78 research outputs found
Supplemental material for NOD1/NOD2-mediated recognition of non-typeable <i>Haemophilus influenzae</i> activates innate immunity during otitis media
No full textSupplemental Material for NOD1/NOD2-mediated recognition of non-typeable Haemophilus influenzae activates innate immunity during otitis media by Jasmine Lee, Anke Leichtle, Emily Zuckerman, Kwang Pak, Meghan Spriggs, Stephen I Wasserman and Arwa Kurabi in Innate Immunity</p
Indication, surgical procedure and clinical performance of the new active osseointegrated implant system, the Osia™ System
No full textImmunmodulation der chronischen Otitis media
No full textChronic otitis media is one of the most common diseases of the ear and is therefore one of the most important causes of acquired and preventable hearing loss. Clinical manifestations range from hearing loss to vestibular dysfunction and facial paralysis to intracranial complications with fatal consequences.
The pathogenesis is still not fully understood, and a multifactorial etiology is currently assumed. The innate immune system and its response to pathogens play an important role here. The most common bacterial pathogens of acute otitis media are Streptococcus pneumoniae and Haemophilus influenzae, or Pseudomonas aeroginosa and Staphylococcus aureus in chronic cases. Previous viral infections of the upper respiratory tract increase the incidence of otitis media and subsequent chronicity. The progressive inflammatory-destructive processes lead to the destruction of sensitive structures of the middle ear and surrounding structures.
Current treatment of chronic otitis media consists of topical and systemic antibiotics, improvement of middle ear ventilation through grommets, and ultimately remedial microsurgical ear surgery.
Due to the central importance of the innate immune system in the pathogenesis of chronic otitis media, the following three studies investigated the innate immune system networks of the middle ear mucosa with a view to potential new immunological therapeutic approaches. The studies were conducted on mouse models, human tissue samples and cell cultures of human middle ear mucosa. Histological and immunohistochemical examinations, gene microarrays, MTT assays, and PCR diagnostics were used.
The first study addressed the role of TNFα in chronic epitympanic otitis media (cholesteatoma). The study included both a TNF-deficient mouse model and the analysis of the expression of genes and effector molecules of the TNFα signaling cascade in human tissue samples. It has been shown that TNFα regulates both inflammatory and apoptotic processes and could therefore represent a potential target for targeted drug therapy.
This study was followed by a more comprehensive investigation of the various networks of the innate immune system. In addition to various mouse models and further gene expression analyses, studies were conducted on a cell culture of human middle ear epithelial cells. The resulting representation of the complex network of the innate immune system enables the explanation of differences in the presentation of chronic otitis media and points of departure for potential further pharmacological therapies.
The third study focused on the processes of the innate immune system in relation to the middle ear epithelium as the first line of defense. Based on the evolutionarily divergent origins, differences in the transformation and distribution of receptors of the innate immune system could be demonstrated. The epithelium could therefore represent the crucial hub for pharmacological therapeutic approaches.
These studies successfully demonstrated important signaling pathways of the innate immune system of the middle ear mucosa following pathogen contact. This regulatory network, with its activating and inhibitory control mechanisms, offers a diverse range of possibilities for pharmacological therapeutic approaches to reduce pro-inflammatory signals or improve negative regulation.Die chronische Otitis media stellt eine der häufigsten Erkrankungen des Ohres dar und ist somit einer der wichtigsten Gründe für einen erworbenen und vermeidbaren Hörverlust. Die klinische Manifestation reicht vom Hörverlust über vestibuläre Dysfunktion und Fazialisparese bis hin zu intrakraniellen Komplikationen mit letalen Folgen.
Die Pathogenese ist bis heute nicht vollständig geklärt, und es wird derzeit von einer multifaktoriellen Ätiologie ausgegangen. Eine wesentliche Rolle kommt hierbei dem angeborenen Immunsystem und seiner Reaktion auf Pathogene zu. Die häufigsten bakteriellen Erreger einer akuten Otitis media sind Streptococcus pneumoniae und Haemophilus influenzae bzw. Pseudomonas aeroginosa und Staphylococcus aureus bei Chronifizierung, vorausgegangene virale Infektionen der oberen Atemwege erhöhen die Inzidenz einer Otitis media und anschließende Chronifizierung. Die fortschreitenden entzündlich-destruierenden Prozesse führen hierbei zur Zerstörung sensibler Strukturen des Mittelohres sowie darüberhinausgehend umgebender Strukturen.
Die derzeitige Therapie der chronischen Otitis media besteht aus topischen und systemischen Antibiotika, Verbesserung der Mittelohrbelüftung durch Paukenröhrchen und schlussendlich einer sanierenden mikrochirurgischen Ohroperation.
Auf Grund der zentralen Bedeutung des angeborenen Immunsystems in der Pathogenese der chronischen Otitis media untersuchten die folgenden 3 Arbeiten die Netzwerke des angeborenen Immunsystems der Mittelohrschleimhaut im Hinblick möglicher neuer immunologischer Therapieansätze. Die Untersuchungen erfolgten an Mausmodellen, menschlichen Gewebeproben und Zellkulturen menschlicher Mittelohrschleimhaut. Hierbei kamen histologische und immunhistochemische Untersuchungen, Gen-Microarray, MTT-Assay und PCR-Diagnostik zur Anwendung.
Die erste Arbeit widmete sich der Rolle von TNFα in chronischer Otitis media epitympanalis (Cholesteatom). In die Untersuchung wurden sowohl ein TNF-defizientes Mausmodell als auch die Analyse der Expression von Genen und Effektormolekülen der TNFα-Signalkaskade an menschlichen Gewebeproben eingeschlossen. Es konnte gezeigt werden, dass TNFα sowohl inflammatorisch als auch apoptotisch reguliert und somit einen möglichen Ansatzpunkt für eine gezielte medikamentöse Therapie darstellen könnte.
