TY  - JOUR
A1  - Werner, Helmut
A1  - Werner, Reiner
A1  - Burschka, Christian
T1  - Aromaten(phosphan)metall-Komplexe, V: zur Addition von Carbanionen an (Benzol)ruthenium(II)- und -osmium(II)-Komplexe. Kristall- und Molekülstruktur von (exo-6-n-C4H9-Pi5-C6H6)OsI(PMe3)2
N2  - No abstract available
KW  - Chemie
Y1  - 1984
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-46652
ER  - 
TY  - JOUR
A1  - Grünewald, Benedikt
A1  - Lange, Maren D
A1  - Werner, Christian
A1  - O'Leary, Aet
A1  - Weishaupt, Andreas
A1  - Popp, Sandy
A1  - Pearce, David A
A1  - Wiendl, Heinz
A1  - Reif, Andreas
A1  - Pape, Hans C
A1  - Toyka, Klaus V
A1  - Sommer, Claudia
A1  - Geis, Christian
T1  - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis
JF  - eLife
N2  - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
KW  - CLN3
KW  - mutation
KW  - mouse model
KW  - synaptic transmission
KW  - amygdala
KW  - hippocampus
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004
VL  - 6
IS  - e28685
ER  - 
TY  - JOUR
A1  - Schmitz, Werner
A1  - Ries, Elena
A1  - Koderer, Corinna
A1  - Völter, Maximilian Friedrich
A1  - Wünsch, Anna Chiara
A1  - El-Mesery, Mohamed
A1  - Frackmann, Kyra
A1  - Kübler, Alexander Christian
A1  - Linz, Christian
A1  - Seher, Axel
T1  - Cysteine restriction in murine L929 fibroblasts as an alternative strategy to methionine restriction in cancer therapy
JF  - International Journal of Molecular Sciences
N2  - Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.
KW  - methionine restriction
KW  - cysteine restriction
KW  - mass spectrometry
KW  - LC/MS
KW  - cancer therapy
KW  - caloric restriction
KW  - homocysteine
KW  - amino acid analogues
KW  - cysteine synthase inhibitor
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265486
SN  - 1422-0067
VL  - 22
IS  - 21
ER  - 
TY  - JOUR
A1  - Estrada, Veronica
A1  - Krebbers, Julia
A1  - Voss, Christian
A1  - Brazda, Nicole
A1  - Blazyca, Heinrich
A1  - Illgen, Jennifer
A1  - Seide, Klaus
A1  - Jürgens, Christian
A1  - Müller, Jörg
A1  - Martini, Rudolf
A1  - Trieu, Hoc Khiem
A1  - Müller, Hans Werner
T1  - Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury
JF  - Communications Biology
N2  - Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.
KW  - implants
KW  - preclinical research
KW  - spinal cord injury
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227357
VL  - 1
ER  - 
TY  - JOUR
A1  - Koderer, Corinna
A1  - Schmitz, Werner
A1  - Wünsch, Anna Chiara
A1  - Balint, Julia
A1  - El-Mesery, Mohamed
A1  - Volland, Julian Manuel
A1  - Hartmann, Stefan
A1  - Linz, Christian
A1  - Kübler, Alexander Christian
A1  - Seher, Axel
T1  - Low energy status under methionine restriction is essentially independent of proliferation or cell contact inhibition
JF  - Cells
N2  - Nonlimited proliferation is one of the most striking features of neoplastic cells. The basis of cell division is the sufficient presence of mass (amino acids) and energy (ATP and NADH). A sophisticated intracellular network permanently measures the mass and energy levels. Thus, in vivo restrictions in the form of amino acid, protein, or caloric restrictions strongly affect absolute lifespan and age-associated diseases such as cancer. The induction of permanent low energy metabolism (LEM) is essential in this process. The murine cell line L929 responds to methionine restriction (MetR) for a short time period with LEM at the metabolic level defined by a characteristic fingerprint consisting of the molecules acetoacetate, creatine, spermidine, GSSG, UDP-glucose, pantothenate, and ATP. Here, we used mass spectrometry (LC/MS) to investigate the influence of proliferation and contact inhibition on the energy status of cells. Interestingly, the energy status was essentially independent of proliferation or contact inhibition. LC/MS analyses showed that in full medium, the cells maintain active and energetic metabolism for optional proliferation. In contrast, MetR induced LEM independently of proliferation or contact inhibition. These results are important for cell behaviour under MetR and for the optional application of restrictions in cancer therapy.
