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Information about the endonasal endoscopic approach (EEA) for the management of posttraumatic tension pneumocephalus (PTTP) remains scarce. Concomitant rhinoliquorrhea and posttraumatic hydrocephalus (PTH) can complicate the clinical course.The authors systematically reviewed pertinent articles published between 1961 and December 2020 and identified 6 patients with PTTP treated by EEA in 5 reports. Additionally, the authors share their institutional experience including a seventh patient, where an EEA resolved a recurrent PTTP without rhinoliquorrhea.Seven PTTP cases in which EEA was used as part of the treatment regime were included in this review. All cases presented with a defect in the anterior skull base, and 3 of them had concomitant rhinoliquorrhea. A transcranial approach was performed in 6/7 cases before EEA was considered to treat PTTP. In 4/7 cases, the PTTP resolved after the first intent; in 2/ 7 cases a second repair was necessary because of recurrent PTTP, 1 with and 1 without rhinoliquorrhea, and 1/7 case because of recurrent rhinoliquorrhea only. Overall, PTTP treated by EEA resolved with a mean radiological resolution time of 69 days (range 23-150 days), with no late recurrences. Only 1 patient developed a cerebrospinal fluid diversion infection probably related to a first incomplete EEA skull base defects repair. A permanent cerebrospinal fluid diversion was necessary in 3/7 cases.Endonasal endoscopic approach repair of air conduits is a safe and efficacious second-line approach after failed transcranial approaches for symptomatic PTTP. However, the strength of recommendation for EEA remains low until further evidence is presented.

Introduction: Sniffin’ Stick test is a quantitative olfactory test first introduced in the 1990s and has since been used in several countries after cultural-based modifications. Objective: To develop a culturally adapted Sniffin’ Stick test suitable for a Malaysian population. Methods: The study was done in 3 phases. The first phase involved a questionnaire rating the familiarity of 70 odors based on a Likert scale. Sixteen items were then selected for the second phase where subjects were tested on the identification of the 16 odors. Odors recognized by less than 75% of the subjects or their distractors were replaced. These steps were repeated until all 16 odors were recognized by more than 75% of the subjects. In the final phase, the mean Odor Identification (OI) scores utilizing the newly selected 16 odors were collected among healthy individuals. Results: A total of 417 subjects participated in the study. In the first-phase, 5 odors from the original Sniffin’ Stick Test which were unfamiliar were replaced for the phase 2 of the study. In the second-phase, modifications were performed 3 times requiring change of 41 distractors and an additional odor. Finally, using the modified Sniffin Stick test version-4, preliminary results of the mean odor identification scoring for the age groups 16-35,36-55 and more than 55 years of age were obtained which showed age-related variations. Conclusion: Our study revealed cultural modifications to the original Sniffin’ Stick Test are required to validate its use in a Malaysian population.

Acid-base homeostasis is critical for normal growth, development, and hearing function. The sodium–hydrogen exchanger 6 (NHE6), a protein mainly expressed in early and recycling endosomes, plays an important role in regulating organellar pH. Mutations in NHE6 cause complex, slowly progressive neurodegeneration. Little is known about NHE6 function in the mouse cochlea. Here, we found that all NHE isoforms were expressed in wild-type (WT) mouse cochlea. Nhe6 knockout (KO) mice showed significant hearing loss compared to WT littermates. Immunohistochemistry in WT mouse cochlea showed that Nhe6 was localized in the organ of Corti (OC), spiral ganglion (SG), stria vascularis (SV), and afferent nerve fibres. The middle and the inner ears of WT and Nhe6 KO mice were not different morphologically. Given the putative role of NHE6 in early endosomal function, we examined Rab GTPase expression in early and late endosomes. We found no change in Rab5, significantly lower Rab7, and higher Rab11 levels in the Nhe6 KO OC, compared to WT littermates. Because Rabs mediate TrkB endosomal signalling, we evaluated TrkB phosphorylation in the OCs of both strains. Nhe6 KO mice showed significant reductions in TrkB and Akt phosphorylation in the OC. In addition, we examined genes used as markers of SG type I (Slc17a7, Calb1, Pou4f1, Cal2) and type II neurons (Prph, Plk5, Cacna1g). We found that all marker gene expression levels were significantly elevated in the SG of Nhe6 KO mice, compared to WT littermates. Anti-neurofilament factor staining showed axon loss in the cochlear nerves of Nhe6 KO mice compared to WT mice. These findings indicated that BDNF/TrkB signalling was disrupted in the OC of Nhe6 KO mice, probably due to TrkB reduction, caused by over acidification in the absence of NHE6. Thus, our findings demonstrated that NHEs play important roles in normal hearing in the mammalian cochlea.

