196 results on '"Athanasia Warnecke"'
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2. Corrigendum: Middle ear anatomy and implant sizes: correlates and the need for uniform implant dimensions
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Thomas Lenarz, Moritz Becker, Athanasia Warnecke, Anja Giesemann, Nils Kristian Prenzler, Uwe Steinhardt, and Daniel Schurzig
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hearing loss ,tympanoplasty ,ossiculoplasty ,stapesplasty ,middle ear reconstruction ,anatomical variability ,Medicine - Published
- 2024
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3. Middle ear anatomy and implant sizes: correlates and the need for uniform implant dimensions
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Thomas Lenarz, Moritz Becker, Athanasia Warnecke, Anja Giesemann, Nils Kristian Prenzler, Uwe Steinhardt, and Daniel Schurzig
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hearing loss ,tympanoplasty ,ossiculoplasty ,stapesplasty ,middle ear reconstruction ,anatomical variability ,Medicine - Abstract
IntroductionConductive hearing loss describes an insufficient sound transfer of the middle ear, often caused by defects or absence of the ossicles. Depending on the specific middle ear dimensions and the kind of defect, surgeons can choose from a variety of passive implants to reconstruct the middle ear and hence restore sound transmission. However, the latter is only achieved if the optimal implant size is available and selected for each individual patient.MethodsAnatomical dimensions relevant for middle ear reconstruction were assessed within high-resolution clinical imaging data of 50 patients (100 ears). The ranges of these dimensions were then compared to implant types and sizes available from different manufacturers.ResultsIn general, total and partial prostheses seem to cover the whole range of anatomical variations. A lack of stapesplasty implants was found for particularly small anatomies. Various implant lengths of all types far exceed dimensions necessary for successful restoration of sound transmission. In some cases, implant lengths are not clearly specified by the manufacturer. Tympanic membrane and stapes axis were not in line for any of the investigated middle ears.ConclusionClear specifications of implant lengths are crucial to allow for successful hearing restoration, and clinics often need to have more than one implant type to cover the entire range of anatomical variations they may encounter. There appears to be an unmet clinical need for smaller stapesplasty implants. Devices which allow for an angular adjustment between distal and proximal end appear to mimic the orientation of the ossicles more naturally.
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- 2024
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4. Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL
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Larissa Nassauer, Hinrich Staecker, Peixin Huang, Bryan Renslo, Madeleine Goblet, Jennifer Harre, Athanasia Warnecke, Juliane W. Schott, Michael Morgan, Melanie Galla, and Axel Schambach
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MT: Delivery Strategies ,hearing loss ,ototoxicity ,cisplatin ,gene therapy ,lentiviral vector ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, Bcl-xl, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, in vivo application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.
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- 2024
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5. Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal
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Arianna Di Stadio, Massimo Ralli, Diego Kaski, Nehzat Koohi, Federico Maria Gioacchini, Jeffrey W. Kysar, Anil K. Lalwani, Athanasia Warnecke, and Evanthia Bernitsas
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brain ,neuroinflammation ,neurodegeneration ,CSF ,perilymph ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer’s disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.
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- 2024
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6. Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment
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Laurence Jonard, Davide Brotto, Miguel A. Moreno-Pelayo, Ignacio del Castillo, Hannie Kremer, Ronald Pennings, Helena Caria, Graça Fialho, An Boudewyns, Guy Van Camp, Monika Ołdak, Dominika Oziębło, Naïma Deggouj, Romolo Daniele De Siati, Paolo Gasparini, Giorgia Girotto, Margriet Verstreken, Silvia Dossena, Sebastian Roesch, Saba Battelino, Katarina Trebušak Podkrajšek, Athanasia Warnecke, Thomas Lenarz, Anke Lesinski-Schiedat, Michel Mondain, Anne-Françoise Roux, Françoise Denoyelle, Natalie Loundon, Margaux Serey Gaut, Patrizia Trevisi, Elisa Rubinato, Alessandro Martini, and Sandrine Marlin
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n/a ,Otorhinolaryngology ,RF1-547 - Abstract
The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...]
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- 2023
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7. Neuroinflammatory disorders of the brain and inner ear: a systematic review of auditory function in patients with migraine, multiple sclerosis, and neurodegeneration to support the idea of an innovative ‘window of discovery’
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Arianna Di Stadio, Pietro De Luca, Nehzat Koohi, Diego Kaski, Massimo Ralli, Anja Giesemann, Hans-Peter Hartung, Marta Altieri, Daniela Messineo, Athanasia Warnecke, Teresa Frohman, and Elliot M. Frohman
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inner ear ,neuroinflammation ,CSF ,Parkinson’s disease ,multiple sclerosis ,headache ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
BackgroundHearing can be impaired in many neurological conditions and can even represent a forme fruste of specific disorders. Auditory function can be measured by either subjective or objective tests. Objective tests are more useful in identifying which auditory pathway (superior or inferior) is most affected by disease. The inner ear’s perilymphatic fluid communicates with the cerebrospinal fluid (CSF) via the cochlear aqueduct representing a window from which pathological changes in the contents of the CSF due to brain inflammation could, therefore, spread to and cause inflammation in the inner ear, damaging inner hair cells and leading to hearing impairment identifiable on tests of auditory function.MethodsA systematic review of the literature was performed, searching for papers with case–control studies that analyzed the hearing and migraine function in patients with neuro-inflammatory, neurodegenerative disorders. With data extracted from these papers, the risk of patients with neurological distortion product otoacoustic emission (DPOAE) was then calculated.ResultsPatients with neurological disorders (headache, Parkinson’s disease, and multiple sclerosis) had a higher risk of having peripheral auditory deficits when compared to healthy individuals.ConclusionExisting data lend credence to the hypothesis that inflammatory mediators transmitted via fluid exchange across this communication window, thereby represents a key pathobiological mechanism capable of culminating in hearing disturbances associated with neuroimmunological and neuroinflammatory disorders of the nervous system.
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- 2023
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8. A potential serological biomarker for inner ear pathologies: OTOLIN-1
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Emilio Avallone, Heike Schmitt, Giorgio Lilli, Athanasia Warnecke, Anke Lesinski-Schiedat, Thomas Lenarz, and Kerstin Willenborg
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Otorhinolaryngology ,RF1-547 - Published
- 2022
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9. Deep intracochlear injection of triamcinolone-acetonide with an inner ear catheter in patients with residual hearing
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Nils K. Prenzler, Rolf Salcher, Thomas Lenarz, Lutz Gaertner, Anke Lesinski-Schiedat, and Athanasia Warnecke
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cochlear implant ,hearing preservation ,impedances ,steroids ,catheter ,drug delivery ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionIn a previous study, an inner ear catheter was used to deliver low- and high-dose steroids into the cochlea prior to cochlear implant electrode insertion. With this approach, more apical regions of the cochlea could be reached and a reduction of electrode impedances in the short term was achieved in cochlear implant recipients. Whether intracochlear application of drugs via the catheter is a safe method also for patients with residual hearing has not been investigated hitherto. The aim of the present study was therefore to investigate the effect of intracochlear triamcinolone application in cochlear implant recipients with residual hearing.Patients and methodsPatients with residual hearing were administered triamcinolone-acetonide (4 mg/ml; n = 10) via an inner ear catheter just prior to insertion of a MED-EL FLEX28 electrode. Impedances were measured at defined time points (intra-operatively, post-operatively and at first fitting) and retrospectively compared with a control group (no steroid application) and low- and high-dose group. Hearing thresholds were measured preoperatively, 3 days after surgery and at first fitting by pure tone audiometry. Pre- to postoperative hearing loss was determined at first fitting and compared to results from a previous study.ResultsThe median hearing loss after implantation (125–1,500 Hz) was 20.6 dB. Four patients (40%) showed a median hearing loss of less than 15 dB, three patients (30%) between 15 and 30 dB and three patients (30%) more than 30 dB. The median hearing loss was similar to the results obtained from our previous study showing a median hearing loss of 24 dB when using FLEX28 electrode arrays.ConclusionNo difference in residual hearing loss was found when comparing application of triamcinolone-acetonide using an inner ear catheter prior to the insertion of a FLEX28 electrode array to the use of the FLEX28 electrode array without the catheter. Thus, we conclude that application of drugs to the cochlea with an inner ear catheter could be a feasible approach in patients with residual hearing.
