Susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on sensory mechanoelectrical transduction channels both Ex Vivo and In Vivo.

Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no highly effective clinical strategies for the prevention of cisplatin-induced ototoxicity. Previous studies have indicated that short-term cisplatin ototoxicity primarily affects the outer hair cells of the cochlea. Therefore, preventing the entry of cisplatin into hair cells may be a promising strategy to prevent cisplatin ototoxicity. This study aimed to investigate the entry route of cisplatin into mouse cochlear hair cells. The competitive inhibitor of organic cation transporter 2 (OCT2), cimetidine, and the sensory mechanoelectrical transduction (MET) channel blocker benzamil, demonstrated a protective effect against cisplatin toxicity in hair cells in cochlear explants. Sensory MET-deficient hair cells explanted from Tmc1Δ;Tmc2Δ mice were resistant to cisplatin toxicity. Cimetidine showed an additive protective effect against cisplatin toxicity in sensory MET-deficient hair cells. However, in the apical turn, cimetidine, benzamil, or genetic ablation of sensory MET channels showed limited protective effects, implying the presence of other entry routes for cisplatin to enter the hair cells in the apical turn. Systemic administration of cimetidine failed to protect cochlear hair cells from ototoxicity caused by systemically administered cisplatin. Notably, outer hair cells in MET-deficient mice exhibited no apparent deterioration after systemic administration of cisplatin, whereas the outer hair cells in wild-type mice showed remarkable deterioration. The susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on the sensory MET channel both ex vivo and in vivo. This result justifies the development of new pharmaceuticals, such as a specific antagonists for sensory MET channels or custom-designed cisplatin analogs which are impermeable to sensory MET channels.

Systemic Fluorescent Gentamicin Enters Neonatal Mouse Hair Cells Predominantly Through Sensory Mechanoelectrical Transduction Channels.

Systemically administered aminoglycoside antibiotics can enter inner ear hair cells and trigger apoptosis. However, the in vivo route(s) by which aminoglycoside antibiotics enter hair cells remains controversial. Aminoglycosides can enter mouse hair cells by endocytosis or by permeation through transmembrane ion channels such as sensory mechanoelectrical transduction (MET) channels, transient receptor potential (TRP) channels, P2X channels, Piezo2-containing ion channels, or a combination of these routes. Transmembrane channel-like 1 (TMC1) and TMC2 are essential for sensory MET and appear to be the pore-forming components of sensory MET channels. The present study tested the hypothesis that systemic fluorescent gentamicin enters mouse hair cells predominantly through sensory MET channels. We employed Tmc1Δ, Tmc2Δ, and Tmc1::mCherry mice. In Tmc1::mCherry mice, the transgene was integrated on the X chromosome, resulting in mosaic expression of TMC1-mCherry in the hair cells of female heterozygous mice. After systemic administration of gentamicin-conjugated Texas Red (GTTR) into Tmc1Δ;Tmc2Δ mice and wild-type mice at postnatal day 4 (P4), robust GTTR fluorescence was detected in wild-type hair cells, whereas little or no GTTR fluorescence was detected in Tmc1Δ;Tmc2Δ hair cells. When GTTR was injected into developing mice at P0, P2, P4, or P6, the GTTR fluorescent intensity gradually increased from P0 to P4 in wild-type hair cells, whereas the intensity was stably low from P0 through P6 in Tmc1Δ;Tmc2Δ hair cells. The increase in the GTTR intensity coincided with the spatio-temporal onset of sensory MET in wild-type hair cells. In Tmc1::mCherry cochleae, only hair cells that showed a significant uptake of systemic GTTR took up FM1-43. Transmission electron microscopy could detect no disruption of normal endocytosis at the apical surface of Tmc1Δ;Tmc2Δ hair cells in vitro. These results provide substantial novel evidence that in vivo gentamicin enters neonatal mouse hair cells predominantly through sensory MET channels and not via endocytosis.

Potential Confounding Factors May Influence the Association Between Configurations of the Vertebrobasilar System and the Incidence of Idiopathic Sudden Sensorineural Hearing Loss and Canal Paresis.