The challenging surgical field of endoscopic skull base surgery has undergone tremendous advancement in the past years. The aim of this review was to discuss the important factors that contributed to the evolution of this exciting field. Endoscopic skull base surgery started with pituitary surgeries and closure of cerebrospinal fluid (CSF) leaks. As the field progresses, it is now possible to operate on selected lesions located in areas ranging from the cribriform plate down to the second cervical vertebra and laterally to the infratemporal fossa and petrous apex. The key factors that contributed to the evolution of endoscopic intracranial surgeries include the development of modern endoscopy equipment, advancement of endoscopic anatomy knowledge, and improvement in skills to perform endoscopic surgical resection, reconstruction, and hemostasis. Extended endonasal approaches can provide skull base surgeons with safe and effective access to the anterior, middle, and posterior cranial fossae in selected cases.

The efficiency of training visual attention in the central and peripheral visual field was investigated by means of a visual detection task that was performed in a naturalistic visual environment including numerous, time-varying visual distractors. We investigated the minimum number of repetitions of the training required to obtain the top performance and whether intra-day training improved performance as efficiently as inter-day training. Additionally, our research aimed to find out whether exposure to a demanding task such as a microsurgical intervention may cancel out the effects of training. Results showed that performance in visual attention peaked within three (for tasks in the central visual field) to seven (for tasks in the periphery) days subsequent to training. Intra-day training had no significant effect on performance. When attention training was administered after exposure to stress, improvement of attentional performance was more pronounced than when training was completed before the exposure. Our findings support the implementation of training in situ at work for more efficient results. Practitioner Summary: Visual attention is important in an increasing number of workplaces, such as with surveillance, inspection, or driving. This study shows that it is possible to train visual attention efficiently within three to seven days. Because our study was executed in a naturalistic environment, training results are more likely to reflect the effects in the real workplace.

Objective To share our experience with a new delivery system for the flowable hemostatic matrix, FloSeal, in endoscopic and microscopic skull base surgery. Methods We prospectively analyzed the use of FloSeal with a hemostatic delivery system in transnasal endoscopic and microscopic skull base procedures performed at the authors' institution from January 1, 2015, to June 30, 2015. In all cases the number of aliquots was noted for the entire operation, and the total number of FloSeal ampules of 5 mL was also recorded. Results Our device allowed controlled application of small amounts (0.5–1 mL) of FloSeal to the site of bleeding. This controlled application resulted not only in increased visibility during its application, but it also reduced the amount of FloSeal required during the procedure. We were able to use 5–10 applications per 5-mL ampule of FloSeal within an individual procedure. No procedure required more than one 5-mL ampule of FloSeal. Therefore, the use of our device results in a reduction of costs. Prior to the use of our device, we were often only able to use 1 vial of 5 ml of material for 1 or 2 applications, especially in transnasal endoscopic procedures when working along a deep corridor. Conclusions Our results indicate that our delivery device of FlowSeal can effectively control hemostasis by applying small amounts of FlowSeal to the site of bleeding. This results in increased visibility during hemostasis and a reduction of cost.

