosylated N,N'-diacetylhexosediamine (tentatively assigned as GalNAcβ1→4GlcNAc, LacdiNAc) modification was detected as the terminal structure of a bi-antennary complex type N-glycan exhibiting also core fucosylation. Replicate analyses did not show microheterogeneities in the fraction of PNGaseF cleaved and permethylated N-glycans when analyzed by MALDI-mass spectrometry. On the glycopeptide level a minor glycan microheterogeneity was evident in liquid chromatography-ESI-mass spectrometry demonstrating the presence of underfucosylated species. The tryptic TFF2 N-glycopeptide p34-39 (LSPHNR N-glycosylated with Fuc3Hex3HexNAc6) was identified both by ESI-MS/MS and MALDI-post-source decay analysis. Lectin analyses with the Wisteria floribunda agglutinin indicated the potential presence of LacdiNAc terminating glycans and revealed minor differences between TFF2 from fundic units, i. e., mucous neck cells, and antral units, i. e. antral gland cells. Strikingly, on the level of the primary structure there was no indication that formation of the proposed LacdiNAc structure is cis-controled by a peptidic determinant related to published sequences.
    Glycobiology 09/2012; · 3.54 Impact Factor
  • Werner Hoffmann
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    ABSTRACT: The gastric mucosa and its glands show continuous bidirectional self-renewal via differentiation from stem and progenitor cells. Here, two types of gastric units, i.e., fundic and antral units, form delicate homeostatic systems. This review focuses on recent developments concerning the different types of gastric stem cells, the central function of parietal cells as organizing centres of fundic units, the stepwise differentiation of zymogenic cells via trans-differentiation of mucous neck cells, and unexpected differences between fundic and antral surface mucous cells. Within the last years, the central role of Sonic hedgehog (Shh) for correct self-renewal of fundic units has become much clearer. Furthermore, also the knowledge concerning the genesis of gastric cancer increased substantially. Here, chronic inflammation leads to dysregulated differentiation processes and finally to cancer. Remarkable progress has been made particularly concerning the genesis of two metaplastic cell lineages, i.e., the TFF2/spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia, which both arise in intestinal-type cancers in fundic units by dysregulated trans-differentiation of the zymogenic cell lineage. Additionally, Shh has been recognized as a target for inflammatory processes and an important player for innate immunity processes. Thus, stem cells, self-renewal, and gastric cancer are intimately linked.
    Current Medicinal Chemistry 09/2012; · 3.72 Impact Factor
  • Werner Hoffmann
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    ABSTRACT: Comment on: Singh SR, et al. Cell Cycle 2011; 10: 1109-20.
    Cell cycle (Georgetown, Tex.) 04/2011; 10(8):1186-7. · 5.24 Impact Factor
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    ABSTRACT: The gastric mucosa is subject to continual bidirectional renewal by differentiation from stem and transit amplifying cells. It was the aim of this study to characterize the self-renewal of the human gastric mucosa and its two major types of glands in the fundus and antrum, respectively. Three characteristic regions (pit, proliferative, and lower neck regions) were isolated from fundic and antral units by the use of laser microdissection, and expression profiles concerning 15 marker genes were generated by RT-PCR analysis. The surface mucous cells (SMCs) of fundic and antral units differed in their expression of at least four secretory genes, i.e., gastric lipase, TFF3, FCGBP, and lysozyme. The maturation of mucous neck cells was shown to occur stepwise, first towards a mucous phenotype followed by a serous differentiation step. Also, a stepwise maturation of both the antral SMCs and antral gland cells was observed. Additionally, the presence of gastric lipase was also demonstrated for the first time in antral gland cells. In conclusion, the different expression profiles of SMCs of the fundic and antral units could be the basis for the different self-renewal rates of fundic and antral SMCs and could influence the spatial organization of the bacterial microbiota within the various parts of the gastric mucosa.