KW  - methionine restriction
KW  - caloric restriction
KW  - mass spectrometry
KW  - LC/MS
KW  - liquid chromatography/mass spectrometry
KW  - metabolomics
KW  - L929
KW  - amino acid
KW  - proliferation
KW  - contact inhibition
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262329
SN  - 2073-4409
VL  - 11
IS  - 3
ER  - 
TY  - JOUR
A1  - Schwaab, Bernhard
A1  - Bjarnason-Wehrens, Birna
A1  - Meng, Karin
A1  - Albus, Christian
A1  - Salzwedel, Annett
A1  - Schmid, Jean-Paul
A1  - Benzer, Werner
A1  - Metz, Matthes
A1  - Jensen, Katrin
A1  - Rauch, Bernhard
A1  - Bönner, Gerd
A1  - Brzoska, Patrick
A1  - Buhr-Schinner, Heike
A1  - Charrier, Albrecht
A1  - Cordes, Carsten
A1  - Dörr, Gesine
A1  - Eichler, Sarah
A1  - Exner, Anne-Kathrin
A1  - Fromm, Bernd
A1  - Gielen, Stephan
A1  - Glatz, Johannes
A1  - Gohlke, Helmut
A1  - Grilli, Maurizio
A1  - Gysan, Detlef
A1  - Härtel, Ursula
A1  - Hahmann, Harry
A1  - Herrmann-Lingen, Christoph
A1  - Karger, Gabriele
A1  - Karoff, Marthin
A1  - Kiwus, Ulrich
A1  - Knoglinger, Ernst
A1  - Krusch, Christian-Wolfgang
A1  - Langheim, Eike
A1  - Mann, Johannes
A1  - Max, Regina
A1  - Metzendorf, Maria-Inti
A1  - Nebel, Roland
A1  - Niebauer, Josef
A1  - Predel, Hans-Georg
A1  - Preßler, Axel
A1  - Razum, Oliver
A1  - Reiss, Nils
A1  - Saure, Daniel
A1  - von Schacky, Clemens
A1  - Schütt, Morten
A1  - Schultz, Konrad
A1  - Skoda, Eva-Maria
A1  - Steube, Diethard
A1  - Streibelt, Marco
A1  - Stüttgen, Martin
A1  - Stüttgen, Michaela
A1  - Teufel, Martin
A1  - Tschanz, Hansueli
A1  - Völler, Heinz
A1  - Vogel, Heiner
A1  - Westphal, Ronja
T1  - Cardiac rehabilitation in German speaking countries of Europe — evidence-based guidelines from Germany, Austria and Switzerland LLKardReha-DACH — part 2
JF  - Journal of Clinical Medicine
N2  - Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients' groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.
KW  - cardiac rehabilitation
KW  - scientific guidelines
KW  - secondary prevention
KW  - physical activity
KW  - exercise training
KW  - psychological interventions
KW  - education
KW  - gender
KW  - frailty
KW  - migration
KW  - old patients
KW  - young patients
KW  - tele-medicine
KW  - home-based-rehabilitation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242645
SN  - 2077-0383
VL  - 10
IS  - 14
ER  - 
TY  - JOUR
A1  - Werner, H.
A1  - Leonhard, K.
A1  - Burschka, Christian
T1  - Basische Metalle: IX. Synthese und Kristallstruktur von C\(_5\)H\(_5\)Co(PMe\(_3\))CS\(_2\) : Reaktionen zu zweikernkomplexen mit Co(SCS)Cr- und Co(SCS)Mn-Brückenbindungen
T1  - Basic metals.  IX.  Synthesis and crystal structure of C\(_5\)H\(_5\)Co(PMe\(_3\))CS\(_2\).  Reactions to binuclear complexes with Co(SCS)Cr and Co(SCS)Mn bridging compounds.