Zusammenfassung: Menschen mit einer Hörminderung sind im klinischen Alltag häufig. Sowohl Kinder als auch Erwachsene können von einer Hörminderung betroffen sein. Unabhängig vom Alter hat eine Hörstörung einen entscheidenden Einfluss auf die Lebensqualität eines Menschen. Glücklicherweise stehen zahlreiche Möglichkeiten einer apparativen und operativen Rehabilitation des Hörvermögens zu Verfügung. Ziel dieser Arbeit ist es, die häufigsten Rehabilitationsmassnahmen für das Gehör vorzustellen. Diese umfassen rein apparative Massnahmen, wie ein konventionelles Hörgerät. Oder aber sie beschreiben rein operative Massnahmen wie zum Beispiel das Einsetzen einer passiven Prothese bei der Verknöcherung des Stapes an der Fussplatte infolge einer Otosklerose. Des Weiteren gibt es Rehabilitatonsmöglichkeiten bei welchen eine Operation mit einer apparativen Massnahme kombiniert wird. Dies ist der Fall bei einem knochenverankertem Hörgerät, einem aktiven Mittelohrimplantat oder bei einem Cochlea Implantat. Der Schwerpunkt dieses Artikels liegt in der Darstellung von exemplarischen klinischen Beispielen der diskutierten Gehörrehabilitation.

Background Data on the endonasal endoscopic approach (EEA) to treat sellar/parasellar synchronous tumors remain sparse. This work aims to describe a minimally invasive approach with intraoperative magnetic resonance imaging (MRI) to remove a large sellar/parasellar synchronous tumor, and presents a systematic literature review. Methods The preoperative MRI of a 54-year-old woman revealed a sellar lesion (28 × 19 × 16 mm), presumably a pituitary macroadenoma, and a second extra-axial lesion (22 × 36 × 20 mm) expanding from the tuberculum sellae to the planum sphenoidale with encasement of the anterior communicating complex, presumably a meningioma. We used intraoperative MRI to assess the extent of the resection before reconstructing the large skull base defect. Furthermore, we systematically reviewed pertinent articles retrieved by a PubMed/Embase database search between 1961 and December 2018. Results Out of 63 patients with synchronous tumors reported in 43 publications, we found 3 patients in which the tumor was removed by EEA. In these 3 patients and the presented case, the resection of both lesions was successful, without major approach-related morbidity or mortality. More extensive removal of endonasal structures to gain an adequate tumor exposure was not necessary. We did not find any previous reports describing the benefits of intraoperative MRI in the presented setting. Conclusions In the rare case of a synchronous meningioma and pituitary adenoma of the sellar region, intraoperative MRI might be beneficial in confirming residual disease before skull base reconstruction, and therefore radiologic follow-up.

Exosomes are nanovesicles involved in intercellular communications. They are released by a variety of cell types; however, their presence in the inner ear has not been described in the literature. The aims of this study were to determine if exosomes are present in the inner ear and, if present, characterize the changes in their protein content in response to ototoxic stress. In this laboratory investigation, inner ear explants of 5-day-old Wistar rats were cultured and treated with either cisplatin or gentamicin. Hair cell damage was assessed by confocal microscopy. Exosomes were isolated using ExoQuick, serial centrifugation, and mini-column methods. Confirmation and characterization of exosomes was carried out using transmission electron microscopy (TEM), ZetaView, BCA protein analysis, and proteomics. Vesicles with a typical size distribution for exosomes were observed using TEM and ZetaView. Proteomic analysis detected typical exosome markers and markers for the organ of Corti. There was a statistically significant reduction in the exosome protein level and number of particles per cubic centimeter when the samples were exposed to ototoxic stress. Proteomic analysis also detected clear differences in protein expression when ototoxic medications were introduced. Significant changes in the proteomes of the exosomes were previously described in the context of hearing loss and ototoxic treatment. This is the first report describing exosomes derived from the inner ear. These findings may present an opportunity to conduct further studies with the hope of using exosomes as a biomarker to monitor inner ear function in the future.

