Tetrabromobisphenol-A induces apoptotic death of auditory cells and hearing loss.

Phenolic tetrabromobisphenol-A (TBBPA) and its derivatives are commonly used flame-retardants, in spite of reported toxic effects including neurotoxicity, immunotoxicity, nephrotoxicity, and hepatotoxicity. However, the effects of TBBPA on ototoxicity have not yet been reported. In this study, we investigated the effect of TBBPA on hearing function in vivo and in vitro.

Panel 4: Recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models.

Background: Otitis media (OM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating OM based on full understanding of molecular pathogenesis in the areas of molecular biology, biochemistry, genetics, and animal model studies in OM.

Objective: To provide a state-of-the-art review concerning recent advances in OM in the areas of molecular biology, biochemistry, genetics, and animal model studies and to discuss the future directions of OM studies in these areas.

Cisplatin ototoxicity involves cytokines and STAT6 signaling network.

We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4(-/-), but not in STAT6(-/-) mice. Moreover, the expression levels of the protein and mRNA of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4(-/-), but not STAT6(-/-) mice.

Evidence that cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/HO-1.

Recently, we demonstrated that pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 played a critical role in cisplatin-induced cochlear injury and that flunarizine, known as a T-type Ca(2+) channel antagonist, induced a cytoprotective effect against cisplatin cytotoxicity in HEI-OC1 cells by the activation of NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade through PI3K-Akt signaling but calcium-independent pathway. We report here that flunarizine markedly attenuates cisplatin-induced pro-inflammatory cytokine secretion and their messenger RNA transcription as well as cisplatin cytotoxicity through the activation of Nrf2/HO-1 and downregulation of NF-kappaB. In HEI-OC1 cells, overexpression of Nrf2/HO-1 by gene transfer or pharmacological approaches attenuated cisplatin-induced cytotoxicity and pro-inflammatory cytokine production.

Expression of water channel proteins (aquaporins) in the rat Eustachian tube and middle ear mucosa.

Conclusion: Diverse expression of the different subtypes of aquaporins in different parts of the Eustachian tube and middle ear suggests region-specific functions of the aquaporins in the normal physiology of the tubotympanum and also suggests that they may play roles in the pathophysiology of otitis media.

Objectives: The epithelial cells of the middle ear and Eustachian tube must maintain adequate water balance for normal function of the mucociliary system. Since aquaporins (AQPs) are known to play critical roles in water homeostasis, we investigated their expression in the tubotympanum of the rat.

Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB.

The ototoxicity of cisplatin, a widely used chemotherapeutic agent, involves a number of mechanisms, including perturbation of redox status, increase in lipid peroxidation, and formation of DNA adducts. In this study, we demonstrate that cisplatin increased the early immediate release and de novo synthesis of proinflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6, through the activation of ERK and NF-kappaB in HEI-OC1 cells, which are conditionally immortalized cochlear cells that express hair cell markers. Both neutralization of proinflammatory cytokines and pharmacologic inhibition of ERK significantly attenuated the death of HEI-OC1 auditory cells caused by cisplatin and proinflammatory cytokines.

Spiral ligament fibrocytes release chemokines in response to otitis media pathogens.

Conclusion: Spiral ligament fibrocytes (SLFs) may be involved in the innate immune response of the inner ear by producing chemoattractants for recruiting inflammatory cells such as neutrophils and monocytes.

Objective: The purpose of this study was to investigate the cellular responses of SLFs when challenged by inflammatory stimuli such as components of otitis media pathogens or proinflammatory cytokines.

Materials And Methods: To detect released inflammatory cytokines and chemokines, cells were treated for 48 h with whole lysates of nontypable Haemophilus influenzae (NTHi), Streptococcus pneumoniae, or with interleukin 1 alpha (IL-1alpha).

Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human beta-defensin 2 in middle ear epithelial cells.

Background: We recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of beta-defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components.

Methods: The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM).

Expression of female sex hormone receptors in human middle-ear cholesteatomas.

The purpose of this study was to establish the eventual presence of progesterone receptor (PGR) and oestrogen receptor (EGR) in human middle-ear cholesteatoma (MECh) tissues and to compare their expression between male and female patients. An immunohistochemical technique was employed for detection of PGR- and EGR-specific immunoreactivity in MECh samples using formalin-fixed paraffin-embedded tissue sections. The positive results were verified with reverse transcriptase polymerase chain reaction (RT-PCR).

Expression of hepatocyte growth factor and c-Met in hypopharyngeal squamous cell carcinoma.

Conclusion: Our results suggest that hepatocyte growth factor (HGF) may play an important role in the progression of hypopharyngeal cancer.

Objective: HGF, a potent stimulator of hepatocyte growth, stimulates the motility, invasiveness, proliferation and morphogenesis of epithelium and may be involved in physiologic and pathologic processes such as embryogenesis, wound healing, organ regeneration, inflammation and tumor invasion. We therefore examined the role of HGF and c-Met in the invasion and metastasis of hypopharyngeal squamous cell carcinoma (SCC).

Nucleoplasm staining patterns and cell cycle-associated expression of Ki-67 in middle ear cholesteatoma.