N2  - Durch Reaktion von C\(_5\)H\(_5\)Co(PMe\(_3\))\(_2\) (I) oder des Hetero-Zweikernkomplexes C\(_5\)H\(_5\)(PMe\(_3\))Co(CO)\(_2\)Mn(CO)C\(_3\)H .. Me (III) mit CS\(_2\) entsteht in praktisch quantitativer Ausbeute C\(_5\)H\(_5\)Co(PMe\(_3\))CS\(_2\) (IV). Die Kristallstruktur zeigt, dass der Carbondisulfid-Ligal'ld iiber Kohlenstoff und ein Schwefelatom (S(2)) dihaptogebunden vorliegt (Co-C = 1.89, Co-S(2) = 2.24 A, S(2)-C-S(1) = 141.2°). Die beiden C-S-AbsUinde in IV (C-S(2) = 1.68, C-S(l) = 1.60 A) sind gegenliber dem C-S-Abstand in freiem CS\(_2\) (1.554 A) aufgeweitet, was in Einklang mit dem aus spektroskopischen Daten zu folgernden starken 1T-Akzeptorcharakter von h\(^2\)-CS\(_2\) steht. IV reagiert mit Cr(CO)\(_5\)THF und C\(_5\)H\(_5\)Mn(CO)\(_2\)THF zu den Komplexen C\(_5\)H\(_5\)(PMe\(_3\))Co(SCS)Cr(CO)\(_5\) (V) bzw. C\(_5\)H\(_5\)(PMe\(_3\))Co(SCS)Mn(CO)\(_2\)C\(_5\)H\(_5\) (VI), in den en das in IV nicht am Cobalt gebundene Schwefelatom S(l) als Koordinationspartner gegenüber den 16-Elektronen-Fragmenten Cr(CO)\(_5\) und Mn(CO)\(_2\)C\(_5\)H\(_5\) fungierl. Die spektroskopischen Daten von IV, V und VI werden diskutiert.
N2  - C\(_5\)H\(_5\)Co(PMe\(_3\))CS\(_2\) (IV) is formed in practically quantitative yield in the reaction of C\(_5\)H\(_5\)Co(PMe\(_3\))\(_2\) (I) or the heterobinuclear complex C\(_5\)H\(_5\)(PMe\(_3\))Co(CO)\(_2\)Mn(CO)C\(_3\)H .. Me (III) with CS\(_2\). The crystal structure shows that the carbon disulfide bonds as a dihapto ligand through the carbon and one sulfur atom (S(2)) (Co-C = 1.89, Co-S(2) = 2.24 ft., S(2)-C-S(1) = 141.2°). The two C-S bond lengths in IV (C-S(2) = 1.68, C-S(l) = 1.60 A) are greater than in free CS\(_2\) (1.554 A) which is in agreement with the strong 7T-acceptor character of h\(^2\)-CS\(_2\) as shown in the spectroscopic data. IV reacts with Cr(CO)\(_5\)THF and C\(_5\)H\(_5\)Mn(CO)\(_2\)THF to give the complexes C\(_5\)H\(_5\)(PMe\(_3\))Co(SCS)Cr(CO)\(_5\) (V) and C\(_5\)H\(_5\)(PMe\(_3\))Co(SCS)Mn(CO)\(_2\)C\(_5\)H\(_5\) (VI) respectively, in which the sulfur atom S(l) that is not bound to cobalt coordinates to the 16-electron fragments Cr(CO)\(_5\) and Mn(CO)\(_2\)C\(_5\)H\(_5\). The spectroscopic data of IV, V and VI are discussed.
KW  - Anorganische Chemie
Y1  - 1978
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-70444
ER  - 
TY  - JOUR
A1  - Werner, Helmut
A1  - Kuehn, Alfred
A1  - Burschka, Christian
T1  - Strukturdynamische Organometall-Komplexe II: Synthese, Struktur und Dynamik der Komplexe C\(_5\)H\(_5\)M(2-R'C\(_3\)H\(_4\))PR\(_3\) (M = Pd, Pt)
T1  - Structurally dynamic organometallic complexes II:  Synthesis, structure, and dynamics of the complexes C\(_5\)H\(_5\)M(2-R'C\(_3\)H\(_4\))PR\(_3\) (M = Pd, Pt)
N2  - No abstract available
KW  - Anorganische Chemie
Y1  - 1980
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57853
ER  - 
TY  - JOUR
A1  - Heisig, Martin
A1  - Frentzen, Alexa
A1  - Bergmann, Birgit
A1  - Gentschev, Katharina Ivaylo
A1  - Hotz, Christian
A1  - Schoen, Christoph
A1  - Stritzker, Jochen
A1  - Fensterle, Joachim
A1  - Rapp, Ulf R.
