Shuho Tanaka

Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity

Expression of antioxidant enzymes is regulated by transcription factor NF-E2-related factor (Nrf2) and induced by oxidative stress. Reactive oxygen species contribute to the formation of several types of cochlear injuries, including age-related hearing loss and gentamicin ototoxicity. In this study, we examined the roles of Nrf2 in age-related hearing loss and gentamicin ototoxicity by measuring auditory brainstem response thresholds in Nrf2-knockout mice. Although Nrf2-knockout mice maintained normal auditory thresholds at 3 months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11 months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11 months of age. To examine the importance of Nrf2 in protecting against gentamicin-induced ototoxicity, 3-day-old mouse organ of Corti explants were cultured with gentamicin. Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. Furthermore, the expressions of some Nrf2-target genes were activated by gentamicin treatment in wild-type mice but not in Nrf2-knockout mice. The present findings indicate that Nrf2 protects the inner ear against age-related hearing injuries and gentamicin ototoxicity by up-regulating antioxidant enzymes and detoxifying proteins.

Ischemia-Reperfusion Injury of the Cochlea: Pharmacological Strategies for Cochlear Protection and Implications of Glutamate and Reactive Oxygen Species

A large amount of energy produced by active aerobic metabolism is necessary for the cochlea to maintain its function. This makes the cochlea vulnerable to blockade of cochlear blood flow and interruption of the oxygen supply. Although certain forms of human idiopathic sudden sensorineural hearing loss reportedly arise from ischemic injury, the pathological mechanism of cochlear ischemia-reperfusion injury has not been fully elucidated. Recent animal studies have shed light on the mechanisms of cochlear ischemia-reperfusion injury. It will help in the understanding of the pathology of cochlear ischemia-reperfusion injury to classify this injury into ischemic injury and reperfusion injury. Excitotoxicity, mainly observed during the ischemic period, aggravates the injury of primary auditory neurons. On the other hand, oxidative damage induced by hydroxyl radicals and nitric oxide enhances cochlear reperfusion injury. This article briefly summarizes the generation mechanisms of cochlear ischemia-reperfusion injury and potential therapeutic targets that could be developed for the effective management of this injury type.

Cochlear protection from acoustic injury by inhibitors of p38 mitogen-activated protein kinase and sequestosome 1 stress protein

This study evaluated the protective role of p38 mitogen-activated protein kinase (p38 MAPK) inhibitors and sequestosome 1 (Sqstm1/A170/p62), a stress-induced signal modulator, in acoustic injury of the cochlea in mice. Two weeks after the exposure of mice to acoustic stress, threshold shifts of the auditory brainstem response (ABR) from the pre-exposure level and hair cell loss were evaluated. The activation of p38 MAPK was observed in cochlea by immunostaining 4 h after acoustic stress. To examine the role of p38 MAPK in tissue injury, its inhibitors were i.p. injected into male wild-type C57BL mice before the acoustic overexposure. The inhibitors SB202190 and SB203580 but not the inactive analogue SB202474 dose-dependently decreased the auditory threshold shift and outer hair cell loss induced by acoustic overexposure, suggesting the involvement of p38 MAPK in ototoxicity. We found that acoustic overexposure induced the up-regulation of Sqstm1 mRNA expression in the cochlea of wild-type mice and that SQSTM1-deficient mice exhibited an enhanced ABR threshold shift and hair cell loss, suggesting a role of SQSTM1 in the protection of tissue from acoustic stress.

Protective effects of exogenous GM-1 ganglioside on acoustic injury of the mouse cochlea

GM-1 ganglioside (GM-1), a glycosphingolipid, is embedded in the lipid layer of neuronal membranes and is one of the neuroprotective agents. To the best of our knowledge, the role of GM-1 has never been examined in hair cell injury. The purpose of this study was therefore to evaluate the effects of GM-1 on acoustic injury of the cochlea. Mice were exposed to 4-kHz pure tone of 128dB SPL (sound pressure level) for 4h. GM-1 was intraperitoneally administered immediately before the onset of acoustic overexposure. The threshold shift of the auditory brainstem response (ABR) and hair cell loss were then evaluated 2 weeks after acoustic overexposure. Immunostaining for 4-hydroxynonenal (4-HNE), indicative of lipid peroxidation, was also examined in animals subjected to acoustic overexposure. GM-1 treatment significantly decreased the ABR threshold shifts and hair cell loss after acoustic overexposure. And immunostaining for 4-HNE was reduced by GM-1 treatment. These findings suggest that GM-1 is involved in the protection of the cochlea against acoustic injury through inhibiting lipid peroxidation.

Cranial Base Repair Using Suturing Technique Combined with a Mucosal Flap for Cerebrospinal Fluid Leakage During Endoscopic Endonasal Surgery

OBJECTIVE To evaluate a cranial base repair method using the dural suturing technique in combination with a mucosal flap in the endoscopic endonasal approach. METHODS We analyzed 190 patients (mean age, 52.3 years; age range, 3-86 years) who underwent 194 endoscopic endonasal approaches. The degree of intraoperative cerebrospinal fluid (CSF) leakage was graded based on previously published criteria: grade 0, absent; grade 1, small; grade 2, moderate; and grade 3, large. Cranial base repair using the dural suturing technique was performed according to the grade of CSF leakage: grades 1 and 2, autologous fat graft anchored by dural suturing covered with a sphenoid sinus mucosal flap, and grade 3, multilayered, inlay sutured and onlay nonsutured fascial grafts covered with a nasoseptal flap. RESULTS Intraoperative CSF leakage was observed in 125 of 194 cases (64.4%). The degree of CSF leakage was grade 0 in 69 cases, grade 1 in 51 cases, grade 2 in 30 cases, and grade 3 in 44 cases. A postoperative CSF leak was encountered in 2 of 125 repaired cases (1.6%). Both cases with CSF leak involved grade 3 CSF leak (4.5%), and both were successfully treated with lumbar drainage. CONCLUSION Our graded cranial base repair method using the dural suturing technique is simple and reliable.