    Molecular BioSystems 01/2011; 7(4):1105-12. · 3.35 Impact Factor
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    ABSTRACT: TFF3 is a secretory peptide belonging to the trefoil factor family with a predicted size of 59 amino acid residues containing seven cysteine residues. It is predominantly expressed in intestinal goblet cells where it plays a key role in mucosal regeneration and repair processes. In the course of these studies, human colonic TFF3 was shown to exist mainly as a high molecular weight heteromer. Purification of this heteromer and characterization by LC-ESI-MS/MS analysis identified the IgG Fc binding protein (FCGBP) as the disulfide-linked partner protein of TFF3. FCGBP is a constituent of intestinal mucus secreted by goblet cells. Furthermore, low amounts of TFF3/monomer and only little TFF3/dimer were detected in human colonic extracts. Here, we show that these TFF3 forms can be released from the purified TFF3-FCGBP heteromer complex in vitro by reduction with hydrogen sulfide (H(2)S). Such a mechanism would be in line with the high H(2)S concentrations reported to occur in the lumen of the colon. Of special note, this points to intestinal mucus as a reservoir for a biologically active peptide. Also proteolytic processing of FCGBP was observed which is in line with multiple autocatalytic cleavages as proposed earlier by Johansson et al. (J. Proteome Res. 2009 , 8 , 3549 - 3557).
    Journal of Proteome Research 06/2010; 9(6):3108-17. · 5.06 Impact Factor
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    ABSTRACT: Trefoil factor family (TFF) peptides promote regeneration and repair processes of mucous epithelia. They also probably play a key role in the remarkable regenerative capacity of the urinary tract epithelia. We have localized TFF1, TFF2, and TFF3 expression systematically in surgical specimens from the urinary tract by reverse transcription with the polymerase chain reaction, Western blot analysis, and immunohistochemistry. Urine samples from patients suffering from nephrolithiasis have been investigated and compared with those of healthy controls. TFF synthesis is detectable along the entire urinary tract epithelia. TFF3 synthesis is the most pronounced followed by TFF1, whereas TFF2 synthesis is occasionally detectable but only in trace amounts. In contrast, TFF2 is the predominant TFF peptide excreted into the urine, and significantly increased urinary TFF2 levels (together with occasionally raised TFF3 levels) have been observed in patients suffering from nephrolithiasis. Thus, we consider that TFF3 plays a major part in regeneration and restitution processes in urinary tract epithelia. TFF2 and probably also TFF3 are candidate biomarkers for nephrolithiasis and possibly other inflammatory conditions of the urinary tract.
    Cell and Tissue Research 03/2010; 339(3):639-47. · 3.68 Impact Factor
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    ABSTRACT: Both the major and minor salivary glands are the sources of saliva, a fluid vital for the maintenance of a healthy oral cavity. Here, the expression profiles of human submandibular (SMG) and labial glands (LG) were compared by RT-PCR analysis of laser microdissected mucous and serous cells, respectively. The focus was on trefoil factor family (TFF) genes, but also other genes encoding secretory proteins (mucins, lysozyme, amylase, statherin, and histatins) or aquaporin 5 were included. Immunofluorescence studies concerning TFF1-3, FCGBP, amylase, and lysozyme are also presented. It was shown that LGs clearly contain serous cells and that these cells differ in their expression profiles from serous SMG cells. Furthermore, all three TFF peptides, together with MUC5B, MUC7, MUC19, and FCGBP, were clearly detectable in mucous acini of both LGs and SMGs. In contrast, lysozyme was differentially expressed in LGs and SMGs. It can be expected that labial saliva may play a particularly important role for protecting the teeth.
    Cellular Physiology and Biochemistry 01/2010; 26(3):375-82. · 3.42 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2010; 48(08).