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- 2023
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10. Variations in microanatomy of the human modiolus require individualized cochlear implantation
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Markus Pietsch, Daniel Schurzig, Rolf Salcher, Athanasia Warnecke, Peter Erfurt, Thomas Lenarz, and Andrej Kral
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Medicine ,Science - Abstract
Abstract Cochlear variability is of key importance for the clinical use of cochlear implants, the most successful neuroprosthetic device that is surgically placed into the cochlear scala tympani. Despite extensive literature on human cochlear variability, few information is available on the variability of the modiolar wall. In the present study, we analyzed 108 corrosion casts, 95 clinical cone beam computer tomographies (CTs) and 15 µCTs of human cochleae and observed modiolar variability of similar and larger extent than the lateral wall variability. Lateral wall measures correlated with modiolar wall measures significantly. ~ 49% of the variability had a common cause. Based on these data we developed a model of the modiolar wall variations and related the model to the design of cochlear implants aimed for perimodiolar locations. The data demonstrate that both the insertion limits relevant for lateral wall damage (approximate range of 4–9 mm) as well as the dimensions required for optimal perimodiolar placement of the electrode (the point of release from the straightener; approximate range of 2–5mm) are highly interindividually variable. The data demonstrate that tip fold-overs of preformed implants likely result from the morphology of the modiolus (with radius changing from base to apex), and that optimal cochlear implantation of perimodiolar arrays cannot be guaranteed without an individualized surgical technique.
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- 2022
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11. Corrigendum: Potentiation of brain-derived neurotrophic factor-induced protection of spiral ganglion neurons by C3 exoenzyme/Rho inhibitor
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Jennifer Harre, Laura Heinkele, Melanie Steffens, Athanasia Warnecke, Thomas Lenarz, Ingo Just, and Astrid Rohrbeck
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spiral ganglion neurons ,RhoA ,C3 exoenzyme ,brain-derived neurotrophic factor ,neuroprotection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2022
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12. Personalized Proteomics for Precision Diagnostics in Hearing Loss: Disease-Specific Analysis of Human Perilymph by Mass Spectrometry
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Heike A. Schmitt, Andreas Pich, Nils K. Prenzler, Thomas Lenarz, Jennifer Harre, Hinrich Staecker, Martin Durisin, and Athanasia Warnecke
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Chemistry ,QD1-999 - Published
- 2021
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13. Improving Control of Gene Therapy-Based Neurotrophin Delivery for Inner Ear Applications
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Madeleine St. Peter, Douglas E. Brough, Anna Lawrence, Jennifer Nelson-Brantley, Peixin Huang, Jennifer Harre, Athanasia Warnecke, and Hinrich Staecker
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brain-derived neurotrophic factor ,neurotrophin 3 ,spiral ganglion neurons ,herpes latency promoter ,ototoxicity ,Biotechnology ,TP248.13-248.65 - Abstract
Background: Survival and integrity of the spiral ganglion is vital for hearing in background noise and for optimal functioning of cochlear implants. Numerous studies have demonstrated that supplementation of supraphysiologic levels of the neurotrophins BDNF and NT-3 by pumps or gene therapy strategies supports spiral ganglion survival. The endogenous physiological levels of growth factors within the inner ear, although difficult to determine, are likely extremely low within the normal inner ear. Thus, novel approaches for the long-term low-level delivery of neurotrophins may be advantageous.Objectives: This study aimed to evaluate the long-term effects of gene therapy-based low-level neurotrophin supplementation on spiral ganglion survival. Using an adenovirus serotype 28-derived adenovector delivery system, the herpes latency promoter, a weak, long expressing promoter system, has been used to deliver the BDNF or NTF3 genes to the inner ear after neomycin-induced ototoxic injury in mice.Results: Treatment of the adult mouse inner ear with neomycin resulted in acute and chronic changes in endogenous neurotrophic factor gene expression and led to a degeneration of spiral ganglion cells. Increased survival of spiral ganglion cells after adenoviral delivery of BDNF or NTF3 to the inner ear was observed. Expression of BDNF and NT-3 could be demonstrated in the damaged organ of Corti after gene delivery. Hearing loss due to overexpression of neurotrophins in the normal hearing ear was avoided when using this novel vector–promoter combination.Conclusion: Combining supporting cell-specific gene delivery via the adenovirus serotype 28 vector with a low-strength long expressing promoter potentially can provide long-term neurotrophin delivery to the damaged inner ear.
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- 2022
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14. Bioinformatic Analysis of the Perilymph Proteome to Generate a Human Protein Atlas
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Alina van Dieken, Hinrich Staecker, Heike Schmitt, Jennifer Harre, Andreas Pich, Willi Roßberg, Thomas Lenarz, Martin Durisin, and Athanasia Warnecke
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cochlea ,perilymph ,hearing loss ,hereditary inner ear disease ,proteome ,bioinformatics ,Biology (General) ,QH301-705.5 - Abstract
The high complexity of the cellular architecture of the human inner ear and the inaccessibility for tissue biopsy hampers cellular and molecular analysis of inner ear disease. Sampling and analysis of perilymph may present an opportunity for improved diagnostics and understanding of human inner ear pathology. Analysis of the perilymph proteome from patients undergoing cochlear implantation was carried out revealing a multitude of proteins and patterns of protein composition that may enable characterisation of patients into subgroups. Based on existing data and databases, single proteins that are not present in the blood circulation were related to cells within the cochlea to allow prediction of which cells contribute to the individual perilymph proteome of the patients. Based on the results, we propose a human atlas of the cochlea. Finally, druggable targets within the perilymph proteome were identified. Understanding and modulating the human perilymph proteome will enable novel avenues to improve diagnosis and treatment of inner ear diseases.
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- 2022
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15. Proteome profile of patients with excellent and poor speech intelligibility after cochlear implantation: Can perilymph proteins predict performance?