Metastasis to the cerebellopontine angle (CPA) or internal auditory meatus (IAM) is rare. We report a rare case of a 69-year-old woman with metastatic lung adenocarcinoma, who presented with 2 weeks history of left-sided hearing loss and progressively worsening vertigo. Examination revealed a left-sided facial nerve palsy while pure tone audiometry (PTA) showed a new left-sided deafness. MRI showed a new enhancing soft tissue lesion in the left IAM, highly suspicious of new metastases from her progressive lung cancer, which contributed to her neuro-otological symptoms. Subsequent MRI scans 4 months later also showed new brain metastases. She continued to be managed with supportive palliative care in view of her extensive disease.

Autophagy is a highly evolutionary conserved quality control defense mechanism within cells, which has also been implicated in cell death processes. In the mammalian inner ear, autophagy has been shown to play a role during early morphogenesis as well as in adult cochlear hair cells exposed to ototoxic insults. Mitophagy, a selective autophagic cell process targeting mitochondria, hasn't been studied in the inner ear so far. On this work, we searched for molecular indicators of mitophagy within House Ear Institute-Organ of Corti-1 (HEI-OC1) cells as well as in the organ of Corti (OC). We first tested for the expression of Pink1/Park2 mRNA in 5-day-old C57BL/6 mice's cochleae using RT-PCR. We focused on the induction of mitophagy in HEI-OC1 cells as well as in the OC and investigated a possible mitophagic potential of the aminoglycoside agent gentamicin. The induction of mitophagy in HEI-OC1 cells was detected by objectivizing the translocation of fluorescence-tagged LC3 to mitochondria using confocal microscopy after a 6-h incubation with a well-described mitochondrial uncoupler and mitophagy-inducing agent: carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Incubation with gentamicin generated no mitochondrial translocation of LC3. Protein levels of COXIV, Atg5/12 and LC3 were evaluated by an immunoblot analysis after a 24-h CCCP treatment as well as gentamicin. We demonstrated mitophagy after CCCP exposure in HEI-OC1 cells by showing a downregulation of COXIV. A downregulation of COXIV could also be visualized in the OC after CCCP. A significant oxygen consumption rate (OCR) changed in cells treated with CCCP as well as significant morphological changes of mitochondria by electron microscopy (EM) strengthen this assumption. Gentamicin exposure generated no impact on OCR or mitochondrial morphological changes by EM. Finally, we demonstrated changes in the expression of Atg12 and LC3 proteins in both the OC and HEI-OC1 cells after CCCP exposure but not after gentamicin. Our data indicate that gentamicin had no impact in the activation of mitophagy-neither in the HEI-OC1 cell line nor in the OC. Therefore, we speculate that mitophagic-independent mechanisms may underly aminoglycoside ototoxicity.

Matrix metalloproteinases (MMPs) play an important role in modeling of the extracellular matrix. There is increasing evidence that these proteases are important in neurite elongation and axonal guidance during development in the central nervous system and retina. Moreover, they are also expressed after acute injury and can be the key mediators of pathogenesis. However, the role of MMPs in the inner ear is largely unknown. Our group recently demonstrated that general inhibition of MMPs resulted in auditory hair cell loss in vitro. In the present study, we investigated the role of MMPs in inner ear spiral ganglion neuron (SGN) survival, neuritogenesis and neurite extension by blocking MMPs known to be involved in axonal guidance, neurite elongation, and apoptosis in other neuronal systems. Spiral ganglion (SG) explants from 5-day-old Wistar rats were treated with different concentrations of the general MMP inhibitor GM6001, a specific MMP-2 inhibitor, and a specific MMP-9 inhibitor, in vitro. The general inhibitor of MMPs and the specific inhibition of MMP-2 significantly reduced both the number of neurites that extended from SG explants, as well as the length of individual neurites. However, neither the general inhibitor of MMPs nor the specific inhibition of MMP-2 influenced SGN survival. Inhibition of MMP-9 had no influence on SGNs. The data suggest that MMPs, and more specifically MMP-2, influence the growth of developing afferent neurites in the mammalian inner ear in vivo.

