The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1α-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1α, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells.

The aim of this study is to elucidate the detailed mechanism of endoplasmic reticulum (ER) stress-induced auditory cell death based on the function of the initiator caspases and molecular complex of necroptosis. Here, we demonstrated that ER stress initiates not only caspase-9-dependent intrinsic apoptosis along with caspase-3, but also receptor-interacting serine/threonine kinase (RIPK)1-dependent necroptosis in auditory cells. We observed the ultrastructural characteristics of both apoptosis and necroptosis in tunicamycin-treated cells under transmission electron microscopy (TEM). We demonstrated that ER stress-induced necroptosis was dependent on the induction of RIPK1, negatively regulated by caspase-8 in auditory cells. Our data suggested that ER stress-induced intrinsic apoptosis depends on the induction of caspase-9 along with caspase-3 in auditory cells. The results of this study reveal that necroptosis could exist for the alternative backup cell death route of apoptosis in auditory cells under ER stress. Interestingly, our data results in a surge in the recognition that therapies aimed at the inner ear protection effect by caspase inhibitors like zVAD-fmk might arrest apoptosis but can also have the unanticipated effect of promoting necroptosis. Thus, RIPK1-dependent necroptosis would be a new therapeutic target for the treatment of sensorineural hearing loss due to ER stress.

In the 19th century, Politzer devised a method to measure passage of the Eustachian tube (ET) by pressurizing the nasopharyngeal cavity, which marked the beginning of the ET function test. Since then, various examination methods have been developed. While ET function testing is important, recent advancements in diagnostic imaging and treatments have renewed interest on its importance. In Japan, the main objective methods used for examining ET function include tubotympanoaero-dynamic graphy (TTAG), sonotubometry, and the inflation-deflation test. The Japan Otological Society (JOS) Eustachian Tube Committee has proposed a manual of ET function tests, which presents typical patterns of the normal ear and typical diseases and suggests the ET function test of choice for each disease. However, the diagnosis of each disease should be made based on a comprehensive history and various examination findings, with ET function tests playing a supplemental role in the diagnosis.

Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance. Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17. In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL. Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.

Background: Bow Hunter’s Syndrome (BHS) is known as one of cervical diseases which causes vertigo, but the details of its vertigo, especially nystagmus and eye movement, are still incompletely understood. This time, we reported the first case of BHS with a nystagmus chart with video record of transitional nystagmus. Case presentation: The patient, a 47-year-old female, complained of vertigo caused by head rotation. When she turned her head leftward, leftward nystagmus appeared, and this was followed by dullness of the right arm. After her head was returned to the central position, downbeat nystagmus appeared, which changed to rightward nystagmus. She was diagnosed with BHS by her symptoms and images. We recorded a nystagmus video and nystagmus chart of this transitional nystagmus including downbeat nystagmus. Her vertigo was cured by the modification of a prescription for her past medical history: hypertension. Conclusion: The vertigo of BHS accompanies nystagmus. In this present case, the transitional nystagmus was observed, and it occurred toward the healthy side. Then the nystagmus direction was changed to the affected side via downbeat nystagmus. This is the first report with both a nystagmus chart with video of BHS. Nowadays, various kinds of vertigo induced by neck movement are known. BHS is a rare disease among vertigo diseases, but we should consider it as a different diagnosis of vertigo patients. A precise interview and proper examination are required to make the final diagnosis.