A1  - Goebel, Werner
T1  - Specific antibody-receptor interactions trigger InlAB-independent uptake of Listeria monocytogenes into tumor cell lines
N2  - Background: Specific cell targeting is an important, yet unsolved problem in bacteria-based therapeutic applications, like tumor or gene therapy. Here, we describe the construction of a novel, internalin A and B (InlAB)-deficient Listeria monocytogenes strain (Lm-spa+), which expresses protein A of Staphylococcus aureus (SPA) and anchors SPA in the correct orientation on the bacterial cell surface. Results: This listerial strain efficiently binds antibodies allowing specific interaction of the bacterium with the target recognized by the antibody. Binding of Trastuzumab (Herceptin®) or Cetuximab (Erbitux®) to Lm-spa+, two clinically approved monoclonal antibodies directed against HER2/neu and EGFR/HER1, respectively, triggers InlABindependent internalization into non-phagocytic cancer cell lines overexpressing the respective receptors. Internalization, subsequent escape into the host cell cytosol and intracellular replication of these bacteria are as efficient as of the corresponding InlAB-positive, SPA-negative parental strain. This specific antibody/receptormediated internalization of Lm-spa+ is shown in the murine 4T1 tumor cell line, the isogenic 4T1-HER2 cell line as well as the human cancer cell lines SK-BR-3 and SK-OV-3. Importantly, this targeting approach is applicable in a xenograft mouse tumor model after crosslinking the antibody to SPA on the listerial cell surface. Conclusions: Binding of receptor-specific antibodies to SPA-expressing L. monocytogenes may represent a promising approach to target L. monocytogenes to host cells expressing specific receptors triggering internalization.
KW  - Listeria monocytogenes
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68705
ER  - 
TY  - JOUR
A1  - Kuehn, A.
A1  - Burschka, Christian
A1  - Werner, H.
T1  - Synthesis and molecular structure of C\(_5\)H\(_5\)(P-/-Pr\(_3\))Pd(η\(^1\), η\(^3\)-C\(_3\)H\(_4\))Pd(P-/-Pr\(_3\))Br: a compound formed through insertion of allene into a metal-metal bond\(^1\)
N2  - No abstract available
KW  - Chemie
Y1  - 1982
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-46592
ER  - 
TY  - JOUR
A1  - Bogdan, Christian
A1  - Moll, Heidrun
A1  - Solbach, Werner
A1  - Röllinghoff, Martin
T1  - Tumor necrosis factor-\(\alpha\) in combination with interferon-\(\gamma\), but not with  interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes
N2  - We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BLl6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) which is known to be a potent maerophage M\(\Phi\) stimulator in other parasitic diseases. In the present study we investigated whether TNF-\(\alpha\) activates M\(\Phi\) for killing of L. major parasites. In the absence of interferon-y (IFN-\(\gamma\)) or lipopolysaccharide, TNF-\(\alpha\) (0.025-25000 U/ml) failed to activate peritoneal exudate M\(\Phi\) from BALB/c mice for killling of L. major amastigotes. In the presence of suboptimal doses of IFN-\(\gamma\) (5 or 10 Vlml), however, TNF-\(\alpha\) mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-\(\gamma\) alone. Tbe combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conelude that the presence of IFN-\(\gamma\) is crucial for TNF-\(\alpha\)-mediated killing of L. major parasites by M\(\Phi\). Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-\(\gamma\) and a predominance of interleukin 4 rather than the result of an excess amount of TNF-\(\alpha\).
KW  - Infektionsbiologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-31614
VL  - 20
SP  - 1131
EP  - 1135
ER  - 
TY  - JOUR
A1  - Werner, H.