Tularaemia is a rare infectious disease endemic in most European countries caused by the bacteriumFrancisella tularensis.1Patients often show acute non-specific symptoms, which causes a delay in diagnosis and proper treatment, potentially resulting in significant morbidities such as deep neck abscess, meningitis, endocarditis and septic shock. The authors present a case of a 5-year old boy with a 4-day history of fever, sore throat and painful cervical lymphadenopathy, whose clinical progression worsened despite being treated with recommended antibiotics as per WHO guidelines once the diagnosis of Tularaemia was confirmed by serologic tests. He developed a parapharyngeal abscess and a persistent left necrotic cervical lymph node, which both were surgically drained and excised, respectively, and an extended course of antibiotic was given. Subsequently, the patient fully recovered from the illness and the follow-up was negative for relapse.

According to WHO 360 million people are hard of hearing. Hearing disorders are not only seen in elderly but also in children. Clinically we differentiate between hearing disorders concerning the transmission of sound from the outer ear to the cochlea (conductive hearing loss) and disorders with reduced sound perception concerning the inner ear an related structures (sensorineural hearing loss). This article summarizes common surgical and technical possibilities for rehabilitation. For each pathology we graphically illustrate the generic working principle of the rehabilitation including the indication range in an exemplary audiogram.

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme necessary for the production of mevalonate. They are widely used as cholesterol-lowering drugs. However, conflicting data about the effect of statins on neuronal cells has been published. To explore the effect of simvastatin on spiral ganglion neurons (SGNs), SG explants of 5-day-old rats were treated with increasing concentrations of simvastatin. In addition, SG explants were treated with mevalonate and with the combination of simvastatin and mevalonate. SGN number, length of the neurites, area of nonneuronal supporting cells, and neuronal survival were analyzed. Simvastatin treatment results in a significant dose-dependent decrease of SG neurite number, length of neurites, area of supporting cells, and SG neuronal survival compared to control. Interestingly, treatment with mevalonate in addition to simvastatin increased SG neuronal survival compared to simvastatin treatment only. However, treatment with mevalonate in addition to simvastatin did not influence SG neurite number, length of neurites, and area of supporting cells compared to simvastatin treatment only. Our results suggest a neurotoxic effect of simvastatin on SGNsin vitro. Neurotoxicity seems to be at least partially mediated by the mevalonate pathway. Therefore, caution is warranted to use simvastatin as a potential otoprotective drug.

OBJECTIVES/HYPOTHESIS: Cadherins are a superfamily of transmembrane glycoproteins, which mediate calcium-dependent intercellular adhesions. T-cadherin is an atypical member of the cadherin family in regard to its structure; it acts as a signalling receptor rather than an adhesion molecule. In this study we examine the role of T-cadherin in the mammalian cochlea. STUDY DESIGN: This study investigated the expression of T-cadherin in the inner ear under physiologic and pathologic conditions. METHODS: Expression of T-cadherin in the rat cochlea was analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, and immunohistochemistry. RESULTS: We detected T-cadherin mRNA expression in three different components in the cochlea of postnatal mouse, namely the organ of Corti (OC), the spiral ganglion (SG), and the stria vascularis (SV). The SG and SV showed a higher T-cadherin mRNA level than the OC. T-cadherin protein was detected by Western blotting in the OC, SG, and SV. Immunofluorescence microscopy of adult mouse cochlea revealed the presence of T-cadherin in the apical parts of the inner and outer hair cells as well as in the SV and SG. OCs treated with gentamicin for 3, 6, or 12 hours did not show any change in T-cadherin gene expression compared to control explants maintained in culture medium alone. CONCLUSIONS: T-cadherin is expressed within the cochlea. T-cadherin seems to have a wide variety of functions in the inner ear, ranging from mechanical functions to functions in response to hair cell damage and loss.