  • Eva B Znalesniak, Werner Hoffmann
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    ABSTRACT: Mucous epithelia represent a major barrier to the outside world and are capable of undergoing rapid repair after injury by cell migration, a process called "restitution". Here, a sensitive RT-PCR method was applied allowing systematic gene expression analysis of separated stationary and migratory non-transformed IEC-18 and IEC-6 cells after scratch wounding. The focus was on genes related to cell-cell contacts. Furthermore, the effect of epidermal growth factor (EGF) on gene expression was studied. Most of the genes investigated here were down-regulated in migratory cells. Many of the alterations are expected to affect the permeability of tight junctions. Also the nectin-afadin complex of adherens junctions was modulated as well as the expression of both the chemokine receptor CXCR4 and the EGF receptor. Of note, restitution was not accompanied by the epithelial-mesenchymal transition (EMT). EGF treatment severely affected the expression of genes important for cell-cell contact and cell communication such as selected tight junction components, CXCR4, and TFF3. Many of these genes are known to be involved in EMT and metastasis. Of special note, most of the expression changes induced by EGF are in contrast to the changes observed in migratory cells.
    Cellular Physiology and Biochemistry 01/2010; 25(4-5):533-42. · 3.42 Impact Factor
  • Werner Hoffmann
    Journal of Medicinal Chemistry 11/2009; 52(21):6505-10. · 5.61 Impact Factor
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    Bernhard Ganss, Werner Hoffmann
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    ABSTRACT: Ependymins are secretory, calcium-binding sialoproteins which are the predominant constituents of the cerebrospinal fluid of many teleost fish. A bound form of these regeneration-responsive glycoproteins is associated with collagen fibrils of the extracellular matrix. Here, the tryptophan fluorescence of ependymins was monitored at various Ca(2+) concentrations. Two distinct states were identified with a relatively sharp transition at about 1 mM Ca(2+). In agreement with previous circular dichroism measurements, this strongly supports the hypothesis that a calcium-induced conformational change is important for the interaction of ependymins with components of the extracellular matrix. Such interactions with constituents of various basal laminae would also explain the important roles of piscine ependymins as well as invertebrate and mammalian ependymin-related proteins for cell adhesion processes and cell migration.
    The Open Biochemistry Journal 02/2009; 3:14-7.
  • Eva B Znalesniak, Uwe Dürer, Werner Hoffmann
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    ABSTRACT: Rapid repair by cell migration, a process called "restitution", is essential for wound healing of mucous epithelia. Here, an established in vitro model for restitution, i.e., migration of the non-transformed intestinal epithelial cell line IEC-18 after scratch wounding, was investigated. This cell line is also known for its retained differentiation potential. The aim of this study was to test by expression profiling whether the differentiation state is altered during restitution in vitro. Using a sensitive RT-PCR method a systematic analysis of separated stationary and migratory cells was performed 48 h after in vitro wounding. Most characteristically, the differentiation state was changed in migratory cells when compared with stationary cells. For example, migratory cells lost markers of terminal differentiation and changed to a phenotype that assists the process of restitution by up-regulating the expression of genes such as plasminogen activator inhibitor-1, transforming growth factor alpha, heparin-binding EGF-like growth factor, alpha-smooth muscle actin, ornithine decarboxylase, and glyceraldehyde-3-phosphate dehydrogenase. However, there were no unequivocal signs of epithelial-mesenchymal transition (EMT) found in migratory cells.
    Cellular Physiology and Biochemistry 02/2009; 24(1-2):125-32. · 3.42 Impact Factor
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    ABSTRACT: Tff peptides are secreted mainly by the gastrointestinal epithelial cells and their primary role is maintaining normal structure and function of mucous epithelia. Ongoing studies on their expression pattern have disclosed other sites of their synthesis thus revealing additional physiological functions in the organism. Here we present new data about Tff3 expression in the cochlea of the rodent inner ear. On the basis of RT-PCR we describe the presence of Tff3 transcripts in both, a mouse cDNA library isolated from whole cochleae from postnatal days 3-15 (P3-P15), and also in cochlear tissue. By using a riboprobe for the fragment containing exon 1, 2 and 3 of Tff3, in situ hybridization, localized Tff3 signals in neurons of spiral ganglion and vestibular organ. We did not observe any abnormalities in the middle ear of Tff3 knock-out mice, neither did histological examination of the inner ear indicate any gross morphological changes in the cochlea. However, ABR (auditory evoked brain stem responses) audiograms revealed that the Tff3 knock-out animals show an accelerated presbyacusis and a hearing loss of about 15 dB at low frequencies increasing to 25 dB loss at higher frequencies. These findings suggest that Tff3 could play a role in neurosensory signaling. Further studies are needed to clarify this new function in the auditory system.