A1  - Otto, H.
A1  - Tri, Ngo Khac
A1  - Burschka, Christian
T1  - Synthese und Eigenschaften neuer Kupfer- und Gold- Komplexe des Typs C\(_5\)H\(_5\)MPR\(_3\), C\(_5\)Me\(_5\)MPR\(_3\) und R"C\(_2\)MPR\(_3\)(M=Cu,Au)sowie die Kristallstruktur von C\(_5\)H\(_5\)AuPPr\(_3\)
N2  - No abstract available
KW  - Chemie
Y1  - 1984
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-46666
ER  - 
TY  - JOUR
A1  - Werner, Helmut
A1  - Heiser, Bernd
A1  - Burschka, Christian
T1  - Cycloadditionsreaktionen von Organometallkomplexen, I: die Synthese viergliedriger Metalla-Heterocyclen durch [2 + 2]-Cycloaddition aus (Isonitril)cobalt-Komplexen und Isocyanaten sowie Isothiocyanaten
T1  - Cycloaddition Reactions of Organometal Complexes, I: The Synthesis of Four-membered Metalla-Heterocycles by [2 + 2] Cycloaddition of (Isonltrile)cobalt Complexes and Isocyanates or Isothiocyanates
N2  - No abstract available
KW  - Chemie
Y1  - 1982
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-46589
ER  - 
TY  - JOUR
A1  - Werner, H.
A1  - Kletzin, H.
A1  - Burschka, Christian
T1  - Aromaten(Phosphan)Metall-Komplexe: VIII. Syntese und Struktur eines Diaromatenruthenium-Komplexes mit Pi-gebundenem Triphenylphosphan-Liganden
N2  - No abstract available
KW  - Chemie
Y1  - 1984
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-46627
ER  - 
TY  - JOUR
A1  - Moll, Heidrun
A1  - Binöder, Kerstin
A1  - Bogdan, Christian
A1  - Solbach, Werner
A1  - Röllinghoff, Martin
T1  - Production of tumour necrosis factor during murine cutaneous leishmaniasis
N2  - We have assessed the role of tumour necrosis factor-a (TNF) during cutaneous leishmaniasis and demonstrated that significant levels of TNF were released by spleen cells from infected mice after in cirro restimulation with Leishmania major promastigotes. Spleen cells from both genetically resistant and genetically susceptible mice were equally capable of producing TNF. After challenge with bacterial endotoxin, TNF activity could also be demonstrated in the serum of L. mujor-infected mice and the titres correlated with the course of cutaneous disease in susceptible and resistant mice. TNF did not exert a direct leishmanicidal effect in uitro. Furthermore, our study indicated that macrophages are the source of L. major-induced TNF activity and that its elicitation is dependent on the presence of T cells. These findings suggest that TNF acts in concert with other cytokines produced during L. major infection and that its role depends on the composition of T cell subsets and cytokines present.
KW  - Immunologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61291
ER  - 
TY  - THES
A1  - Werner, Christian
T1  - Effect of autoantibodies targeting amphiphysin or glutamate decarboxylase 65 on synaptic transmission of GABAergic neurons
T1  - Einfluss von Autoantikörpern gegen Amphiphysin oder Glutamatdecarboxylase 65 auf synaptische Transmission GABAerger Neurone
N2  - The number of newly detected autoantibodies (AB) targeting synaptic proteins in neurological disorders of the central nervous system (CNS) is steadily increasing. Direct interactions of AB with their target antigens have been shown in first studies but the exact pathomecha-nisms for most of the already discovered AB are still unclear. The present study investigates pathophysiological mechanisms of AB-fractions that are associated with the enigmatic CNS disease Stiff person syndrome (SPS) and target the synaptically located proteins amphiphysin or glutamate decarboxylase 65 (GAD65).