Studies conducted over the last few years demonstrated that signaling pathways that operate in the organs of Corti (OC) play a central role in survival and death of hair cells. An important goal of molecular otology is to characterize these signaling pathways in normal inner ears and inner ears exposed to a variety of different forms of stress, such as ototoxic substances and noise overexposure. In this study, we used high-performance reverse protein microarray technology and phospho-specific antibodies to examine the activation status of defined molecules involved in cellular signaling. We demonstrate that reverse protein microarrays based on the highly sensitive planar-waveguide technology provide an effective and high-throughput means to assess the activation state of key molecules involved in apoptotic and prosurvival signaling in microdissected OC explants over time. In this study, we show that gentamicin and a specific NF-ĸB inhibitor increase the ratio of phospho-c-Jun/c-Jun in OC explants of postnatal rats soon after exposure to these drugs. In addition, we found a decrease in the phospho-Akt/Akt ratio in OC explants early after NF-ĸB inhibition. Finally, we observed an early and consistent decrease in the phospho-p38/p38 ratio in OC explants exposed to the NF-ĸB inhibitor and only a transient decrease in this ratio in OC examples after gentamicin exposure.

Purpose of review To review cause, clinical evaluation, medical and surgical management of isolated sphenoid sinus diseases. Recent findings Early diagnosis of isolated sphenoid sinus diseases requires a high index of clinical suspicion and appropriate radiological imaging. Sphenoid sinus can be approached endoscopically via a few different surgical techniques. Summary Isolated sphenoid sinus diseases are uncommon, with nonspecific clinical presentation. Early diagnosis requires a high index of clinical suspicion, proper endoscopic nasal examination, and appropriate radiological imaging. Surgical intervention is the primary treatment modality for most of the isolated sphenoid sinus diseases. Endoscopic endonasal approach to sphenoid sinus is the technique of choice. The location of sphenoid sinus disease, the extent of the surgery, and anatomic configuration of the sphenoid sinus are the main factors that help to decide the most suitable surgical approach to the sphenoid sinus.

We present our experience in managing pathologies involving the anterior and middle cranial base using an endoscopic transnasal approach, highlighting the surgical technique, indications, and complications. The different types of endoscopic approaches used include the transtuberculum/transplanum, transcribiform, transsellar, and cavernous sinus approaches. The common indications include repair of cerebrospinal fluid leaks (both spontaneous and post traumatic) and excision of pituitary adenomas, meningiomas, craniopharyngiomas, esthesioneuroblastomas, and other malignancies of the anterior cranial base. Careful reconstruction is performed with the multilayer technique utilizing fat, fascia lata, and fibrin sealant. The endoscopic transnasal approach, coupled with the present-day sophisticated neuronavigation systems, allows access to lesions in the midline extending from the cribriform plate to the craniovertebral junction. However, preoperative planning and careful selection of cases with evaluation of each case on an individual basis with regard to the lateral extension of the lesion are imperative.

Background:Endoscopic endonasal techniques have recently become the method of choice in dealing with cerebrospinal fluid leak involving the anterior cranial fossa. However, most surgeons prefer an intracranial approach when leaks involve the middle cranial fossa. This case report illustrates the possibilities of using endoscopic techniques for cerebrospinal fluid leaks involving the middle fossa.Case report:A 37-year-old male patient presented with multiple areas of cranial defect with cerebrospinal fluid leak due to osteoradionecrosis following radiation for nasopharyngeal carcinoma 4 years earlier. Clinical examination showed involvement of all cranial nerves except the IInd and XIth nerves on the left side. A prior attempt to repair the cerebrospinal fluid leak with craniotomy was not successful.Conclusion:This case demonstrates the successful endoscopic repair of a large cranial defect with cerebrospinal fluid leak.