OBJECTIVE: To investigate the impact of configurations of the vertebrobasilar system on the incidence of idiopathic sudden sensorineural hearing loss (ISSNHL) and canal paresis (CP). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Two hundred and forty-eight consecutive patients diagnosed with ISSNHL and 152 patients with unilateral CP of an uncertain cause who were managed between January 2011 and December 2017. The contralateral side of 144 patients with Bell's palsy or cerebellopontine angle tumor served as a control. INTERVENTIONS: All patients underwent magnetic resonance cisternography. CP was diagnosed based on caloric testing. MAIN OUTCOME MEASURES: 1) Branching patterns of the anterior/posterior inferior cerebellar artery (AICA/PICA) in the cerebellopontine angle area. 2) The direction of the basilar artery (BA) curvature. 3) Vertebral artery (VA) dominance. RESULTS: The incidence of vascular loops of the AICA/PICA entering the internal acoustic canal was significantly higher on both the affected and unaffected sides in patients with ISSNHL and CP in comparison to controls (p < 0.05). The curved BA was observed more frequently in the ISSNHL and CP groups than in the control group (p < 0.05), whereas the direction of the BA curvature was not associated with the laterality of ISSNHL or CP. The incidence of asymmetric VA in CP patients was significantly higher than that in controls (p = 0.0304), while no significant difference was observed between ISSNHL patients and controls. Remarkably, while the incidence rate of irregular vascular configurations was high in both the ISSNHL and CP groups, there was no marked difference between the affected and unaffected ears of the ISSNHL and CP groups. CONCLUSIONS: Our results indicate that the vascular configurations of the vertebrobasilar system do not directly cause ISSNHL and CP. Instead, they suggest the presence of confounding factors that influence the vascular configurations and the development of ISSNHL and CP.

Vestibular Dysfunction in Patients With Superficial Siderosis of the Central Nervous System.

OBJECTIVE: To describe the vestibular function in patients with superficial siderosis of the central nervous system (SSCN). STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENTS: Ten consecutive patients with SSCN. This study is the largest case series of SSCN in which detailed neuro-otological findings, including electronystagmography recording, video head impulse test (vHIT), and posturography, were described. INTERVENTIONS: Audiological and neuro-otological examinations, including pure-tone audiometry, distortion product otoacoustic emissions, speech audiometry, auditory brainstem responses, electronystagmography recording, vHIT, and posturography. MAIN OUTCOME MEASURES: Pure-tone average, DP level, maximum speech discrimination score, interpeak latency between auditory brainstem responses waves I and V, eye tracking test, examination of optokinetic nystagmus, caloric response, visual suppression, vestibulo-ocular reflex gains, total center of pressure path length, and Romberg's ratio. RESULTS: Audiological examinations suggested that the sensorineural hearing loss was of a cochlear etiology in 3 ears, a retrocochlear etiology in 11 ears, and a combined cochlear and retrocochlear etiology in 6 ears. Neuro-otological examinations revealed that eight out of nine patients had cerebellar disorders, while all patients also had peripheral vestibular dysfunction. CONCLUSION: In addition to cerebellar disorders, SSCN patients suffer from severe peripheral vestibular dysfunction, which can exacerbate the patient's imbalance. When otolaryngologists encounter patients with distinctly progressive sensorineural hearing loss and imbalance, they should include SSCN in the differential diagnosis and perform neuro-otological examinations, including an electronystagmography recording and vHIT and brain magnetic resonance imaging.

Sensorineural hearing loss associated with a factitious disorder.

Factitious disorders are characterized by intentionally abnormal physical and/or psychological behavior, and affected patients often make up their symptoms and clinical histories. The most serious and chronic type of factitious disorder is Munchausen syndrome. We report the case of a 24-year-old woman with a 2-year history of sensorineural hearing loss (SNHL) who later confessed to feigning her hearing loss. She was eventually diagnosed with a factitious disorder. During those 2 years, she was able to induce her SNHL by exposing herself to excessive noise or high doses of aspirin. To the best of our knowledge, this is the first report describing an association between a factitious disorder and SNHL.

Relations between contact force, bipolar voltage amplitude, and mapping point distance from the left atrial surfaces of 3D ultrasound- and merged 3D CT-derived images: Implication for atrial fibrillation mapping and ablation.