In the first part of the project, effects of AB to the presynaptic endocytic protein amphiphysin were investigated. Ultrastructural investigations of spinal cord presynaptic boutons in an es-tablished in-vivo passive-transfer model after intrathecal application of human anti-amphiphysin AB showed a defect of endocytosis. This defect was apparent at high synaptic activity and was characterized by reduction of the synaptic vesicle pool, clathrin coated vesi-cles (CCVs), and endosome like structures (ELS) in comparison to controls. Molecular inves-tigation of presynaptic boutons in cultured murine hippocampal neurons with dSTORM microscopy after pretreatment with AB to amphiphysin revealed that marker proteins involved in vesicle exocytosis (synaptobrevin 2 and synaptobrevin 7) had an altered expression in GA-BAergic presynapses. Endophilin, a direct binding partner of amphiphysin also displayed a disturbed expression pattern. Together, these results point towards an anti-amphiphysin AB-induced defective organization in GABAergic synapses and a presumably compensatory rearrangement of proteins responsible for CME.
In the second part, functional consequences of SPS patient derived IgG fractions containing AB to GAD65, the rate limiting enzyme for GABA synthesis, were investigated by patch clamp electrophysiology and immunohistology. GABAergic neurotransmission at low and high activity as well as short term plasticity appeared normal but miniature synaptic potentials showed an enhanced frequency with constant amplitudes. SPS patient IgG after preabsorption of GAD65-AB using recombinant GAD65 still showed specific synaptic binding to neu-rons and brain slices supporting the hypothesis that additional, not yet characterized AB are present in patient IgG responsible for the exclusive effect on frequency of miniature potentials.
In conclusion, the present thesis uncovered basal pathophysiological mechanisms underlying paraneoplastic SPS induced by AB to amphiphysin leading to disturbed presynaptic architec-ture. In idiopathic SPS, the hypothesis of a direct pathophysiological role of AB to GAD65 was not supported and additional IgG AB are suspected to induce distinct synaptic malfunction.
N2  - Die Anzahl neu charakterisierter Autoantikörper (AAK) gegen synaptische Proteine bei Er-krankungen des zentralen Nervensystems (ZNS) ist stetig wachsend. Direkte Interaktionen der AAK mit ihren Zielantigenen konnten in ersten Studien belegt werden, jedoch besteht weiterhin Unklarheit über die exakten zugrunde liegenden Pathomechanismen.
In der vorliegenden Arbeit wurden pathophysiologische Mechanismen von AAK gegen die synaptisch lokalisierten Proteine Amphiphysin und Glutamatdecarboxylase 65 (GAD65) untersucht, die mit der ZNS Erkrankung Stiff Person Syndrom (SPS) assoziiert sind.
Im ersten Projektteil wurden die Effekte von AAK gegen das Endozytoseprotein Amphiphysin analysiert: in einem etablierten in-vivo Tiermodell konnten nach intrathekalem passiven Transfer von AAK gegen Amphiphysin ultrastrukturelle Untersuchungen von präsynaptischen Terminalen im Rückenmark eine Störung der Endozytose aufzeigen. Dieser Defekt, der bei hoher synaptischer Aktivität eintrat, war durch eine Verminderung synaptischen Vesikelpools, Clathrin-ummantelter Vesikel und endosomähnlicher Strukturen charakterisiert. Molekulare Untersuchungen präsynaptischer Terminale kultivierter hippokampaler Zellkulturen mit dSTORM Mikroskopie zeigten, dass an der Exozytose beteiligte synaptische Vesikelproteine (Synaptobrevin 2 und Synaptobrevin 7) ein verändertes Expressionsmuster innerhalb GA-BAerger Synapsen aufweisen. Die Expression von Endophilin, einem direkten Bindungs-partner von Amphiphysin, war ebenso verändert. Zusammengefasst weisen diese Ergebnis-se auf einen Organisationsdefekt GABAerger Synapsen hin, die durch anti-Amphiphysin AAK induziert sind und eine kompensatorische Umverteilung von Endozytoseproteinen vermuten lassen.