    Cellular Physiology and Biochemistry 02/2008; 21(5-6):437-44. · 3.42 Impact Factor
  • Werner Hoffmann
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    ABSTRACT: Mucous epithelia and their glands represent vital surfaces of the body which are topologically in direct contact and communicate with the environment. These highly specialized epithelia are protected by several lines of defence, such as mucous gels, regeneration and repair mechanisms, and acute inflammatory processes. Pathologically, chronic inflammation is associated with cancer. There are two different regeneration and repair mechanisms of mucous epithelia known which also cover different time scales. First, rapid repair of superficial lesions via cell migration - a process called restitution - starts within minutes. Second, continuous regeneration via differentiation and proliferation of stem and progenitor cells is responsible for self-renewal within days to months. This article reviews molecular mechanisms responsible for the regeneration of various mucous epithelia with a special emphasis on the complex situation in the gastric mucosa and its glands. For example, the two gross types of gastric units, i.e., the fundic and the antral types, respectively, differ largely by their histology, regeneration rates and regeneration profiles. Currently, a rough picture is emerging on the molecular mechanisms behind including the characterization of different somatic stem cell types and stem cell signaling pathways. Furthermore, dysregulated regeneration is well known now as a cause of various metaplasias (reversible remodeling of epithelia) and cancer, with chronic inflammation playing a key role. Understanding the molecular mechanisms of regeneration and their dysregulation is essential for the development of new strategies for cancer prevention and therapy and it will also promote the emerging field of regenerative medicine and tissue engineering.
    Current Medicinal Chemistry 02/2008; 15(29):3133-44. · 3.72 Impact Factor
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    ABSTRACT: TFF3 (trefoil factor family 3), which is a major secretory product of the gastric antrum and the intestine, but which is nearly absent in the gastric corpus, plays a key role in the maintenance of mucosal integrity. Here, we have systematically investigated TFF3 expression in the esophagus and gastric cardia by the use of reverse transcription/polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Synthesis of TFF3, but not TFF1 or TFF2, is detectable in esophageal submucosal glands. The stratified squamous epithelium is devoid of TFF synthesis. Prominent TFF3 expression starts at the Z-line with a sharply decreasing gradient toward the cardia. Immunohistochemistry has localized TFF3 to surface mucous cells of the proximal cardia. TFF3 distribution differs characteristically from that of TFF1 (secreted primarily by superficial surface mucous cells), whereas TFF3, together with the mucin MUC5AC, is also found in deeper lying cells toward the isthmus. This is the first report of TFF3 as a typical secretory peptide of esophageal submucosal glands and gastric cardia. The different expression patterns of TFF3 and TFF1 in the cardia suggest a stepwise maturation of surface mucous cells from TFF3/MUC5AC-positive cells close to the isthmus to TFF1/TFF3/MUC5AC-positive cells at the pit. The gradient of TFF3 expression along the gastric rostro-caudal axis defines two types of gastric pit cells: those secreting TFF3 in the cardia and the antrum and those nearly devoid of TFF3 synthesis in the corpus. This indicates the special requirement, particularly of the esophagogastric junction, for TFF3-triggered protection and repair.