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Martin Durisin, Caroline Krüger, Andreas Pich, Athanasia Warnecke, Melanie Steffens, Carsten Zeilinger, Thomas Lenarz, Nils Prenzler, and Heike Schmitt
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Medicine ,Science - Abstract
Modern proteomic analysis and reliable surgical access to gain liquid inner ear biopsies have enabled in depth molecular characterization of the cochlea microenvironment. In order to clarify whether the protein composition of the perilymph can provide new insights into individual hearing performance after cochlear implantation (CI), computational analysis in correlation to clinical performance after CI were performed based on the proteome profile derived from perilymph samples (liquid biopsies). Perilymph samples from cochlear implant recipients have been analyzed by mass spectrometry (MS). The proteins were identified using the shot-gun proteomics method and quantified and analyzed using Max Quant, Perseus and IPA software. A total of 75 perilymph samples from 68 (adults and children) patients were included in the analysis. Speech perception data one year after implantation were available for 45 patients and these were used for subsequent analysis. According to their hearing performance, patients with excellent (n = 22) and poor (n = 14) performance one year after CI were identified and used for further analysis. The protein composition and statistically significant differences in the two groups were detected by relative quantification of the perilymph proteins. With this procedure, a selection of 287 proteins were identified in at least eight samples in both groups. In the perilymph of the patients with excellent and poor performance, five and six significantly elevated proteins were identified respectively. These proteins seem to be involved in different immunological processes in excellent and poor performer. Further analysis on the role of specific proteins as predictors for poor or excellent performance among CI recipients are mandatory. Combinatory analysis of molecular inner ear profiles and clinical performance data using bioinformatics analysis may open up new possibilities for patient stratification. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
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- 2022
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16. Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor
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Inga Wille, Jennifer Harre, Sarah Oehmichen, Maren Lindemann, Henning Menzel, Nina Ehlert, Thomas Lenarz, Athanasia Warnecke, and Peter Behrens
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cochlea implant ,implant-associated drug delivery ,BDNF ,heparan sulfate ,polycaprolactone ,polyglycolide ,Biotechnology ,TP248.13-248.65 - Abstract
State-of-the-art treatment for sensorineural hearing loss is based on electrical stimulation of residual spiral ganglion neurons (SGNs) with cochlear implants (CIs). Due to the anatomical gap between the electrode contacts of the CI and the residual afferent fibers of the SGNs, spatial spreading of the stimulation signal hampers focused neuronal stimulation. Also, the efficiency of a CI is limited because SGNs degenerate over time due to loss of trophic support. A promising option to close the anatomical gap is to install fibers as artificial nerve guidance structures on the surface of the implant and install on these fibers drug delivery systems releasing neuroprotective agents. Here, we describe the first steps in this direction. In the present study, suture yarns made of biodegradable polymers (polyglycolide/poly-ε-caprolactone) serve as the basic fiber material. In addition to the unmodified fiber, also fibers modified with amine groups were employed. Cell culture investigations with NIH 3T3 fibroblasts attested good cytocompatibility to both types of fibers. The fibers were then coated with the extracellular matrix component heparan sulfate (HS) as a biomimetic of the extracellular matrix. HS is known to bind, stabilize, modulate, and sustainably release growth factors. Here, we loaded the HS-carrying fibers with the brain-derived neurotrophic factor (BDNF) which is known to act neuroprotectively. Release of this neurotrophic factor from the fibers was followed over a period of 110 days. Cell culture investigations with spiral ganglion cells, using the supernatants from the release studies, showed that the BDNF delivered from the fibers drastically increased the survival rate of SGNs in vitro. Thus, biodegradable polymer fibers with attached HS and loaded with BDNF are suitable for the protection and support of SGNs. Moreover, they present a promising base material for the further development towards a future neuronal guiding scaffold.
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- 2022
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17. Successful Treatment of Noise-Induced Hearing Loss by Mesenchymal Stromal Cells: An RNAseq Analysis of Protective/Repair Pathways
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Athanasia Warnecke, Jennifer Harre, Matthew Shew, Adam J. Mellott, Igor Majewski, Martin Durisin, and Hinrich Staecker
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noise trauma ,hearing loss ,mesenchymal stroma cells ,Wharton’s jelly ,cochlear transcriptome ,hearing protection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton’s jelly were injected into the perilymph. Controls consisted of mice exposed to sound trauma only. Forty-eight hours post-cell delivery, total RNA was extracted from the cochlea and RNAseq performed to evaluate the gene expression induced by the cell therapy. Changes in gene expression were grouped together based on gene ontology classification. A separate cohort of animals was treated in a similar fashion and allowed to survive for 2 weeks post-cell therapy and hearing outcomes determined. Treatment with MSCs after severe sound trauma induced a moderate hearing protective effect. MSC treatment resulted in an up-regulation of genes related to immune modulation, hypoxia response, mitochondrial function and regulation of apoptosis. There was a down-regulation of genes related to synaptic remodeling, calcium homeostasis and the extracellular matrix. Application of MSCs may provide a novel approach to treating sound trauma induced hearing loss and may aid in the identification of novel strategies to protect hearing.
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- 2021
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18. Probing interneuronal cell communication via optogenetic stimulation
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Patrick Heeger, Jennifer Harre, Athanasia Warnecke, Dominik Mueller, Stefan Kalies, and Alexander Heisterkamp
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cell communication ,light ,neuroprosthesis ,optogenetics ,Applied optics. Photonics ,TA1501-1820 ,Medical technology ,R855-855.5 - Abstract
Abstract This study uses an all‐optical approach to probe interneuronal communication between spiral ganglion neurons (SGNs) and neurons of other functional units, in this case cortex neurons (CNs) and hippocampus neurons (HNs), for the first time. We combined a channelrhodopsin variant (CheRiff) with a red genetically encoded calcium indicator (jRCaMP1a), enabling simultaneous optical stimulation and recording from spatially separated small neuronal populations. Stimulation of SGNs was possible with both optogenetic manipulated HNs and CNs, respectively. Furthermore, a dependency on the pulse duration of the stimulating light in regard to the evoked calcium response in the SGNs was also observed. Our results pave the way to enable innovative technologies based on “biohybrid” systems utilizing the functional interaction between different biological (eg, neural) systems. This can enable improved treatment of neurological and sensorineural disorders such as hearing loss.
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- 2021
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19. Distinct MicroRNA Profiles in the Perilymph and Serum of Patients With Menière's Disease
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Matthew Shew, Helena Wichova, Madeleine St. Peter, Athanasia Warnecke, and Hinrich Staecker
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Meniere disease ,microRNA ,liquid biopsy ,perilymph ,biomarker ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Hypothesis: Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients.Background: Development of effective biomarkers for Menière's disease are needed. miRNAs are small RNA sequences that downregulate mRNA translation and play a significant role in a variety of disease states, ultimately making them a promising biomarker. miRNAs can be readily isolated from human inner ear perilymph and serum, and may exhibit disease-specific profiles.Methods: Perilymph sampling was performed in 10 patients undergoing surgery; 5 patients with Meniere's disease and 5 patients with otosclerosis serving as controls. miRNAs were isolated from the serum of 5 patients with bilateral Menière's disease and compared to 5 healthy age-matched controls. For evaluation of miRNAs an Agilent miRNA gene chip was used. Analysis of miRNA expression was carried out using Qlucore and Ingenuitey Pathway Analysis software. Promising miRNAs biomarkers were validated using qPCR.Results: In the perilymph of patients with Menière's disease, we identified 16 differentially expressed miRNAs that are predicted to regulate over 220 different cochlear genes. Six miRNAs are postulated to regulate aquaporin expression and twelve miRNAs are postulated to regulate a variety of inflammatory and autoimmune pathways. When comparing perilymph with serum samples, miRNA-1299 and−1270 were differentially expressed in both the perilymph and serum of Ménière's patients compared to controls. Further analysis using qPCR confirmed miRNA-1299 is downregulated over 3-fold in Meniere's disease serum samples compared to controls.Conclusions: Patients with Ménière's disease exhibit distinct miRNA expression profiles within both the perilymph and serum. The altered perilymph miRNAs identified can be linked to postulated Ménière's disease pathways and may serve as biomarkers. miRNA-1299 was validated to be downregulated in both the serum and perilymph of Menière's patients.