Im zweiten Teil der Arbeit wurden die funktionellen Effekte von SPS AAK gegen GAD65, dem geschwindigkeitsbestimmenden Enzym der GABA-Synthese, mittels Patch-Clamp Mes-sungen und Immunhistologie untersucht. Die GABAerge synaptische Übertragung bei niedri-ger als auch hoher synaptischer Aktivität sowie die synaptische Kurzzeitplastizität wurden durch die IgG Fraktionen mit GAD65-AAK nicht beeinträchtigt. Die Frequenz von GABAergen Miniaturpotentialen war jedoch bei ansonsten gleichbleibender Amplitude erhöht. SPS-Patienten-IgG zeigte allerdings auch nach Präabsorbtion von GAD65-AAK mit Hilfe von rekombinanten GAD65 eine spezifische Anfärbung neuronaler Synapsen, was die Hypothese von weiteren, funktionell wirksamen, aber noch nicht identifizierten AAK im Patienten-IgG unterstützt.
Zusammenfassend konnten in der vorliegenden Arbeit grundlegende pathophysiologische Mechanismen aufgezeigt werden, wie pathogene Antikörper gegen Amphiphysin die Struktur präsynaptischer Boutons beeinträchtigen können. Im Falle des idiopathischen SPS konnte keine unterstützenden Befunde für die Hypothese einer direkten pathophysiologischen Rolle von GAD65 AAK erhoben werden. Nach den vorliegenden Ergebnissen wird das Vorhandensein weiterer, derzeit noch nicht beschriebener IgG AAK postuliert, die die synaptische Fehlfunktion erklären können.
KW  - Autoaggressionskrankheit
KW  - Zentralnervensystem
KW  - Stiff person syndrome
KW  - autoimmunity
KW  - glutamate decarboxylase 65
KW  - amphiphysin
KW  - Synapse
KW  - Glutamat-Decarboxylase
KW  - Autoimmunität
KW  - Endocytose
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-105648
ER  - 
TY  - JOUR
A1  - Wurmb, Thomas Erik
A1  - Schlereth, Stefan
A1  - Kredel, Markus
A1  - Muellenbach, Ralf M.
A1  - Wunder, Christian
A1  - Brederlau, Jörg
A1  - Roewer, Norbert
A1  - Kenn, Werner
A1  - Kunze, Ekkehard
T1  - Routine Follow-Up Cranial Computed Tomography for Deeply Sedated, Intubated, and Ventilated Multiple Trauma Patients with Suspected Severe Head Injury
JF  - BioMed Research International
N2  - Background. Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome. We investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients. Methods. The study design is a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan. We defined 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies. Results. A progression of intracranial injury was found in 63 patients (42%) and 18 patients (12%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44%) had therapeutic consequences due to the results of the follow-up cCT. Conclusion. We found new diagnosis or progression of intracranial pathology in 54% of the patients. In 54% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT. In trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial.
KW  - Computertomographie
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120084
IS  - 361949
ER  - 
TY  - JOUR
A1  - Burschka, Christian
A1  - Leonhard, K.
A1  - Werner, H.
T1  - Basische Metalle. XIV. Synthese und Kristallstruktur von C\(_5\)H\(_5\)(PMe\(_3\))CoS\(_5\) : Ein neuer Metallapentathia-Heterocyclus
T1  - Basic Metals. XIV. Synthesis and Crystal Structure of C\(_5\)H\(_5\)(PMe\(_3\))CoS\(_5\) : A New Metallapentathia Heterocycle
N2  - Der Zweikernkomplex C\(_5\)H\(_5\)(PMe\(_3\))Co(\(\mu\)-CO)\(_2\)Mn(CO)C\(_5\)H\(_4\)Me (8) reagiert mit stöchiometrischen Mengen S\(_8\) in praktisch quantitativer Ausbeute zu C\(_5\)H\(_5\)(PMe\(_3\))CoS\(_5\) (4). Der Koba.ltapentathia-Heterocyclus 4 ist ebenfalls aus C\(_5\)H\(_5\)(PMe\(_3\))Co(h\(^2\)-CS\(_2\)) (5) und S\(_8\) zugänglich. 4 kristallisiert monoklin mit den Gitterkonstanten a = 8,467(3) A, b = 12,128(4) A, c = 14,210(4) A und \(\beta\) = 102,20(2)°_ Die Sesselform des sechsgliedrigen CoS\(_5\)-Rings entspricht derjenigen in den bekannten Verbindungen (C\(_5\)H\(_5\))\(_2\)TiS\(_5\) und (C\(_5\)H\(_5\))\(_2\)VS\(_5\) , wobei in 4 der Cyclopentadienylligand die axiale und die Trimethylphosphingruppe die ä.quatoriale Position einnehmen.