BACKGROUND: Catheter tip-derived contact force (CF) and 3-dimensional (3D) maps are key to mapping and ablation of atrial fibrillation. OBJECTIVE: This study sought to determine the relation between CF and 3D map surfaces. METHODS: We conducted a validation study of Carto-based 3D ultrasound (3D-US) and 3D-US merged with computed tomography (3D-Merge-CT) left atrium/pulmonary vein images. Under fluoroscopic guidance, 1361 mapping points (20 patients) with CFs and electrogram information were randomly acquired around the PVs. RESULTS: CF correlated weakly with the distance of mapping points from the 3D-Merge-CT (r = 0.27; P < .001) and 3D-US (r = 0.22; P < .001) surfaces but not with bipolar voltage (r = -0.01; P = .2400). Low CF (0-4 g) yielded points close to the 3D-US surface; moderate (5-9 g) and high CFs (10-20 g) generated points beyond the surface (0.1 ± 3.9, 1.4 ± 3.4, and 2.3 ± 3.4 mm; P < .05 for each). Low, moderate, and high CFs yielded points below, close to, and beyond the 3D-Merge-CT surface (-1.2 ± 3.7, 0.4 ± 3.0, and 1.0 ± 2.9 mm; P < .05 for each). CONCLUSION: Poor correlation between CF and the distance of mapping points from the 3D map surfaces and electrogram information shows the limitation of 3D mapping and electrogram information for predicting good contact. In addition, mapping seems to require far less CF than ablation requires.

Pleomorphic adenoma presenting with conductive hearing loss in the ear canal: a case report and review of the literature.

INTRODUCTION: Pleomorphic adenoma accounts for 65 percent of all salivary gland tumors. It has been identified in several anatomical regions, but pleomorphic adenoma arising in the ear canal, first described in 1951, is extremely rare. CASE PRESENTATION: A 40-year-old Japanese man's left ear canal was obstructed by a pleomorphic adenoma that caused mild conductive hearing loss. The tumor was resected and he remains disease-free two years after surgery. CONCLUSIONS: Pleomorphic adenoma usually arises from a major and minor salivary gland, but pleomorphic adenoma of the ear canal is derived from the ceruminous gland. We discuss the present case and 37 other case reports in our effort to clarify the clinical features and the course of pleomorphic adenoma in the ear canal.

Nasopharyngeal pleomorphic adenoma presenting as otitis media with effusion: case report and literature review.

Most tumors arising in the nasopharynx are malignant and frequently develop otitis media with effusion (OME). On the contrary, benign nasopharyngeal tumors are very rare, and pleomorphic adenoma, which is a benign mixed tumor of the nasopharynx, is also rarely encountered. We herein report a case of nasopharyngeal pleomorphic adenoma which initially presented as OME. This tumor completely blocked the orifice of the Eustachian tube but was removed by a combination of transnasal and transoral endoscopic resection. A defect in the mucous membrane was covered with polyglycolic acid sheet and fibrin glue. Mucous membrane completely covered the exposed tubal cartilage without adhesion near the tubal orifice. OME and hearing loss completely subsided 3 months after the surgery. She was disease-free 2 years after the surgery. Use of polyglycolic acid sheet could be a feasible mesh for closure of surgical defect without scarring, and it also led to healing of OME.

Effect of catheter tip-tissue surface contact on three-dimensional left atrial and pulmonary vein geometries: potential anatomic distortion of 3D ultrasound, fast anatomical mapping, and merged 3D CT-derived images.

UNLABELLED: Anatomic Distortion of 3D Mapping. BACKGROUND: Although catheter tip-tissue contact is known as a reliable basis for mapping and ablation of atrial fibrillation (AF), the effects of different mapping methods on 3-dimensional (3D) map configuration remain unknown. METHODS AND RESULTS: Twenty AF patients underwent Carto-based 3D ultrasound (US) evaluation. Left atrium (LA)/pulmonary vein (PV) geometry was constructed with the 3D US system. The resulting geometry was compared to geometries created with a fast electroanatomical mapping (FAM) algorithm and 3D US merged with computed tomography (merged 3D US-CT). The 3D US-derived LA volumes were smaller than the FAM- and merged 3D US-CT-derived volumes (75 ± 21 cm(3) vs 120 ± 20 cm(3) and 125 ± 25 cm(3) , P < 0.0001 for both). Differences in anatomic PV orifice fiducials between 3D US- and FAM- and merged 3D US-CT-derived geometries were 6.0 (interquartile range 0-9.3) mm and 4.1 (0-7.0) mm, respectively. Extensive encircling PV isolation guided by 3D US images with real-time 2D intracardiac echocardiography-based visualization of catheter tip-tissue contact generated ablation point (n = 983) drop-out at 1.9 ± 3.8 mm beyond the surface of the 3D US-derived LA/PV geometry. However, these same points were located 1.5 ± 5.4 and 0.4 ± 4.1 mm below the FAM- and merged 3D US-CT-derived surfaces. CONCLUSIONS: Different mapping methods yield different 3D geometries. When AF ablation is guided by 3D US-derived images, ablation points fall beyond the 3D US surface but below the FAM- or merged 3D US-CT-derived surface. Our data reveal anatomic distortion of 3D images, providing important information for improving the safety and efficacy of 3D mapping-guided AF ablation. (J Cardiovasc Electrophysiol, Vol. 24, pp. 259-266, March 2013).

Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M.

The human and Old World primate genomes possess conserved endogenous retrovirus sequences that have been implicated in evolution, reproduction, and carcinogenesis. Human endogenous retrovirus (HERV)-K with 5'LTR-gag-pro-pol-env-rec/np9-3'LTR sequences represents the newest retrovirus family that integrated into the human genome 1 to 5 million years ago. Although a high-level expression of HERV-K in melanomas, breast cancers, and teratocarcinomas has been demonstrated, the mechanism of the lineage-specific activation of the long terminal repeat (LTR) remains obscure. We studied chromosomal HERV-K expression in MeWo melanoma cells in comparison with the basal expression in human embryonic kidney 293 (HEK293) cells. Cloned LTR of HERV-K (HML-2.HOM) was also characterized by mutation and transactivation experiments. We detected multiple transcriptional initiator (Inr) sites in the LTR by rapid amplification of complementary DNA ends (5' RACE). HEK293 and MeWo showed different Inr usage. The most potent Inr was associated with a TATA box and three binding motifs of microphthalmia-associated transcription factor (MITF). Both chromosomal HERV-K expression and the cloned LTR function were strongly activated in HEK293 by transfection with MITF-M, a melanocyte/melanoma-specific isoform of MITF. Coexpression of MITF and the HERV-K core antigen was detected in retinal pigmented epithelium by an immunofluorescence analysis. Although malignant melanoma lines MeWo, G361, and SK-MEL-28 showed enhanced HERV-K transcription compared with normal melanocytes, the level of MITF-M messenger RNA persisted from normal to transformed melanocytes. Thus, MITF-M may be a prerequisite for the pigmented cell lineage-specific function of HERV-K LTR, leading to the high-level expression in malignant melanomas.

Relationship between peroxisome proliferator-activated receptor-gamma activation and the ameliorative effects of ascochlorin derivatives on type II diabetes.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a crucial factor in the development of insulin resistance associated with type II diabetes. We previously found that 4-O-carboxymethyl ascochlorin, a derivative of ascochlorin, ameliorates diabetes and activates PPAR-gamma. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-gamma activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-gamma. Administration of these compounds significantly reduces blood glucose in a dose-dependent manner, whereas blood cholesterol is significantly elevated in 4-O-carboxymethyl-ascochlorin-treated mice but is significantly decreased in 4-O-methyl-ascochlorin-treated mice. Pioglitazone, a potent PPAR-gamma agonist with a thiazolidinedione structure, reduces glucose but elevates cholesterol blood levels. These results suggest that ascochlorin derivatives ameliorate diabetes through a mechanism that is probably independent of PPAR-gamma activation, although PPAR-gamma activation could be partially involved in the ameliorative effect in certain derivatives.

Synthesis of an alpha-fucosidase inhibitor, 5a-carba-beta-L-fucopyranosylamine, and fucose-type alpha- and beta-DL-valienamine unsaturated derivatives.

Discovery of a very potent alpha-fucosidase inhibitor 5a-carba-alpha-L-fucopyranosylamine led to preparation of its beta-anomer and the respective unsaturated derivatives, fucose-type alpha- and beta-valienamines, in order to elucidate the structure-activity relationship of carba-aminosugar inhibitors of this kind. Compound was demonstrated to be a potent inhibitor (K(i)=2.0 x 10(-7) M, bovine kidney), possessing ca. one-tenth of the activity of the parent. Interestingly, and were found to be rather weak inhibitors, contrary to the expectations based on the activity relationships between the alpha-glucosidase inhibitors, alpha-glucose-type validamine and valienamine.