The skull base is one of the most complex anatomical regions and forms the floor of the cranial cavity. Skull base surgery involves open, microscopic, and endoscopic approaches to the anterior, middle, or posterior cranial fossa. A multispecialty team approach is essential in treating patients with skull base lesions. Traditionally, rhinologists are involved in providing access to anterior skull base lesions while otologists are involved in the treatment of lesions of the posterior skull base. This is the case in most skull base centers today. In this article, we share a new perspective of an integrated skull base unit where a team of otolaryngologists and neurosurgeons treat anterior, middle, and posterior skull base pathologies. The rationale for this approach is that most technical skills required in skull base surgery are interchangeable and apply whether an endoscopic or microscopic approach is used. We show how the different skills apply to the different approaches and share our experience with an integrated skull base unit.

Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzedin vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.

Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs). The thiazolidinediones (TZDs; e.g., pioglitazone) and fibrate (e.g., fenofibrate) drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC) explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS), lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE) and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific), tesaglitazar (PPARγ/α-specific), and fenofibric acid (PPARα-specific) all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

Neuron-glial-related cell adhesion molecule (NrCAM) is a neuronal cell adhesion molecule involved in neuron-neuron and neuron-glial adhesion as well as directional signaling during axonal cone growth. NrCAM has been shown to be involved in several cellular processes in the central and peripheral nervous systems, including neurite outgrowth, axonal pathfinding and myelination, fasciculation of nerve fibers, and cell migration. This includes sensory systems such as the eye and olfactory system. However, there are no reports on the expression/function of NrCAM in the auditory system. The aim of the present study was to elucidate the occurrence of NrCAM in the mammalian cochlea and its role in innervation of the auditory end organ. Our work indicates that NrCAM is highly expressed in the developing mammalian cochlea (position consistent with innervation). Moreover, we found that NrCAM, presented in stripe micropatterns, provide directional cues to neonatal rat inner ear spiral ganglion neurites in vitro. Our results are consistent with a role for NrCAM in the pathfinding of spiral ganglion dendrites toward their hair cell targets in the sensory epithelium.

Metformin is a commonly used antidiabetic drug. It has been shown that this drug activates the AMP-activated protein kinase, which inhibits downstream the mammalian target of rapamycin. In addition, several studies indicate that metformin reduces intracellular reactive oxygen species. Our data, using an in vitro rat model, indicate that metformin is able to protect auditory hair cells (HCs) from gentamicin-induced apoptotic cell death. Moreover, metformin has no toxic effect on spiral ganglion neuronal survival or outgrowth in vitro. These results suggest a protective effect of metformin on auditory HC survival in gentamicin-induced HC loss in vitro.

The cochlear implant (CI) is one of the most successful neural prostheses developed to date. It offers artificial hearing to individuals with profound sensorineural hearing loss and with insufficient benefit from conventional hearing aids. The first implants available some 30 years ago provided a limited sensation of sound. The benefit for users of these early systems was mostly a facilitation of lip-reading based communication rather than an understanding of speech. Considerable progress has been made since then. Modern, multichannel implant systems feature complex speech processing strategies, high stimulation rates and multiple sites of stimulation in the cochlea. Equipped with such a state-of-the-art system, the majority of recipients today can communicate orally without visual cues and can even use the telephone. The impact of CIs on deaf individuals and on the deaf community has thus been exceptional. To date, more than 300,000 patients worldwide have received CIs. In Switzerland, the first implantation was performed in 1977 and, as of 2012, over 2,000 systems have been implanted with a current rate of around 150 CIs per year. The primary purpose of this article is to provide a contemporary overview of cochlear implantation, emphasising the situation in Switzerland.

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is widely expressed in the nervous system and important in axonal outgrowth, guidance, synapse formation, and signaling. Gene deletion studies emphasize the significance of L1 during development of the central nervous system and L1 is crucial for the topographic targeting of retinal axons. In contrast to the brain and retina, the role of L1 in the inner ear is largely unknown. While previous studies have localized L1 in the developing inner ear of the chicken and mouse, its function during the innervation of the cochlea still remains largely unclear. We therefore investigated the functional role of L1 in the mammalian inner ear. Our aim was to determine whether or not L1 can modulate type I and/or type II spiral ganglion neuron outgrowth using an in vitro alternate choice assay. We found that L1, presented in stripe micropatterns, provide directional cues to neonatal rodent type I but not type II inner ear spiral ganglion neurites. The results suggest that L1 may play a role in axonal pathfinding of type I spiral ganglion dendrites toward their inner hair cell targets but not of type II toward the outer hair cells.