    Cell and Tissue Research 06/2007; 328(2):365-74. · 3.68 Impact Factor
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    ABSTRACT: Asthma is a chronic inflammatory disease of the airways that is accompanied by goblet cell metaplasia and mucus hypersecretion. Trefoil factor family (TFF) peptides represent major secretory products of the respiratory tract and are synthesized together with mucins. In the murine lung, TFF2 is mainly expressed, whereas TFF1 transcripts represent only a minor species. TFF peptides are well known for their motogenic and anti-apoptotic effects, and they modulate the inflammatory response of bronchial epithelial cells. Here, an established mouse model of asthma was investigated (i.e., exposure to Aspergillus fumigatus [AF] antigens). RT-PCR analysis of lung tissue showed elevated levels particularly of TFF1 transcripts in AF-sensitized/challenged animals. In contrast, transcripts encoding Clara cell secretory protein (CCSP/CC10) were strongly diminished in these animals. For comparison, the expression of the goblet cell secretory granule marker mCLCA3/Gob-5, the mucins Muc1-Muc6 and Muc19, and the secretoglobins ScgB3A1 and ScgB3A2, as well as the mammalian ependymin-related gene MERP2, were monitored. Immunohistochemistry localized TFF1 mainly in cells with a mixed phenotype (e.g., TFF1-positive cells stain with the lectin wheat germ agglutinin (WGA), which recognizes mucins characteristic of goblet cells). In addition, these cells express CCSP/CC10, a Clara cell marker. When compared with mucins or CCSP/CC10, TFF1 was stored in a different population of secretory granules localized at the more basolateral portion of these cells. Thus, the results presented indicate for the first time that allergen exposure leads to the trans-differentiation of Clara cells toward a TFF1-expressing mucous phenotype.
    American Journal of Respiratory Cell and Molecular Biology 04/2007; 36(3):286-95. · 4.15 Impact Factor
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    ABSTRACT: Human airway surface epithelium is frequently damaged by inhaled factors (viruses, bacteria, xenobiotic substances) as well as by inflammatory mediators that contribute to the shedding of surface epithelial cells. To regain its protective function, the epithelium must rapidly repair and redifferentiate. The Trefoil Factor Family (TFF) peptides are secretory products of many mucous cells. TFF3, the major TFF in the airways, is able to enhance airway epithelial cell migration, but the role of this protein in differentiation has not been defined. To identify the specific role of TFF3 in the differentiation of the human airway surface epithelium, we analyzed the temporal expression pattern of TFF3, MUC5AC, and MUC5B mucins (goblet cells) and ciliated cell markers beta-tubulin (cilia) and FOXJ1 (ciliogenesis) during human airway epithelial regeneration using in vivo humanized airway xenograft and in vitro air-liquid interface (ALI) culture models. We observed that TFF3, MUC5AC, MUC5B, and ciliated cell markers were expressed in well-differentiated airway epithelium. The addition of exogenous recombinant human TFF3 to epithelial cell cultures before the initiation of differentiation resulted in no change in MUC5AC or cytokeratin 13 (CK13, basal cell marker)-positive cells, but induced an increase in the number of FOXJ1-positive cells and in the number of beta-tubulin-positive ciliated cells (P < 0.05). Furthermore, this effect on ciliated cell differentiation could be reversed by specific epidermal growth factor (EGF) receptor (EGF-R) inhibition. These results indicate that TFF3 is able to induce ciliogenesis and to promote airway epithelial ciliated cell differentiation, in part through an EGF-R-dependent pathway.
    American Journal of Respiratory Cell and Molecular Biology 03/2007; 36(3):296-303. · 4.15 Impact Factor

Publication Stats

568 Citations
133.01 Total Impact Points


  • 1997–2013
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Molecular Biology and Medical Chemistry
      Magdeburg, Saxony-Anhalt, Germany
  • 2012
    • University of Cologne
      • Center for Molecular Medicine (CMMC)
      Köln, North Rhine-Westphalia, Germany
  • 2009
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
  • 2002
    • Christian-Albrechts-Universität zu Kiel
      • Anatomisches Institut
      Kiel, Schleswig-Holstein, Germany