Dieser Arbeit schloss sich eine umfassendere Untersuchung der verschiedenen Netzwerke des angeborenen Immunsystems an. Neben verschiedenen Mausmodellen und weiterer Genexpressionsanalysen erfolgten Untersuchungen an einer Zellkultur menschlicher Mittelohepithelzellen. Die resultierende Darstellung des komplexen Netzwerks des angeborenen Immunsystems ermöglicht die Erklärung von Unterschieden im Erscheinungsbild der chronischen Otitis media und Ansatzpunkte für mögliche weitere pharmakologische Therapien.
Die dritte Arbeit fokussierte sich auf die Prozesse des angeborenen Immunsystems in Bezug auf das Epithel des Mittelohres als erste Abwehrbarriere. Es konnten, basierend auf den entwicklungsgeschichtlich divergenten Ursprüngen, Unterschiede in der Transformation und Verteilung von Rezeptoren des angeborenen Immunsystems dargestellt werden. Das Epithel könnte damit die entscheidende Schaltstelle für pharmakologische Therapieansätze darstellen.
Erfolgreich konnten mit diesen Arbeiten wichtige Signalwege des angeborenen Immunsystems der Mittelohrschleimhaut in Folge eines Pathogenkontakt dargestellt werden. Dieses regulatorische Netzwerk mit seinen aktivierenden und hemmenden Steuerungsmechanismen bietet eine vielfältige Möglichkeit für pharmakologische Therapieansätze um entzündungsfördernde Signale zu reduzieren oder die negative Regulation zu verbessern
Hemmung der Mikrovesikel-induzierten Tumorzellmigration durch das niedermolekulare Heparin Tinzaparin
No full textSerum Levels of Acylcarnitines Are Altered in Prediabetic Conditions
No full textOBJECTIVE: The role of mitochondrial function in the complex pathogenesis of type 2 diabetes is not yet completely understood. Therefore, the aim of this study was to investigate serum concentrations of short-, medium- and long-chain acylcarnitines as markers of mitochondrial function in volunteers with normal, impaired or diabetic glucose control. METHODS: Based on a 75 g oral glucose tolerance test, 1019 studied subjects were divided into a group with normal glucose tolerance (NGT; n = 636), isolated impaired fasting glycaemia (IFG; n = 184), impaired glucose tolerance (IGT; n = 87) or type 2 diabetes (T2D; n = 112). Serum concentrations of free carnitine and 24 acylcarnitines were measured by mass spectrometry. RESULTS: Serum levels of acetylcarnitine (C2), propionylcarnitine (C3), octanoylcarnitine (C8), malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH), hexanoylcarnitine (C6), octenoylcarnitine (C8:1), decanoylcarnitine (C10), decenoylcarnitine (C10:1), dodecanoylcarnitine (C12), tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), hydroxytetradecanoylcarnitine (C14OH), hydroxyhexadecanoylcarnitine (C16OH) and octadecenoylcarnitine (C18:1) were significantly different among the groups (all p<0.05 adjusted for age, gender and BMI). Between the prediabetic states C14:1, C14:2 and C18:1 showed significantly higher serum concentrations in persons with IGT (p<0.05). Compared to T2D the IFG and the IGT subjects showed lower serum concentrations of malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) (p<0.05). CONCLUSION: Alterations in serum concentrations of several acylcarnitines, in particular tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), octadecenoylcarnitine (C18:1) and malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) are associated not only with T2D but also with prediabetic states
NOD-Like Receptor Signaling in Cholesteatoma
No full textLeichtle A, Klenke C, Ebmeyer J, et al. NOD-Like Receptor Signaling in Cholesteatoma. BioMed Research International. 2015;2015: 408169 .Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma
Pathological cerebrospinal fluid protein concentration and albumin quotient at relapse predicts short-term disability progression in multiple sclerosis: a retrospective single center observational study
No full textGlial cell line-derived neurotrophic factor (GDNF) induces neuritogenesis in the cochlear spiral ganglion via neural cell adhesion molecule (NCAM)
No full textGlial cell line-derived neurotrophic factor (GDNF) increases survival and neurite extension of spiral ganglion neurons (SGNs), the primary neurons of the auditory system, via yet unknown signaling mechanisms. In other cell types, signaling is achieved by the GPI-linked GDNF family receptor α1 (GFRα1) via recruitment of transmembrane receptors: Ret (re-arranged during transformation) and/or NCAM (neural cell adhesion molecule). Here we show that GDNF enhances neuritogenesis in organotypic cultures of spiral ganglia from 5-day-old rats and mice. Addition of GFRα1-Fc increases this effect. GDNF/GFRα1-Fc stimulation activates intracellular PI3K/Akt and MEK/Erk signaling cascades as detected by Western blot analysis of cultures prepared from rats at postnatal days 5 (P5, before the onset of hearing) and 20 (P20, after the onset of hearing). Both cascades mediate GDNF stimulation of neuritogenesis, since application of the Akt inhibitor Wortmannin or the Erk inhibitor U0126 abolished GDNF/GFRα1-Fc stimulated neuritogenesis in P5 rats. Since cultures of P5 NCAM-deficient mice failed to respond by neuritogenesis to GDNF/GFRα1-Fc, we conclude that NCAM serves as a receptor for GDNF signaling responsible for neuritogenesis in early postnatal spiral ganglion
Transsphenoidal and infralabyrinthine approach of the petrous apex cholesterol granuloma
No full textEndocrinological and inflammatory markers in individuals with spinal cord injury: A systematic review and meta-analysis [supplementary materials].
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