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- 2021
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20. First‐in‐human intracochlear application of human stromal cell‐derived extracellular vesicles
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Athanasia Warnecke, Nils Prenzler, Jennifer Harre, Ulrike Köhl, Lutz Gärtner, Thomas Lenarz, Sandra Laner‐Plamberger, Georg Wietzorrek, Hinrich Staecker, Teresa Lassacher, Julia Hollerweger, Mario Gimona, and Eva Rohde
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cochlear implantation ,EVs from umbilical cord‐derived mesenchymal stromal cells (UC‐MSC‐EV) ,extracellular vesicles ,first‐in‐human intracochlear EV‐therapy ,hearing loss ,immunomodulation ,Cytology ,QH573-671 - Abstract
Abstract Extracellular vesicles (EVs) derived from the secretome of human mesenchymal stromal cells (MSC) contain numerous factors that are known to exert anti‐inflammatory effects. MSC‐EVs may serve as promising cell‐based therapeutics for the inner ear to attenuate inflammation‐based side effects from cochlear implantation which represents an unmet clinical need. In an individual treatment performed on a ‘named patient basis’, we intraoperatively applied allogeneic umbilical cord‐derived MSC‐EVs (UC‐MSC‐EVs) produced according to good manufacturing practice. A 55‐year‐old patient suffering from Menière's disease was treated with intracochlear delivery of EVs prior to the insertion of a cochlear implant. This first‐in‐human use of UC‐MSC‐EVs demonstrates the feasibility of this novel adjuvant therapeutic approach. The safety and efficacy of intracochlear EV‐application to attenuate side effects of cochlea implants have to be determined in controlled clinical trials.
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- 2021
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21. Triiodothyronine Acts as a Smart Influencer on Hsp90 via a Triiodothyronine Binding Site
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Lu Fan, Athanasia Warnecke, Julia Weder, Matthias Preller, and Carsten Zeilinger
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triiodothyronine ,Hsp90 ,protein microarray ,thermophoresis ,molecular docking ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Microarray-based experiments revealed that thyroid hormone triiodothyronine (T3) enhanced the binding of Cy5-labeled ATP on heat shock protein 90 (Hsp90). By molecular docking experiments with T3 on Hsp90, we identified a T3 binding site (TBS) near the ATP binding site on Hsp90. A synthetic peptide encoding HHHHHHRIKEIVKKHSQFIGYPITLFVEKE derived from the TBS on Hsp90 showed, in MST experiments, the binding of T3 at an EC50 of 50 μM. The binding motif can influence the activity of Hsp90 by hindering ATP accessibility or the release of ADP.
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- 2022
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22. Potentiation of Brain-Derived Neurotrophic Factor-Induced Protection of Spiral Ganglion Neurons by C3 Exoenzyme/Rho Inhibitor
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Jennifer Harre, Laura Heinkele, Melanie Steffens, Athanasia Warnecke, Thomas Lenarz, Ingo Just, and Astrid Rohrbeck
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spiral ganglion neurons ,RhoA ,C3 exoenzyme ,brain-derived neurotrophic factor ,neuroprotection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Preservation of the excitability of spiral ganglion neurons (SGN) may contribute to an improved speech perception after cochlear implantation. Thus, the application of exogenous neurotrophic factors such as the neurotrophin brain-derived neurotrophic factor (BDNF) to increase SGN survival in vitro and in vivo is a promising pharmacological approach in cochlear implant (CI) research. Due to the difficult pharmacokinetic profile of proteins such as BDNF, there is a quest for small molecules to mediate the survival of SGN or to increase the efficacy of BDNF. The C3 exoenzyme from Clostridium botulinum could be a potential new candidate for the protection and regeneration of SGN. Inhibition of the RhoA GTPase pathway which can be mediated by C3 is described as a promising strategy to enhance axonal regeneration and to exert pro-survival signals in neurons. Nanomolar concentrations of C3, its enzymatically inactive form C3E174Q, and a 26mer C-terminal peptide fragment covering amino acid 156–181 (C3156-181) potentiated the neuroprotective effect on SGN mediated by BDNF in vitro. The neuroprotective effect of C3/BDNF was reduced to the neuroprotective effect of BDNF alone after the treatment with wortmannin, an inhibitor of the phosphatidylinositol-3-kinase (PI3K).The exoenzyme C3 (wild-type and enzyme-deficient) and the C3 peptide fragment C3154–181 present novel biologically active compounds for the protection of the SGN. The exact underlying intracellular mechanisms that mediate the neuroprotective effect are not clarified yet, but the combination of BDNF (TrkB stimulation) and C3 exoenzyme (RhoA inhibition) can be used to protect SGN in vitro.
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- 2021
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23. Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo
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Athanasia Warnecke, Jennifer Harre, Hinrich Staecker, Nils Prenzler, Dirk Strunk, Sebastien Couillard‐Despres, Pasquale Romanelli, Julia Hollerweger, Teresa Lassacher, Daniela Auer, Karin Pachler, Georg Wietzorrek, Ulrike Köhl, Thomas Lenarz, Katharina Schallmoser, Sandra Laner‐Plamberger, Christine S. Falk, Eva Rohde, and Mario Gimona
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extracellular vesicles (EVs) ,inner ear ,neuroprotection ,spiral ganglion neurons ,umbilical cord‐derived mesenchymal stromal cells (UC‐MSC) ,Medicine (General) ,R5-920 - Abstract
Abstract The lack of approved anti‐inflammatory and neuroprotective therapies in otology has been acknowledged in the last decades and recent approaches are heralding a new era in the field. Extracellular vesicles (EVs) derived from human multipotent (mesenchymal) stromal cells (MSC) can be enriched in vesicular secretome fractions, which have been shown to exert effects (eg, neuroprotection and immunomodulation) of their parental cells. Hence, MSC‐derived EVs may serve as novel drug candidates for several inner ear diseases. Here, we provide first evidence of a strong neuroprotective potential of human stromal cell‐derived EVs on inner ear physiology. In vitro, MSC‐EV preparations exerted immunomodulatory activity on T cells and microglial cells. Moreover, local application of MSC‐EVs to the inner ear significantly attenuated hearing loss and protected auditory hair cells from noise‐induced trauma in vivo. Thus, EVs derived from the vesicular secretome of human MSC may represent a next‐generation biological drug that can exert protective therapeutic effects in a complex and nonregenerating organ like the inner ear.
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- 2020
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24. Medical-Grade Silicone Rubber–Hydrogel-Composites for Modiolar Hugging Cochlear Implants
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Suheda Yilmaz-Bayraktar, Katharina Foremny, Michaela Kreienmeyer, Athanasia Warnecke, and Theodor Doll
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sensorineural hearing loss ,cochlear implants ,self-bending electrode arrays ,silicone rubber–hydrogel composites ,actuators ,swelling behavior ,Organic chemistry ,QD241-441 - Abstract
The gold standard for the partial restoration of sensorineural hearing loss is cochlear implant surgery, which restores patients’ speech comprehension. The remaining limitations, e.g., music perception, are partly due to a gap between cochlear implant electrodes and the auditory nerve cells in the modiolus of the inner ear. Reducing this gap will most likely lead to improved cochlear implant performance. To achieve this, a bending or curling mechanism in the electrode array is discussed. We propose a silicone rubber–hydrogel actuator where the hydrogel forms a percolating network in the dorsal silicone rubber compartment of the electrode array to exert bending forces at low volume swelling ratios. A material study of suitable polymers (medical-grade PDMS and hydrogels), including parametrized bending curvature measurements, is presented. The curvature radii measured meet the anatomical needs for positioning electrodes very closely to the modiolus. Besides stage-one biocompatibility according to ISO 10993-5, we also developed and validated a simplified mathematical model for designing hydrogel-actuated CI with modiolar hugging functionality.