N2  - The dinuclear complex C\(_5\)H\(_5\)(PMe\(_3\))Co(\(\mu\)-CO)\(_2\)Mn(CO)C\(_5\)H\(_4\)Me (8) reaots with stoichiometric amounts of S\(_8\) to form C\(_5\)H\(_5\)(PMe\(_3\))CoS\(_5\) (4) in practica.lly quantitative yields. The cobalt. apentathia heterocycle 4 is a.lso obtained by the reaction of C\(_5\)H\(_5\)(PMe\(_3\))Co(h\(^2\)-CS\(_2\)) (5) with S\(_8\), Cry. stals of 4 are monoclinic with a = 8.467(3) A, b = 12.128(4) A, c = 14.210(4) A and \(\beta\) = 102.20(2)°. The chair form of the six·membered CoS\(_5\) ringcorresponds to that of the compounds (C\(_5\)H\(_5\))\(_2\)TiS\(_5\) and (C\(_5\)H\(_5\))\(_2\)VS\(_5\) In 4, the cyclopentadienyl ligand occupies the axial and the trimethylphosphine group the equatorial position.
KW  - Chemie
Y1  - 1980
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-31407
ER  - 
TY  - JOUR
A1  - Doppler, Kathrin
A1  - Schuster, Yasmin
A1  - Appeltshauser, Luise
A1  - Biko, Lydia
A1  - Villmann, Carmen
A1  - Weishaupt, Andreas
A1  - Werner, Christian
A1  - Sommer, Claudia
T1  - Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model
JF  - Journal of Neuroinflammation
N2  - Background:
Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown.

Methods:
In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison.

Results:
Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1.

Conclusions:
Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.
KW  - complement deposition
KW  - paranodopathy
KW  - anti-contactin-1
KW  - CIDP
KW  - passive transfer
KW  - autoantibody
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200476
VL  - 16
IS  - 73
ER  - 
TY  - JOUR
A1  - Harter, Philipp
A1  - Hauke, Jan
A1  - Heitz, Florian
A1  - Reuss, Alexander
A1  - Kommoss, Stefan
A1  - Marmé, Frederik
A1  - Heimbach, André
A1  - Prieske, Katharina
A1  - Richters, Lisa
A1  - Burges, Alexander
A1  - Neidhardt, Guido
A1  - de Gregorio, Nikolaus
A1  - El-Balat, Ahmed
A1  - Hilpert, Felix
A1  - Meier, Werner
A1  - Kimmig, Rainer
A1  - Kast, Karin
A1  - Sehouli, Jalid
A1  - Baumann, Klaus
A1  - Jackisch, Christian
A1  - Park-Simon, Tjoung-Won
A1  - Hanker, Lars
A1  - Kröber, Sandra
A1  - Pfisterer, Jacobus
A1  - Gevensleben, Heidrun
A1  - Schnelzer, Andreas
A1  - Dietrich, Dimo
A1  - Neunhöffer, Tanja
A1  - Krockenberger, Mathias
A1  - Brucker, Sara Y.
A1  - Nürnberg, Peter
A1  - Thiele, Holger
A1  - Altmüller, Janine
A1  - Lamla, Josefin
A1  - Elser, Gabriele
A1  - du Bois, Andreas
A1  - Hahnen, Eric
A1  - Schmutzler, Rita
T1  - Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1)
JF  - PLoS ONE
N2  - Background
Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.

Methods
Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.

Results
In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5%), \(BRCA2\) (5.5%), \(RAD51C\) (2.5%) and \(PALB2\) (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients \(\geq\)60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.

Conclusions
26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be
not sufficient.
KW  - medicine
KW  - Genetic causes of cancer
KW  - ovarian cancer
KW  - cancer risk factors
KW  - histology
KW  - cancer detection and diagnosis
KW  - breast cancer
KW  - genetic testing
KW  - human genetics
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173553
VL  - 12
IS  - 10
ER  -