In vitro impact of platinum nanoparticles on inner ear related cell culture models.

So far, it was supposed that the increase of electrical impedance following cochlear implant (CI) insertion was due to technical defects of the electrode, inflammatory and/or formation of scar tissue along the electrode. However, it was recently reported that corrosion of the platinum electrode contacts may be the reason for high impedances. It could be shown that platinum particles were stripped from the electrode surfaces. Its potential cytotoxic effects within the inner ear remains to be examined. In this study in vitro cell culture models of the mouse organ of Corti cell line (HEI-OC1) and the spiral ganglion (SG) cells derived from the cochleae neonatal rats were used to investigate the effects of the polyvinylpyrrolidone coated platinum nanoparticles (Pt-NPPVP, 3 nm) on cell metabolism, neuronal survival and neurite outgrowth. Our data revealed no decrease of the metabolic activity of the HEI-OC1 cells at Pt-NPPVP concentrations between 50-150 µg/ml. Also, staining with Calcein AM/EthD demonstrated prevalent presence of vital cells. As shown by transmission electron microscopy no Pt-NPPVP could be found at the cell surface or in the cytosol of the HEI-OC1 cells. Similarly, the SG cells exposed to 20-100 µg/ml Pt-NPPVP did not show any reduced survival rate and neurite outgrowth following staining of the neurofilament antigen even at the highest Pt-NPPVP concentration. Although the SG cells were exposed to Pt-NPPVP for further 72 h and 96 h immunocytochemical staining of the glial cells and fibroblasts presented normal cell morphology and growth independently of the cultivation period. Our data indicates that the used Pt-NPPVP do not trigger the cellular uptake and, thus, presumable do not initiate apoptotic pathways in cells of the organ of Corti cell line or the auditory nerve. The protection mechanisms to the Pt-NPPVP interactions remain to be clarified.

[Hypertrophy of lingual tonsil following tonsillectomy and correlation with BMI]. / Zungengrundhyperplasie nach Tonsillektomie und Korrelation mit dem BMI.

OBJECTIVE: The hyperplasia of the lingual tonsil is a rare and at the same time potentially dangerous change in the area of the upper respiratory tract. The pathogenesis of the lingual tonsillar hyperplasia is still largely unknown. In this study, we investigated if there is a compensatory lingual tonsil hyperplasia after tonsillectomy. MATERIAL AND METHODS: 300 patients were examined consecutively in the ENT clinic of the Hannover Medical School. In the context of indirect laryngoscopy, the lingual tonsil, the visibility of the larynx and its subregions were assessed according to a scheme. The data were then evaluated depending on the status of the palatal tonsils. In addition, the body mass index (BMI) was determined and compared with the results of laryngoscopy. RESULTS: Out of 300 patients, 89 (29.6%) were in condition after bilateral tonsillectomy. In the total population, a greatly enlarged lingual tonsil was only detectable in 14 cases (4.6%). Of these 14 patients, 4 had a history of tonsillectomy. In patients with severe lingual tonsil hyperplasia the mean BMI was 27.3 compared to 24.4 in patients with a normal lingual tonsil. CONCLUSION: In our population the incidence of severe lingual tonsil hyperplasia is 4.7%. We couldn't prove s a connection between a condition after tonsillectomy and compensatory lingual hyperplasia statistically. However, there was a significant relationship between BMI and lingual tonsil hyperplasia.

Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC - What Difference Does it Make?

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, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.

Bioinformatic Analysis of the Perilymph Proteome to Generate a Human Protein Atlas.

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.

Moderately Hypofractionated Radiotherapy Without Chemotherapy in Elderly or Frail Patients With Head and Neck Cancer.

BACKGROUND: Comorbidity and frailty are relevant limitations of normofractionated combined radiochemotherapy for squamous cell head and neck cancer (HNSCC), especially in elderly patients. This retrospective study aimed to evaluate the efficacy and toxicity of moderately hypofractionated radiotherapy (HRT) without chemotherapy in patients ineligible for concurrent radiochemotherapy. PATIENTS AND METHODS: Between 2011 and 2018, 51 elderly/frail patients with HNSCC were treated with either definitive (n=23) or adjuvant (n=28) moderate HRT. A dose of 45 Gy was given to the primary tumour region and cervical nodes with a sequential boost up to 50 in the adjuvant and 55 Gy in the definitive cure setting (2.5 Gy/fraction). Patient outcomes of locoregional control, overall survival, and acute and late toxicity were analysed. RESULTS: After a median follow-up of 6 months for the definitive HRT group and 28.5 months for the adjuvant HRT group, we found a median overall survival of 6 vs. 55 months (log-rank test: p<0.001) and a median locoregional control of 9 months vs. not reached (log-rank test: p=0.008), respectively. The 2-year rates of locoregional control were 28.5% for the definitive HRT group vs. 75.2% for the adjuvant HRT group. No acute or late grade 4-5 toxicity occurred; grade 3 toxicity was rarely documented. CONCLUSION: HRT in elderly/frail patients with HNSCC who are unfit for chemotherapy leads to acceptable local control with moderate toxicity in a short overall treatment time. Especially in the postoperative situation, HRT can be considered an appropriate alternative to normofractionated radio(chemo)therapy. Definitive HRT can be a treatment alternative, especially for multimorbid patients.