- Published
- 2022
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25. Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation–1 Year Data
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Nils K. Prenzler, Rolf Salcher, Thomas Lenarz, Lutz Gaertner, and Athanasia Warnecke
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cochlear implant ,impedances ,steroids ,catheter ,drug delivery ,inner ear ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Administration of low-dose steroids via a catheter inserted into the cochlea to apply pharmaceuticals to more apical regions was previously shown not to be sufficient for long-term reduction of electrode impedances. The aim of the present study was to investigate the effect of intra-cochlear high-dose triamcinolone application on impedances in cochlear implant recipients. Patients received low-dose (4 mg/ml; n = 5) or high-dose (20 mg/ml; n = 5) triamcinolone via a cochlear catheter just prior to the insertion of a Med-El Flex28 electrode. Impedances were measured at defined time points from intra-operatively up to 12 months after first fitting and retrospectively compared with a control group (no steroid application). Patients who received a high-dose application of crystalloid triamcinolone showed significantly reduced impedances in the first fitting measurements compared to the control group. This effect was no longer detectable in patients of the low-dose group at that time. Looking at the different regions of the electrode, the impedance values were lowered significantly only at the basal and medial contacts. At later time points, there were no significant differences between any of the groups. This is the first study to demonstrate a dose-dependent reduction of impedances by deep intra-cochlear injection of triamcinolone in cochlear implant patients. With a high-dose, single application of triamcinolone using a cochlear catheter prior to insertion of a Flex28 electrode, the impedances can be significantly reduced up to and including the first fitting. Although the effect was longer lasting than when compared to low-dose triamcinolone, it was also not permanent.
- Published
- 2020
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26. Level of sex hormones and their association with acetylsalicylic acid intolerance and nasal polyposis.
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Julia Espersen, Ursula Weber, Ariane Römer-Franz, Thomas Lenarz, Stefan R O Stolle, and Athanasia Warnecke
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Medicine ,Science - Abstract
BackgroundChronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet.AimExamine the relationship between levels of sex hormones and nasal polyposis.MethodsHormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy.ResultsOur results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01).ConclusionVariation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required.SignificanceRetrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.
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- 2020
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27. Computational analysis based on audioprofiles: A new possibility for patient stratification in office-based otology
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Oren Weininger, Athanasia Warnecke, Anke Lesinski-Schiedat, Thomas Lenarz, and Stefan Stolle
- Subjects
Machine learning ,Progressive hearing loss ,Audiogram ,Phenotype ,Genotype ,Otorhinolaryngology ,RF1-547 - Abstract
Genetic contribution to progressive hearing loss in adults is underestimated. Established machine learning-based software could offer a rapid supportive tool to stratify patients with progressive hearing loss. A retrospective longitudinal analysis of 141 adult patients presenting with hearing loss was performed. Hearing threshold was measured at least twice 18 months or more apart. Based on the baseline audiogram, hearing thresholds and age were uploaded to AudioGene v4® (Center for Bioinformatics and Computational Biology at The University of Iowa City, IA, USA) to predict the underlying genetic cause of hearing loss and the likely progression of hearing loss. The progression of hearing loss was validated by comparison with the most recent audiogram data of the patients. The most frequently predicted loci were DFNA2B, DFNA9 and DFNA2A. The frequency of loci/genes predicted by AudioGene remains consistent when using the initial or the final audiogram of the patients. In conclusion, machine learning-based software analysis of clinical data might be a useful tool to identify patients at risk for having autosomal dominant hearing loss. With this approach, patients with suspected progressive hearing loss could be subjected to close audiological followup, genetic testing and improved patient counselling.
- Published
- 2019
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28. Defining the Inflammatory Microenvironment in the Human Cochlea by Perilymph Analysis: Toward Liquid Biopsy of the Cochlea
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Athanasia Warnecke, Nils K. Prenzler, Heike Schmitt, Kerstin Daemen, Jana Keil, Martin Dursin, Thomas Lenarz, and Christine S. Falk
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hearing loss ,neuroinflammation ,cochlear implantation ,cytokines ,chemokines ,endothelial factors ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The molecular pathomechanisms in the majority of patients suffering from acute or progressive sensorineural hearing loss cannot be determined yet. The size and the complex architecture of the cochlea make biopsy and in-depth histological analyses impossible without severe damage of the organ. Thus, histopathology correlated to inner disease is only possible after death. The establishment of a technique for perilymph sampling during cochlear implantation may enable a liquid biopsy and characterization of the cochlear microenvironment. Inflammatory processes may not only participate in disease onset and progression in the inner ear, but may also control performance of the implant. However, little is known about cytokines and chemokines in the human inner ear as predictive markers for cochlear implant performance. First attempts to use multiplex protein arrays for inflammatory markers were successful for the identification of cytokines, chemokines, and endothelial markers present in the human perilymph. Moreover, unsupervised cluster and principal component analyses were used to group patients by lead cytokines and to correlate certain proteins to clinical data. Endothelial and epithelial factors were detected at higher concentrations than typical pro-inflammatory cytokines such as TNF-a or IL-6. Significant differences in VEGF family members have been observed comparing patients with deafness to patients with residual hearing with significantly reduced VEGF-D levels in patients with deafness. In addition, there is a trend toward higher IGFBP-1 levels in these patients. Hence, endothelial and epithelial factors in combination with cytokines may present robust biomarker candidates and will be investigated in future studies in more detail. Thus, multiplex protein arrays are feasible in very small perilymph samples allowing a qualitative and quantitative analysis of inflammatory markers. More results are required to advance this method for elucidating the development and course of specific inner ear diseases or for perioperative characterization of cochlear implant patients.
- Published
- 2019
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29. Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss
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Ines de Vries, Heike Schmitt, Thomas Lenarz, Nils Prenzler, Sameer Alvi, Hinrich Staecker, Martin Durisin, and Athanasia Warnecke
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inner ear ,perilymph ,BDNF ,neurotrophin ,bioinformatic analysis ,proteomics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients (n = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph (n = 41) obtained from hearing-impaired patients (n = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
- Published
- 2019
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30. Long-term delivery of brain-derived neurotrophic factor (BDNF) from nanoporous silica nanoparticles improves the survival of spiral ganglion neurons in vitro.
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Nadeschda Schmidt, Jennifer Schulze, Dawid P Warwas, Nina Ehlert, Thomas Lenarz, Athanasia Warnecke, and Peter Behrens
- Subjects
Medicine ,Science - Abstract
Sensorineural hearing loss (SNHL) can be overcome by electrical stimulation of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Restricted CI performance results from the spatial gap between the SGNs and the electrode, but the efficacy of CI is also limited by the degeneration of SGNs as one consequence of SHNL. In the healthy cochlea, the survival of SGNs is assured by endogenous neurotrophic support. Several applications of exogenous neurotrophic supply have been shown to reduce SGN degeneration in vitro and in vivo. In the present study, nanoporous silica nanoparticles (NPSNPs), with an approximate diameter of
- Published
- 2018
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31. Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics.
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Jennifer Schulze, Odett Kaiser, Gerrit Paasche, Hans Lamm, Andreas Pich, Andrea Hoffmann, Thomas Lenarz, and Athanasia Warnecke
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Medicine ,Science - Abstract
Hyperbaric oxygen therapy (HBOT) is a noninvasive widely applied treatment that increases the oxygen pressure in tissues. In cochlear implant (CI) research, intracochlear application of neurotrophic factors (NTFs) is able to improve survival of spiral ganglion neurons (SGN) after deafness. Cell-based delivery of NTFs such as brain-derived neurotrophic factor (BDNF) may be realized by cell-coating of the surface of the CI electrode. Human mesenchymal stem cells (MSC) secrete a variety of different neurotrophic factors and may be used for the development of a biohybrid electrode in order to release endogenously-derived neuroprotective factors for the protection of residual SGN and for a guided outgrowth of dendrites in the direction of the CI electrode. HBOT could be used to influence cell behaviour after transplantation to the inner ear. The aim of this study was to investigate the effect of HBOT on the proliferation, BDNF-release and secretion of neuroprotective factors. Thus, model cells (an immortalized fibroblast cell line (NIH3T3)-native and genetically modified) and MSCs were repeatedly (3 x - 10 x) exposed to 100% oxygen at different pressures. The effects of HBO on cell proliferation were investigated in relation to normoxic and normobaric conditions (NOR). Moreover, the neuroprotective and neuroregenerative effects of HBO-treated cells were analysed by cultivation of SGN in conditioned medium. Both, the genetically modified NIH3T3/BDNF and native NIH3T3 fibroblasts, showed a highly significant increased proliferation after five days of HBOT in comparison to normoxic controls. By contrast, the number of MSCs was decreased in MSCs treated with 2.0 bar of HBO. Treating SGN cultures with supernatants of fibroblasts and MSCs significantly increased the survival rate of SGN. HBO treatment did not influence (increase / reduce) this effect. Secretome analysis showed that HBO treatment altered the protein expression pattern in MSCs.