Objectives: To compare Ki-67 expression patterns in middle ear cholesteatoma with the corresponding retroauricular and external auditory canal skins, and to determine the cell cycle-dependent localization of Ki-67.

Material And Methods: MIB-1 monoclonal antibody was used for comparative assessment of proliferative activity of middle ear cholesteatoma, external auditory canal skin, and retroauricular skin samples on formalin-fixed paraffin-embedded tissue sections. Primary keratinocytes from cholesteatoma tissue were isolated and subjected to kinetic analysis of the cell cycle.

Three cases of Waardenburg syndrome type 2 in a Korean family.

Waardenburg syndrome (WS) is a rare, autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary disturbances of the skin, hair, and iris, and other developmental defects such as lateral displacement of both medial canthi and lacrimal puncta called dystopia canthorum. While mutations of the PAX3 (paired box) gene have been identified in about 99% of WS type 1 cases, WS type 2 is a heterogeneous group, with about 15% of cases caused by mutations in microphthalmia associated transcription factor (MITF). We have experienced three cases of typical WS type 2 in a Korean family, for whom full ocular examination and genetic studies were performed.

3D micro-CT images of ossicles destroyed by middle ear cholesteatoma.

Objectives: To reconstruct the 3D structures of normal ossicles and ossicles destroyed by different cholesteatomas, and to compare the volume fractions of the two types of ossicles.

Materials And Method: Thirteen pathological ossicles from four kinds of middle ear cholesteatoma obtained during surgery were used. Normal ossicles harvested from cadaveric temporal bone specimens were used as controls.

Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae.

Background: Despite its direct connection to the nasopharynx which harbors otitis media pathogens as part of its normal flora, the middle ear cavity is kept free of these bacteria by as yet unknown mechanisms. Respiratory mucosal epithelia, including those of the middle ear and eustachian tube, secrete antimicrobial effectors including lysozyme, lactoferrin and beta defensins-1 and -2. To elucidate the role of these innate immune molecules in the normal defense and maintenance of sterility of respiratory mucosa such as that of the middle ear, we assessed their effect on the respiratory pathogens nontypeable Haemophilus influenzae (NTHi) 12, Moraxella catarrhalis 035E, and Streptococcus pneumoniae 3, and 6B.

Various causes and clinical characteristics in vertigo in children with normal eardrums.

Objective: The differential diagnosis of vertigo in children is extensive. Otitis media and middle ear effusion could be the most common causes of vertigo in children, but there are some problems in detecting the other causes for vertigo because they are one of most frequent diseases of childhood. The purpose of this study is to review the clinical characteristics and both the audiological and vestibular findings of vertigo in children with normal eardrums, who do not show otitis media or middle ear effusion, and to assist in making a differential diagnosis of vertigo.

Expression of beta-defensins in human middle ear cholesteatoma.

Objective: To establish the eventual presence of human beta-defensins (hBD) in middle ea r cholesteatoma and paired retroauricular skin samples obtained during surgical treatment.

Material And Methods: hBD were detected using immunohistochemical techniques and reverse transcriptase-polymerase chain reaction (RT-PCR).

Results: It is hypothesized that hBD-1 and -2 are upregulated in cholesteatoma in comparison with retroauricular skin.

Immortalization of rat eustachian tube epithelial cells by adenovirus 12-simian virus 40 hybrid virus.

The eustachian tube epithelial cells play an important role in the initial pathogenesis of otitis media. In order to study the role of the eustachian tube epithelial cells in the pathogenesis of otitis media, we have established a rat eustachian tube epithelial cell line. The cell line was derived by infecting primary cultures of eustachian tube epithelial cells with the adenovirus 12-simian virus 40 (Adl2-SV40) hybrid virus.

Functional study of GJB2 in hereditary hearing loss.

Objectives/hypothesis: The gene of the gap junction protein connexin 26 (Cx26) was found to be the main causative gene of autosomal recessive nonsyndromic hearing loss (DFNB1). Although 35delG has been known as the major mutation in Western countries, 235delC was reported to be a specific form of mutation in Asian populations. The objective of the study was to identify how 235delC and E114G changes found in the Korean population affected the function of using molecular biological techniques.

Immortalization of normal adult human middle ear epithelial cells using a retrovirus containing the E6/E7 genes of human papillomavirus type 16.

A human middle ear epithelial cell line (HMEEC-1) was established using human papillomavirus E6/E7 genes. HMEEC-1 has remained morphologically and phenotypically stable, even after 50 passages. The cells are anchorage-dependent and nontumorigenic when injected into nude mice.

Activation of a Src-dependent Raf-MEK1/2-ERK signaling pathway is required for IL-1alpha-induced upregulation of beta-defensin 2 in human middle ear epithelial cells.

beta-defensin 2 is produced by a variety of epithelial cell types in the body and exhibits potent antimicrobial activity against a variety of pathogens, including the bacteria that are most commonly associated with otitis media (OM). The human beta-defensin 2 (hBD-2) gene is an NF-kappa B regulated gene and a variety of proinflammatory stimuli can induce its expression. Although the presence of molecules of innate immunity such as lysozyme and lactoferrin has been demonstrated in the middle ear, to date there have been no reports on the expression of beta-defensin 2.