Proteome profile of patients with excellent and poor speech intelligibility after cochlear implantation: Can perilymph proteins predict performance?

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.

Successful Treatment of Noise-Induced Hearing Loss by Mesenchymal Stromal Cells: An RNAseq Analysis of Protective/Repair Pathways.

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.

Personalized Proteomics for Precision Diagnostics in Hearing Loss: Disease-Specific Analysis of Human Perilymph by Mass Spectrometry.

Despite a vast amount of data generated by proteomic analysis on cochlear fluid, novel clinically applicable biomarkers of inner ear diseases have not been identified hitherto. The aim of the present study was to analyze the proteome of human perilymph from cochlear implant patients, thereby identifying putative changes of the composition of the cochlear fluid perilymph due to specific diseases. Sampling of human perilymph was performed during cochlear implantation from patients with clinically or radiologically defined inner ear diseases like enlarged vestibular aqueduct (EVA; n = 14), otosclerosis (n = 10), and Ménière's disease (n = 12). Individual proteins were identified by a shotgun proteomics approach and data-dependent acquisition, thereby revealing 895 different proteins in all samples. Based on quantification values, a disease-specific protein distribution in the perilymph was demonstrated. The proteins short-chain dehydrogenase/reductase family 9C member 7 and esterase D were detected in nearly all samples of Ménière's disease patients, but not in samples of patients suffering from EVA and otosclerosis. The presence of both proteins in the inner ear tissue of adult mice and neonatal rats was validated by immunohistochemistry. Whether these proteins have the potential for a biomarker in the perilymph of Ménière's disease patients remains to be elucidated.

Moderately Hypofractionated Intensity-modulated Radiotherapy With a Simultaneous Integrated Boost for Locally Advanced Head and Neck Cancer - Do Modern Techniques Fulfil Their Promise?

BACKGROUND: Intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) and moderate hypofractionation offers an opportunity for defining individual doses and a reduction in overall treatment time in locally advanced head and neck cancer (HNSCC). We present retrospective data on toxicity and locoregional control of a patient cohort treated with an IMRT-SIB concept in comparison to normo-fractionated 3D-conformal radiotherapy (3D-RT). PATIENTS AND METHODS: Between 2012 and 2014, 67 patients with HNSCC (stages III-IVB) were treated with IMRT-SIB either definitively or in the postoperative setting. These patients were matched with those of patients treated with normo-fractionated 3D-RT before mid-2012 and their clinical courses were compared. Chemotherapy or cetuximab was given concomitantly in both groups in the definitive situation (postoperatively, dependent on risk factors). RESULTS: Significantly less toxicity was found in favor of IMRT-SIB concerning dysphagia, dermatitis, xerostomia, fibrosis, and lymphedema. After a median follow-up of 31 months (range=2-104 months), 3-year locoregional control was 73% for those treated with IMRT-SIB versus 78% for those treated with 3D-RT. CONCLUSION: This moderately hypofractionated IMRT-SIB concept was shown to be feasible, incurring less toxicity than conventional 3D-RT.

Auditory performance in a group of elderly patients after cochlear implantation.

PURPOSE: The retrospective case review investigated the effect of cochlear implantation in subjects aged 61 years or older with respect to their auditory performance. The study also analysed the effect of age on the performance, and it drew a comparison between the outcomes of older and younger adults. METHODS: The outcome in a group of 446 patients aged 61 to 89 years at the time of unilateral cochlear implantation was compared with the outcome in a group of 110 patients aged 17 to 42 years. Auditory performance was measured with open-set monosyllabic word testing and sentences in quiet and in noise. RESULTS: In the monosyllabic word recognition test, the group of older adults performed significantly better after cochlear implantation compared with their scores prior to implantation (p < 0.001; r = 0.59). Their auditory performance correlated negatively with their age. However, the correlation was of small strength. Significant differences in auditory performance were detected between sexagenarians and octogenarians (p < 0.001; r = 0.27). Additionally, a statistically significant difference was revealed between the groups of older and younger adults in the monosyllabic word test (p = 0.001; r = 0.15). CONCLUSION: Elderly cochlear implant recipients can benefit significantly from cochlear implantation. Although higher age correlates negatively with auditory performance, its influence in the presented sample is small.