- Published
- 2017
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32. Scanning laser optical tomography for in toto imaging of the murine cochlea.
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Lena Nolte, Nadine Tinne, Jennifer Schulze, Dag Heinemann, Georgios C Antonopoulos, Heiko Meyer, Hans Gerd Nothwang, Thomas Lenarz, Alexander Heisterkamp, Athanasia Warnecke, and Tammo Ripken
- Subjects
Medicine ,Science - Abstract
The mammalian cochlea is a complex macroscopic structure due to its helical shape and the microscopic arrangements of the individual layers of cells. To improve the outcomes of hearing restoration in deaf patients, it is important to understand the anatomic structure and composition of the cochlea ex vivo. Hitherto, only one histological technique based on confocal laser scanning microscopy and optical clearing has been developed for in toto optical imaging of the murine cochlea. However, with a growing size of the specimen, e.g., human cochlea, this technique reaches its limitations. Here, we demonstrate scanning laser optical tomography (SLOT) as a valuable imaging technique to visualize the murine cochlea in toto without any physical slicing. This technique can also be applied in larger specimens up to cm3 such as the human cochlea. Furthermore, immunolabeling allows visualization of inner hair cells (otoferlin) or spiral ganglion cells (neurofilament) within the whole cochlea. After image reconstruction, the 3D dataset was used for digital segmentation of the labeled region. As a result, quantitative analysis of position, length and curvature of the labeled region was possible. This is of high interest in order to understand the interaction of cochlear implants (CI) and cells in more detail.
- Published
- 2017
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33. Coatings of Different Carbon Nanotubes on Platinum Electrodes for Neuronal Devices: Preparation, Cytocompatibility and Interaction with Spiral Ganglion Cells.
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Niklas Burblies, Jennifer Schulze, Hans-Christoph Schwarz, Katharina Kranz, Damian Motz, Carla Vogt, Thomas Lenarz, Athanasia Warnecke, and Peter Behrens
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Medicine ,Science - Abstract
Cochlear and deep brain implants are prominent examples for neuronal prostheses with clinical relevance. Current research focuses on the improvement of the long-term functionality and the size reduction of neural interface electrodes. A promising approach is the application of carbon nanotubes (CNTs), either as pure electrodes but especially as coating material for electrodes. The interaction of CNTs with neuronal cells has shown promising results in various studies, but these appear to depend on the specific type of neurons as well as on the kind of nanotubes. To evaluate a potential application of carbon nanotube coatings for cochlear electrodes, it is necessary to investigate the cytocompatibility of carbon nanotube coatings on platinum for the specific type of neuron in the inner ear, namely spiral ganglion neurons. In this study we have combined the chemical processing of as-delivered CNTs, the fabrication of coatings on platinum, and the characterization of the electrical properties of the coatings as well as a general cytocompatibility testing and the first cell culture investigations of CNTs with spiral ganglion neurons. By applying a modification process to three different as-received CNTs via a reflux treatment with nitric acid, long-term stable aqueous CNT dispersions free of dispersing agents were obtained. These were used to coat platinum substrates by an automated spray-coating process. These coatings enhance the electrical properties of platinum electrodes, decreasing the impedance values and raising the capacitances. Cell culture investigations of the different CNT coatings on platinum with NIH3T3 fibroblasts attest an overall good cytocompatibility of these coatings. For spiral ganglion neurons, this can also be observed but a desired positive effect of the CNTs on the neurons is absent. Furthermore, we found that the well-established DAPI staining assay does not function on the coatings prepared from single-wall nanotubes.
- Published
- 2016
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34. Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear.
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Pooyan Aliuos, Jennifer Schulze, Markus Schomaker, Günter Reuter, Stefan R O Stolle, Darja Werner, Tammo Ripken, Thomas Lenarz, and Athanasia Warnecke
- Subjects
Medicine ,Science - Abstract
INTRODUCTION:Long-term drug delivery to the inner ear may be achieved by functionalizing cochlear implant (CI) electrodes with cells providing neuroprotective factors. However, effective strategies in order to coat implant surfaces with cells need to be developed. Our vision is to make benefit of electromagnetic field attracting forces generated by CI electrodes to bind BDNF-secreting cells that are labelled with magnetic beads (MB) onto the electrode surfaces. Thus, the effect of MB-labelling on cell viability and BDNF production were investigated. MATERIALS AND METHODS:Murine NIH 3T3 fibroblasts-genetically modified to produce BDNF-were labelled with MB. RESULTS:Atomic force and bright field microscopy illustrated the internalization of MB by fibroblasts after 24 h of cultivation. Labelling cells with MB did not expose cytotoxic effects on fibroblasts and allowed adhesion on magnetic surfaces with sufficient BDNF release. DISCUSSION:Our data demonstrate a novel approach for mediating enhanced long-term adhesion of BDNF-secreting fibroblasts on model electrode surfaces for cell-based drug delivery applications in vitro and in vivo. This therapeutic strategy, once transferred to cells suitable for clinical application, may allow the biological modifications of CI surfaces with cells releasing neurotrophic or other factors of interest.
- Published
- 2016
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35. Neuronal Survival, Morphology and Outgrowth of Spiral Ganglion Neurons Using a Defined Growth Factor Combination.
- Author
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Jana Schwieger, Athanasia Warnecke, Thomas Lenarz, Karl-Heinz Esser, and Verena Scheper
- Subjects
Medicine ,Science - Abstract
The functionality of cochlear implants (CI) depends, among others, on the number and excitability of surviving spiral ganglion neurons (SGN). The spatial separation between the SGN, located in the bony axis of the inner ear, and the CI, which is inserted in the scala tympani, results in suboptimal performance of CI patients and may be decreased by attracting the SGN neurites towards the electrode contacts. Neurotrophic factors (NTFs) can support neuronal survival and neurite outgrowth.Since brain-derived neurotrophic factor (BDNF) is well known for its neuroprotective effect and ciliary neurotrophic factor (CNTF) increases neurite outgrowth, we evaluated if the combination of BDNF and CNTF leads to an enhanced neuronal survival with extended neurite outgrowth. Both NTFs were added in effective high concentrations (BDNF 50 ng/ml, CNTF 100 ng/ml), alone and in combination, to cultured dissociated SGN of neonatal rats for 48 hours.The neuronal survival and neurite outgrowth were significantly higher in SGN treated with the combination of the two NTFs compared to treatment with each factor alone. Additionally, with respect to the morphology, the combination of BDNF and CNTF leads to a significantly higher number of bipolar neurons and a decreased number of neurons without neurites in culture.The combination of BDNF and CNTF shows a great potential to increase the neuronal survival and the number of bipolar neurons in vitro and to regenerate retracted nerve fibers.
- Published
- 2015
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36. Phosphodiesterase type 4 inhibitor rolipram improves survival of spiral ganglion neurons in vitro.