Endoscopic endonasal management of esthesioneuroblastoma: A retrospective multicenter study

OBJECTIVE The aim of the present study was to illustrate the safety and utility of the endoscopic endonasal approach (EEA) for the treatment of esthesioneuroblastomas (ENB). METHODS We retrospectively reviewed patients with a diagnosis of ENB between March 2008 and February 2016 at 10 tertiary referral hospitals in Japan, and assessed demographic data, stage of disease, surgical approach, outcomes and postoperative complications. RESULTS A total of 22 patients (10 males and 12 females; mean age at presentation, 49.0 years) underwent endoscopic endonasal resection of newly diagnosed ENBs. Dulguerov staging at presentation was T1, 6 patients; T2, 9 patients; T3, 5 patients; and T4, 2 patients. As surgical procedures, unilateral resection via EEA was performed in 12 patients aiming preservation of the contralateral olfactory system, and bilateral resection via EEA was done in 10 patients. Post-operative radiotherapy was done in 20 patients. Pathological margin studies revealed margin-free resections in 21 patients (95.5%). The mean period of follow-up was 44 months. Local recurrence was observed in one T2 patient 12 months after bilateral resection. All patients were alive at the last follow-up, and 21 patients showed no evidence of disease. No post-operative complications including bleeding, CSF leak and meningitis were identified. Preservation of olfactory function was achieved in 11 patients (91.7%). CONCLUSION The results of the present study indicate the safety and utility of multilayer resection using EEA for treatment of ENBs.

Combined simultaneous transcranial and endoscopic endonasal resection of sphenoorbital meningioma extending into the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa

Background: Sphenoorbital meningiomas are surgically challenging because of their nature to extend to adjacent structures. Here, we describe a case of recurrent sphenoorbital meningioma extending into the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa, which was resected using combined simultaneous transcranial and endoscopic endonasal approaches. Case Description: A 62-year-old man who had 15 years earlier undergone partial resection of a left sphenoorbital meningioma presented with a 1-year history of progressive proptosis of the left eye. Magnetic resonance imaging (MRI) showed a Gd-enhancing tumor occupying the left sphenoid wing and orbital lateral wall and extending into extracranial structures such as the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa as well as adjacent structures such as the cavernous sinus and superior orbital fissure (SOF). Based on the MRI findings of tumor extension into the sphenoid sinus with broad continuity, the risk of postoperative cerebrospinal fluid (CSF) leakage through the large defect in the sphenoid sinus was considered high. Subtotal resection using combined simultaneous transzygomatic and endoscopic endonasal approaches was performed, leaving residual tumor in the cavernous sinus and SOF. The large skull base defect between the middle fossa and sphenoid sinus was covered with a free graft of fascia lata from the transcranial side and with a vascularized nasoseptal flap from the endonasal side. No CSF rhinorrhea and no neurological deficits developed postoperatively. Conclusion: Combined simultaneous transcranial and endoscopic endonasal approaches may become a safe and feasible alternative for sphenoorbital meningioma with a large skull base defect penetrating to the paranasal sinus.

A case of spontaneous cerebrospinal fluid rhinorrhea: Accurate detection of the leak point by magnetic resonance cisternography

Background: Spontaneous cerebrospinal fluid (CSF) rhinorrhea is a rare entity. The accurate preoperative localization of the leak point is essential for planning surgical treatment, but is sometimes difficult. To localize the leak point, magnetic resonance cisternography (MRC) is the method of choice, but its effectiveness remains unclear. Case Description: A 34-year-old mildly obese female experienced spontaneous CSF rhinorrhea after an attack of bronchial asthma. High-resolution computed tomography (CT) failed to reveal the leak point, while MRC demonstrated an arachnoid herniation at the olfactory cleft. The patient underwent endoscopic endonasal repair of the CSF leak with success. There has been no recurrence of CSF rhinorrhea for 14 months after surgery followed by the administration of acetazolamide. Conclusion: We report a rare case of spontaneous CSF rhinorrhea associated with benign intracranial hypertension, in which the leak point was successfully detected by MRC. The CSF leak was completely repaired by minimally invasive endoscopic endonasal surgery. MRC may be a reliable method for detecting CSF leak points.

Modified combination of platelet count and neutrophil “to” lymphocyte ratio as a prognostic factor in patients with advanced head and neck cancer

We evaluated the prognostic potential of the combination of platelet count and neutrophil to lymphocyte ratio (COP‐NLR) in patients with advanced head and neck cancer.

Vessel Sealing Device in Parotid Gland Surgery: Clinical and Pathological Study

Facial palsy, salivary leakage and postoperative bleeding are the main complications in parotid gland surgery. To find ways to reduce the occurrence of these complications, we compare traditional methods using the hand-tie ligation technique with a bipolar electrode knife against LigaSure TM Small Jaw, a newly developed vessel sealing device, in parotid gland operations.