Endogenous α1-antitrypsin levels in the perilymphatic fluid correlates with severity of hearing loss.

OBJECTIVES: To determine the levels of endogenous α1-antitrypsin in the perilymph of patients undergoing cochlear implant (CI), and its reverse association with the severity of hearing loss. STUDY DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study includes 38 patients undergoing CI surgery, 11 patients diagnosed with congenital deafness and 27 non-congenital deafness, eight patients diagnosed with moderate hearing loss (N = 8; PTA = 70 dB), severe hearing loss (N = 11; PTA 70-90 dB) and profound hearing loss (N = 19; PTA > 90 dB). MAIN OUTCOME AND MEASURE: 1 to 12 µL perilymphatic fluids were collected by micropipette. α1-antitrypsin levels were determined, and current and historic audiological parameters were obtained. RESULTS: The congenital and non-congenital group exhibited AAT concentrations of 2.5 ± 1.9 × 106 LFQ and 3.2 ± 1.2 × 106 LFQ, respectively (mean ± SD; P = .38). Mean levels of α1-antitrypsin in the perilymph fluid within the moderate group was 3.64 × 106  ± 2.1 × 106 LFQ vs 3.5 × 106  ± 1.2 × 106 in severe hearing loss (P = .81) and 2.4 × 106  ± 1.1 × 106 LFQ in the profound hearings loss group (P = .06). The difference in levels of AAT in samples from the severe hearings loss group vs the profound hearings loss group reached statistical significance (P = .04). CONCLUSION: Insufficiency in α1-antitrypsin levels in the perilymph fluid of the inner ear appears to display a relationship with the severity of hearing loss. The prospect of introducing clinical-grade plasma-purified α1-antitrypsin directly onto the site of cochlear injury deserves thorough investigation.

Computed Tomography Versus Dacryocystography for the Evaluation of the Nasolacrimal Duct-A Study With 72 Patients.

OBJECTIVES: In patients with epiphora, imaging of the nasolacrimal duct is essential not only for differential diagnosis, but also for preoperative planning. Advances in imaging technology and introduction of cone beam computed tomography (CB-CT) enable the combination of contrast agent-based imaging with a three dimensional tomography with low radiation exposure. However, the value of CT/CB-CT as an alternative to conventional dynamic dacryocystography (DCG) has not been evaluated yet. STUDY DESIGN: Retrospective study. METHODS: Conventional DCG was performed preoperatively in 72 consecutive patients treated for epiphora between 01/2013 and 04/2015 in our department. CB-CT or conventional CT was performed afterward with the contrast media still in place. Three separate experts (two radiologists and one otorhinolaryngologist) analyzed the radiographic images without any information about the respective clinical or surgical findings. The presence of further findings in the CT/CB-CT (eg, septal deviation, sinusitis) that were not detected in DCG and the overall visibility of the lacrimal duct system in both modalities were evaluated. RESULTS: Good delineations of bone, soft tissue, and contrast agent in the lacrimal system were achieved with both methods. No side effects were noted. Beside the pathology of the lacrimal duct, CT/CB-CT scans enabled the additional diagnosis of pathologies in the nose and the sinus system in 65.7% of the patients. Accordance in the identified level of obstruction between the two modalities was achieved in 71.4% of the patients. CONCLUSION: Thus, CT/CB-CT should be used in conjunction with contrast agent to reliably identify the level of obstruction as preoperative standard and can be used as diagnostic tool in addition to or even instead of conventional DCG. LEVEL OF EVIDENCE: 4.

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss.

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.

Cochlear implantation in children with meningitis related deafness: The influence of electrode impedance and implant charge on auditory performance - A case control study.