- Author
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Katharina Kranz, Athanasia Warnecke, Thomas Lenarz, Martin Durisin, and Verena Scheper
- Subjects
Medicine ,Science - Abstract
Sensorineural deafness is caused by damage of hair cells followed by degeneration of the spiral ganglion neurons and can be moderated by cochlear implants. However, the benefit of the cochlear implant depends on the excitability of the spiral ganglion neurons. Therefore, current research focuses on the identification of agents that will preserve their degeneration. In this project we investigated the neuroprotective effect of Rolipram as a promising agent to improve the viability of the auditory neurons. It is a pharmaceutical agent that acts by selective inhibition of the phosphodiesterase 4 leading to an increase in cyclic AMP. Different studies reported a neuroprotective effect of Rolipram. However, its significance for the survival of SGN has not been reported so far. Thus, we isolated spiral ganglion cells of neonatal rats for cultivation with different Rolipram concentrations and determined the neuronal survival rate. Furthermore, we examined immunocytologically distinct proteins that might be involved in the neuroprotective signalling pathway of Rolipram and determined endogenous BDNF by ELISA. When applied at a concentration of 0.1 nM, Rolipram improved the survival of SGN in vitro. According to previous studies, our immunocytological data showed that Rolipram application induces the phosphorylation and thereby activation of the transcription factor CREB. This activation can be mediated by the cAMP-PKA-signalling pathway as well as via ERK as a part of the MAP-kinase pathway. However, only in cultures pre-treated with BDNF, an endogenous increase of BDNF was detected. We conclude that Rolipram has the potential to improve the vitality of neonatal auditory nerve cells in vitro. Further investigations are necessary to prove the effect of Rolipram in vivo in the adult organism after lesion of the hair cells and insertion of cochlear implants.
- Published
- 2014
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37. Dissociated neurons and glial cells derived from rat inferior colliculi after digestion with papain.
- Author
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Odett Kaiser, Pooyan Aliuos, Kirsten Wissel, Thomas Lenarz, Darja Werner, Günter Reuter, Andrej Kral, and Athanasia Warnecke
- Subjects
Medicine ,Science - Abstract
The formation of gliosis around implant electrodes for deep brain stimulation impairs electrode-tissue interaction. Unspecific growth of glial tissue around the electrodes can be hindered by altering physicochemical material properties. However, in vitro screening of neural tissue-material interaction requires an adequate cell culture system. No adequate model for cells dissociated from the inferior colliculus (IC) has been described and was thus the aim of this study. Therefore, IC were isolated from neonatal rats (P3_5) and a dissociated cell culture was established. In screening experiments using four dissociation methods (Neural Tissue Dissociation Kit [NTDK] T, NTDK P; NTDK PN, and a validated protocol for the dissociation of spiral ganglion neurons [SGN]), the optimal media, and seeding densities were identified. Thereafter, a dissociation protocol containing only the proteolytic enzymes of interest (trypsin or papain) was tested. For analysis, cells were fixed and immunolabeled using glial- and neuron-specific antibodies. Adhesion and survival of dissociated neurons and glial cells isolated from the IC were demonstrated in all experimental settings. Hence, preservation of type-specific cytoarchitecture with sufficient neuronal networks only occurred in cultures dissociated with NTDK P, NTDK PN, and fresh prepared papain solution. However, cultures obtained after dissociation with papain, seeded at a density of 2×10(4) cells/well and cultivated with Neuro Medium for 6 days reliably revealed the highest neuronal yield with excellent cytoarchitecture of neurons and glial cells. The herein described dissociated culture can be utilized as in vitro model to screen interactions between cells of the IC and surface modifications of the electrode.
- Published
- 2013
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38. Zungengrundhyperplasie nach Tonsillektomie und Korrelation mit dem BMI
- Author
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Willi Roßberg, Ahmad Dagistani, Dragana Mitovska, Caroline Krüger, Athanasia Warnecke, Thomas Lenarz, and Martin Durisin
- Subjects
Otorhinolaryngology - Abstract
Zusammenfassung Hintergrund Die Hyperplasie der Zungengrundtonsille ist eine seltene und zugleich auch potenziell gefährliche Veränderung im Bereich der oberen Atemwege. Die Pathogenese der Zungengrundhyperplasie (ZGH) ist immer noch weitgehend unbekannt. Im Rahmen dieser Studie wurde der Zusammenhang zwischen Zustand nach Tonsillektomie und kompensatorischer Zungengrundhyperplasie untersucht. Material und Methoden In der HNO-Klinik der Medizinischen Hochschule Hannover wurden 300 Patienten konsekutiv untersucht. Im Rahmen der indirekten Laryngoskopie wurden die Zungengrundtonsille, Einsehbarkeit des Larynx sowie seiner Subregionen nach einem Schema beurteilt. Die Daten wurden anschließend in Abhängigkeit vom Status der Gaumentonsillen ausgewertet. Ergänzend wurde der Body-Mass-Index (BMI) ermittelt und mit Ergebnissen der Laryngoskopie verglichen. Ergebnisse Von den 300 untersuchten Patienten war bei 89 (29,6%) eine Tonsillektomie beidseits durchgeführt worden. In der Gesamtpopulation war eine stark vergrößerte Zungengrundtonsille nur in 14 Fällen (4,6%) nachweisbar. Von diesen 14 wurde bei 4 Patienten in der Vorgeschichte eine Tonsillektomie durchgeführt. Der BMI zeigte bei Patienten mit einer normal großen Zungengrundtonsille einen Wert von 24,4 und bei Patienten mit starker Zungengrundhyperplasie 27,3. Schlussfolgerungen Die Inzidenz der ZGH fällt nach unseren Ergebnissen mit 4,7 % gering aus. Ein Zusammenhang zwischen einem Zustand nach Tonsillektomie und kompensatorischer Zungengrundhyperplasie konnte nicht nachgewiesen werden. Es zeigte sich jedoch ein statistisch signifikanter Zusammenhang zwischen BMI und ZGH.
- Published
- 2022
39. Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC – What Difference Does it Make?
- Author
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Hendrik Eggers, Lea Häbel, Arnold Ganser, Viktor Grünwald, Roland Merten, Athanasia Warnecke, Martin Durisin, and Philipp Ivanyi
- Subjects
Cancer Research ,Oncology ,Medizin ,General Medicine - Abstract
Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8
- Published
- 2022
40. The Augmented Cochlear Implant: a Convergence of Drugs and Cochlear Implantation for the Treatment of Hearing Loss
- Author
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Alexandra Arambula, Christoph Arnoldner, Athanasia Warnecke, and Hinrich Staecker
- Subjects
Otorhinolaryngology ,Immunology and Allergy ,Surgery ,Neurology (clinical) - Published
- 2022
41. CAR-NK Cells Targeting HER1 (EGFR) Show Efficient Anti-Tumor Activity against Head and Neck Squamous Cell Carcinoma (HNSCC)
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Morgan, Juliette Nowak, Marco Bentele, Ivana Kutle, Katharina Zimmermann, Jonathan Lukas Lühmann, Doris Steinemann, Stephan Kloess, Ulrike Koehl, Willi Roßberg, Amed Ahmed, Dirk Schaudien, Lavinia Neubert, Jan-Christopher Kamp, Mark P. Kuehnel, Athanasia Warnecke, Axel Schambach, and Michael
- Subjects
chimeric antigen receptor ,CAR-NK cells ,NK-92 cells ,HER1 ,EGFR ,CD44v6 ,EpCAM ,HNSCC ,head and neck cancer ,immunotherapy - Abstract
(1) Background: HNSCC is a highly heterogeneous and relapse-prone form of cancer. We aimed to expand the immunological tool kit against HNSCC by conducting a functional screen to generate chimeric antigen receptor (CAR)-NK-92 cells that target HER1/epidermal growth factor receptor (EGFR). (2) Methods: Selected CAR-NK-92 cell candidates were tested for enhanced reduction of target cells, CD107a expression and IFNγ secretion in different co-culture models. For representative HNSCC models, patient-derived primary HNSCC (pHNSCC) cell lines were generated by employing an EpCAM-sorting approach to eliminate the high percentage of non-malignant cells found. (3) Results: 2D and 3D spheroid co-culture experiments showed that anti-HER1 CAR-NK-92 cells effectively eliminated SCC cell lines and primary HNSCC (pHNSCC) cells. Co-culture of tumor models with anti-HER1 CAR-NK-92 cells led to enhanced degranulation and IFNγ secretion of NK-92 cells and apoptosis of target cells. Furthermore, remaining pHNSCC cells showed upregulated expression of putative cancer stem cell marker CD44v6. (4) Conclusions: These results highlight the promising potential of CAR-NK cell therapy in HNSCC and the likely necessity to target multiple tumor-associated antigens to reduce currently high relapse rates.