The neuropeptide somatostatin (SST) is an important modulator of neurotransmission in the central nervous system (CNS) and binds to G-protein-coupled receptors (SSTR1-5) on target cells. Little is known about the expression and function of the somatostatinergic system in the mammalian cochlea. We analyzed the expression of SSTR1-SSTR5 in the immature mammalian cochlea. The peak in the expression of SSTR1 and SSTR2 at mRNA and protein level is around the onset of hearing to airborne sound, at postnatal day (P)14. This suggests their involvement in the maturation of the mammalian cochlea. We demonstrated that all five receptors are expressed in the inner hair cells (IHC) and outer hear cells (OHC) as well as in defined supporting cells of the organ of Corti (OC) in the adult mouse cochlea. A similar expression of the SSTRs in the IHC and OHC was found in cultivated P6 mouse OC explants as well as in neuroepithelial cell culture. In order to learn more about the regulation of SSTRs, we used mice with either a deletion of SSTR1, SSTR2 or SSTR1/SSTR2 double knock out (DKO). In DKO mice, SSTR5 was up-regulated and SSTR3 and SSTR4 were down regulated. These findings provide evidence of a compensatory regulation in the mammalian cochlea as a consequence of a receptor subtype deletion. In addition, we observed reduced levels of phospho-Akt and total-Akt in SSTR1 KO and DKO mice as compared to wild type (WT) mice. Akt is likely to be involved in hair cell survival. Most importantly, we found improved hair cell survival in somatostatin and octreotide treated OC explants that had been exposed to gentamicin compared to those explants exposed to gentamicin alone. These findings propose that the somatostatinergic system within the cochlea may have neuroprotective properties.

L'hypoacousie retrocochleaire est un important diagnostic differentiel d’une hypoacousie de perception…

Item does not contain fulltext The neuropeptide somatostatin (SST) exerts several important physiological actions in the adult central nervous system through interactions with membrane-bound receptors. Transient expression of SST and its receptors has been described in several brain areas during early ontogeny. It is therefore believed that SST may play a role in neural maturation. The present study provides the first evidence for the developmental expression of SST receptors in the mammalian cochlea, emphasizing their possible roles in cochlear maturation. In the developing mouse cochlea, cells immunoreactive to somatostatin receptor 1 (SSTR1) and somatostatin receptor 2 (SSTR2) were located in the embryonic cochlear duct on Kolliker's organ as early as embryonic day (E) 14 (E14). At E17, the expression of both receptors was high and already located at the hair cells and supporting cells along the length of the cochlear duct, which have become arranged into the characteristic pattern for the organ of Corti (OC) at this stage. At birth, SSTR1- and SSTR2-containing cells were only localized in the OC. In general, immunoreactivity for both receptors increased in the mouse cochlea from postnatal day (P) 0 (P0) to P10; the majority of immunostained cells were inner hair cells, outer hair cells, and supporting cells. Finally, a peak in the mRNA and protein expression of both receptors is present near the time when they respond to physiological hearing (i.e., hearing of airborne sound) at P14. At P21, SSTR1 and SSTR2 levels decrease dramatically. A similar developmental pattern was observed for SSTR1 and SSTR2 mRNA, suggesting that the expression of the SSTR1 and SSTR2 genes is controlled at the transcriptional level throughout development. In addition, we observed reduced levels of phospho-Akt and total Akt in SSTR1 knockout and SSTR1/SSTR2 double-knockout mice compared with wild-type mice. We know from previous studies that Akt is involved in hair cell survival. Taken together, the dynamic nature of SSTR1 and SSTR2 expression at a time of major developmental changes in the cochlea suggests that SSTR1 and SSTR2 (and possibly other members of this family) are involved in the maturation of the mammalian cochlea.