OBJECTIVES: Bacterial meningitis can cause a labyrinthitis. Consequences often are intracochlear soft tissue neoformation (cochlear obliteration) or intracochlear osteoneogenesis (cochlear ossification) and deafness. Cochlear implantation becomes challenging and hearing rehabilitation is complicated. This retrospective case-control-study aimed to find correlations between morphologic, electric and functional parameters. METHODS: The study group included children, who lost hearing due to a bacterial meningitis (n = 35 cases). Using preoperative computed tomography and intraoperative findings we grouped into 'unaltered cochleae', 'obliterated cochleae' and 'ossified cochleae'. Control group children suffered from deafness (n = 16) of other aetiology and presented with radiologically unchanged cochleae. Postoperative routine controls documented impedances, stimulation charge and hearing tests a various time points, which all were analysed. RESULTS: Control group patients showed a mean impedance of 6.3 kΩ and the mean charge applied was 19 nC. The study group averaged at 7.9 kΩ and 24.6 nC respectively. Patients with ossified cochleae had increased values of 8.6 kΩ and 29.7 nC. The control group reached a monosyllabic word understanding of 74% and the study group of 58%. Patients with ossified cochleae reached 36%. CONCLUSIONS: Impedances and stimulation charge influence each other. Increased charge is necessary for higher cochlear implant output. Despite higher charges, patients with obliterated and patients with ossified cochleae significantly perform worse in hearing rehabilitation. Reduced audiological outcome in study group patients without morphologic cochlear changes furthermore hints at additional factors besides cochlear tissue neogenesis like postinflammational changes at the neural pathway.

Microenvironmental support for cell delivery to the inner ear.

Transplantation of mesenchymal stromal cells (MSC) presents a promising approach not only for the replacement of lost or degenerated cells in diseased organs but also for local drug delivery. It can potentially be used to enhance the safety and efficacy of inner ear surgeries such as cochlear implantation. Options for enhancing the effects of MSC therapy include modulating cell behaviour with customized bio-matrixes or modulating their behaviour by ex vivo transfection of the cells with a variety of genes. In this study, we demonstrate that MSC delivered to the inner ear of guinea pigs or to decellularized cochleae preferentially bind to areas of high heparin concentration. This presents an opportunity for modulating cell behaviour ex vivo. We evaluated the effect of carboxymethylglucose sulfate (Cacicol®), a heparan sulfate analogue on spiral ganglion cells and MSC and demonstrated support of neuronal survival and support of stem cell proliferation.

Platinum corrosion products from electrode contacts of human cochlear implants induce cell death in cell culture models.

Despite the technological progress made with cochlear implants (CI), impedances and their diagnosis remain a focus of interest. Increases in impedance have been related to technical defects of the electrode as well as inflammatory and/or fibrosis along the electrode. Recent studies have demonstrated highly increased impedances as the result of corroded platinum (Pt) electrode contacts. This in vitro study examined the effects of Pt ions and compounds generated by corrosion of the electrode contacts of a human CI on cell metabolism. Since traces of solid Pt in surrounding cochlear tissues have been reported, the impact of commercially available Pt nanoparticles (Pt-NP, size 3 nm) on the cell culture model was also determined. For this purpose, the electrode contacts were electrically stimulated in a 0.5% aqueous NaCl solution for four weeks and the mass fraction of the platinum dissolute (Pt-Diss) was determined by mass spectrometry (ICP-MS). Metabolic activity of the murine fibroblasts (NIH 3T3) and the human neuroblastoma (SH-SY5Y) cells was determined using the WST-1 assay following exposure to Pt-Diss and Pt-NP. It was found that 5-50 µg/ml of the Pt-NP did not affect the viability of both cell types. In contrast, 100 µg/ml of the nanoparticles caused significant loss in metabolic activity. Furthermore, transmission electron microscopy (TEM) revealed mitochondrial swelling in both cell types indicating cytotoxicity. Additionally, TEM demonstrated internalized Pt-NP in NIH 3T3 cells in a concentration dependent manner, whereas endocytosis in SH-SY5Y cells was virtually absent. In comparison with the Pt-NP, the corrosion products (Pt-Diss) with concentrations between 1.64 µg/ml and 8.2 µg/ml induced cell death in both cell lines in a concentration dependent manner. TEM imaging revealed both mitochondrial disintegration and swelling of the endoplasmic reticulum, suggesting that Pt ions trigger cytotoxicity in both NIH 3T3 and SH-SY5Y cell lines by interacting with the respiratory chain.

Feasibility of 15O-water PET studies of auditory system activation during general anesthesia in children.