- Published
- 2023
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42. MicroRNA Profiling in the Perilymph of Cochlear Implant Patients: Identifying Markers that Correlate to Audiological Outcomes
- Author
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Helena Wichova, Matthew Shew, Jennifer Nelson-Brantley, Athanasia Warnecke, Sandra Prentiss, and Hinrich Staecker
- Subjects
MicroRNAs ,Speech and Hearing ,Cochlear Implants ,Treatment Outcome ,Speech Perception ,Humans ,Perilymph ,Cochlear Implantation - Abstract
Hypothesis MicroRNA (miRNA) expression profiles from human perilymph correlate to post cochlear implantation (CI) hearing outcomes. Background The high inter-individual variability in speech perception among cochlear implant recipients is still poorly understood. MiRNA expression in perilymph can be used to characterize the molecular processes underlying inner ear disease and to predict performance with a cochlear implant. Methods Perilymph collected during CI from 17 patients was analyzed using microarrays. MiRNAs were identified and multivariable analysis using consonant-nucleus-consonant testing at 6 and 18 months post implant activation was performed. Variables analyzed included age, gender, preoperative pure tone average (PTA), and preoperative speech discrimination (word recognition [WR]). Gene ontology analysis was performed to identify potential functional implications of changes in the identified miRNAs. Results Distinct miRNA profiles correlated to preoperative PTA and WR. Patients classified as poor performers showed downregulation of six miRNAs that potentially regulate pathways related to neuronal function and cell survival. Conclusion Individual miRNA profiles can be identified in microvolumes of perilymph. Distinct non-coding RNA expression profiles correlate to preoperative hearing and postoperative cochlear implant outcomes.
- Published
- 2021
43. Extracellular Vesicles in Inner Ear Therapies-Pathophysiological, Manufacturing, and Clinical Considerations
- Author
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Athanasia Warnecke, Hinrich Staecker, Eva Rohde, Mario Gimona, Anja Giesemann, Agnieszka Szczepek, Arianna Di Stadio, Ingeborg Hochmair, and Thomas Lenarz
- Subjects
General Medicine - Abstract
(1) Background: Sensorineural hearing loss is a common and debilitating condition. To date, comprehensive pharmacologic interventions are not available. The complex and diverse molecular pathology that underlies hearing loss may limit our ability to intervene with small molecules. The current review foccusses on the potential for the use of extracellular vesicles in neurotology. (2) Methods: Narrative literature review. (3) Results: Extracellular vesicles provide an opportunity to modulate a wide range of pathologic and physiologic pathways and can be manufactured under GMP conditions allowing for their application in the human inner ear. The role of inflammation in hearing loss with a focus on cochlear implantation is shown. How extracellular vesicles may provide a therapeutic option for complex inflammatory disorders of the inner ear is discussed. Additionally, manufacturing and regulatory issues that need to be addressed to develop EVs as advanced therapy medicinal product for use in the inner ear are outlined. (4) Conclusion: Given the complexities of inner ear injury, novel therapeutics such as extracellular vesicles could provide a means to modulate inflammation, stress pathways and apoptosis in the inner ear.
- Published
- 2022
44. Cochlear Implantation in Obliterated Cochlea: A Retrospective Analysis and Comparison between the IES Stiff Custom-Made Device and the Split-Array and Regular Electrodes
- Author
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Julia Anna Christine Hoffmann, Athanasia Warnecke, Max Eike Timm, Eugen Kludt, Nils Kristian Prenzler, Lutz Gärtner, Thomas Lenarz, and Rolf Benedikt Salcher
- Subjects
inner ear ,cochlear implant ,obliteration of the inner ear ,ossification ,fibrous tissue growth ,electrode impedance ,insertion probe ,General Medicine - Abstract
Anatomical malformations, obliterations of the cochlea, or re-implantations pose particular challenges in cochlear implantation. Treatment methods rely on radiological and intraoperative findings and include incomplete insertion, the implantation of a double array, and radical cochleostomy. In addition, a stiff electrode array, e.g., the IE stiff (IES) custom-made device (CMD, MED-EL), was prescribed individually for those special cases and pre-inserted prior to facilitate cochlear implantation in challenging cases. Data on outcomes after implantation in obliterated cochleae are usually based on individual case reports since standardised procedures are lacking. A retrospective analysis was conducted to analyse our cases on obliterated cochleae treated with MED-EL devices in order to allow the different cases to be compared. Impedances and speech perception data of patients treated with the IES CMD and the double array were retrospectively compared to patients treated with a STANDARD or FLEX electrode array (the REGULAR group). Patients with a Split-Array CMD had a poor speech perception when compared to patients treated with the IES CMD device. Thus, the IES CMD can successfully be used in patients with obliterated cochleae who would otherwise be non-users, candidates for a Split-Array CMD, or candidates for partial insertion with insufficient cochlear coverage.
- Published
- 2022
45. Humangenetische Untersuchungen bei Schwerhörigen in der HNO Klinik – notwendige Routine?
- Author
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Anke Lesinski-Schiedat, Athanasia Warnecke, Andreas Büchner, Thomas Lenarz, and Christian Landgraf
- Published
- 2022
46. Activation of intracellular signalling pathways by mesenchymal stromal cells protect against noise-induced hearing loss
- Author
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Athanasia Warnecke, Jennifer Harre, Matthew Shew, AdamJ Mellott, Igor Majewski, Martin Durisin, and Hinrich Staecker
- Published
- 2022
47. Incidence and impact of cavitary otosclerosis in CI-treated patients
- Author
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Melanie Steffens, Gülan Demir, Anja Giesemann, Thomas Lenarz, Martin Durisin, and Athanasia Warnecke
- Published
- 2022
48. Possibilities of Molecular Perilymph Diagnostics in Patients with Cochlea Implant Surgeries
- Author
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Heike Schmitt, Andreas Pich, Karsten Hiller, Tushar More, Athanasia Warnecke, Martin Durisin, and Thomas Lenarz
- Published
- 2022
49. Effects of clinically used corticosteroids on the survival and neurite length of spiral ganglion neurons in vitro
- Author
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Jennifer Harre, JanicL. Nickel, Athanasia Warnecke, Thomas Lenarz, and Odett Kaiser
- Published
- 2022
50. Inzidenz und Auswirkung der kavitären Otosklerose bei CI versorgten Patienten
- Author
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Melanie Steffens, Gülan Demir, Anja Giesemann, Thomas Lenarz, Martin Durisin, and Athanasia Warnecke
- Published
- 2022
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