BACKGROUND: 15O-Water positron emission tomography (PET) enables functional imaging of the auditory system during stimulation via a promontory electrode or cochlear implant, which is not possible using functional magnetic resonance imaging (fMRI). Although PET has been introduced in this context decades ago, its feasibility when performed during general anesthesia has not yet been explored. However, due to a shift to earlier (and bilateral) auditory implantation, the need to study children during general anesthesia appeared, since they are not able to cooperate during scanning. Therefore, we evaluated retrospectively results of individual SPM (statistical parametric mapping) analysis of 15O-water PET in 17 children studied during general anesthesia and compared them to those in 9 adults studied while awake. Specifically, the influence of scan duration, smoothing filter kernel employed during preprocessing, and cut-off value used for statistical inferences were evaluated. Frequencies, peak heights, and extents of activations in auditory and extra-auditory brain regions (AR and eAR) were registered. RESULTS: It was possible to demonstrate activations in auditory brain regions during general anesthesia; however, the frequency and markedness of positive findings were dependent on some of the abovementioned influence factors. Scan duration (60 vs. 90 s) had no significant influence on peak height of auditory cortex activations. To achieve a similar frequency and extent of AR activations during general anesthesia compared to waking state, a lower cut-off for statistical inferences (p < 0.05 or p < 0.01 vs. p < 0.001) had to be applied. However, this lower cut-off was frequently associated with unexpected, "artificial" activations in eAR. These activations in eAR could be slightly reduced by the use of a stronger smoothing filter kernel during preprocessing of the data (e.g., [30 mm]3). CONCLUSIONS: Our data indicate that it is feasible to detect auditory cortex activations in 15O-water PET during general anesthesia. Combined with the improved signal to noise ratios of modern PET scanners, this suggests reasonable prospects for further evaluation of the method for clinical use in auditory implant users. Adapted parameters for data analysis seem to be helpful to improve the proportion of signals in AR versus eAR.

Heat Shock Proteins in Human Perilymph: Implications for Cochlear Implantation.

OBJECTIVE: Biomarkers reflecting the etiology and pathophysiology of inner ear diseases are limited. Evaluation of proteins in the perilymph may improve our understanding of inner ear disease. Heat shock proteins (HSP) belong to a superfamily of stress proteins and promote refolding of denatured proteins. The aim of the study was to analyze HSP in human perilymph and to identify possible correlation with audiological and etiologic data. METHODS: Sampling of the perilymph was performed during cochlear implantation and vestibular schwannoma removal. Individual proteins were identified by a shot-gun proteomics approach by orbitrap mass spectrometry. Expression of HSP genes was determined in human cochlear tissue that was obtained during transcochlear surgeries. RESULTS: Ten subgroups of HSP were identified in human perilymph samples. Increased levels of HSP were detected in a higher percentage in the perilymph of patients with residual hearing when compared with patients with no residual hearing in cochlear implantation. In patients with complete preservation of residual hearing, HSP 90 is identified in a lower percentage whereas HSP 70 1A/1B and 6 was identified in all the samples. Constitutive expression of HSP family members was verified in normal cochlear tissue. CONCLUSION: The 10 HSP variants are not identified in all the perilymph samples, but in a higher proportion in patients with residual hearing compared with patients with no residual hearing. In-depth proteome analysis of perilymph samples in correlation to patients' audiogram data shows an increased concentration of HSP in patients with residual hearing. An increase in specific HSP in patients with loss of residual hearing after cochlear implantation was not observed.

Human Plasma Rich in Growth Factors Improves Survival and Neurite Outgrowth of Spiral Ganglion Neurons In Vitro.

BACKGROUND: Platelet-rich and platelet-poor plasma (PRP and PPP) are autologous preparations from peripheral blood and contain several growth factors and cytokines involved in tissue repair. Although their neuroprotective and neuroregenerative properties have been already described, little is known about their effects in the inner ear. We, therefore, examined the effects of PRP and PPP on spiral ganglion neurons (SGN) in vitro. RESULTS: For all experiments, spiral ganglia were isolated from neonatal rats and were cultured in serum-free medium. PRP from human venous blood was added to dissociated SGN. Treatment with PRP (1:10, 1:50) significantly increased the neuronal survival and the neuronal outgrowth of SGN. This effect was completely reversed by the addition of Bay 11 (nuclear factor kappa B-inhibitor) and SB203580 (p38 mitogen-activated protein kinase [p38MAPK]-inhibitor). Furthermore, PPP was used as a cell-free matrix for the attachment of spiral ganglion explants. Coating with activated PPP improved the adhesion and neurite outgrowth of spiral ganglia explants. Therefore, activated PPP is a promising alternative for poly d/l-ornithine and laminin coating due to the gelatinous composition through the activation of PPP with calcium gluconate. PRP promotes neuroprotective and neuroregenerative effects on SGN when administered in adequate concentrations. These beneficial effects seem to be depending on NF-κB and the p38MAPK pathways. CONCLUSION: Preparations from autologous whole blood (PRP and PPP, respectively) present an interesting alternative for pharmacological intervention to the inner ear since they contain a balanced and natural composition of trophic factors.