Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

Reactive oxygen and reactive nitrogen species (ROS, RNS) formed in the inner ear in response to high-intensity noise are thought to play an important role in noise-induced hearing loss (NIHL). ROS appear rapidly and transiently in the inner ear during and following noise exposure, while hair cell loss progresses over time stabilizing two or more weeks after insult. Although the delayed loss may, in part, reflect slowly progressing apoptotic or necrosis pathways, an alternate hypothesis is that a continued formation of free radicals contributes to cell death. To evaluate this hypothesis, we measured auditory brain stem responses (ABRs), hair cell loss, and free radical activity in the guinea pig following noise exposure (5 h, 120 dB SPL, 1 OCB). Nitrotyrosine (NT) and 4-hydroxy-2-noneal (4-HNE) were used as histochemical markers of RNS and ROS formation, respectively. Assessments were performed prior to and on Days 1, 3, 7, 10, 14 and 21 after exposure. Immunoreactivity to NT and 4-HNE was low initially, reached a maximum at 7 to 10 days, and then declined. ABR thresholds increased maximally immediately after exposure, with partial recovery stabilizing at 7 to 10 days. Correlating with the delayed formation of ROS/RNS, there was a progressive hair cell loss, stabilizing at approximately 2 weeks. Based on these findings, we suggest that initial hair cell damage after noise may primarily reflect mechanical events plus transient intense ROS formation, while continued formation of ROS/RNS contributes to the long-term hair cell loss. The late formation of free radicals may provide a window of opportunity for pharmacological rescue immediately following exposure, requiring both ROS and RNS scavengers.

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Xeroderma pigmentosum (XP) is a genetic photosensitive disorder in which patients are highly susceptibe to skin cancers on the sun-exposed body sites. In Japan, more than half of patients (30% worldwide) with XP show complications of idiopathic progressive, intractable neurological symptoms with poor prognoses. Therefore, this disease does not merely present with dermatological symptoms, such as photosensitivity, pigmentary change and skin cancers, but is "an intractable neurological and dermatological disease". For this reason, in March 2007, the Japanese Ministry of Health, Labor and Welfare added XP to the neurocutaneous syndromes that are subject to government research initiatives for overcoming intractable diseases. XP is one of the extremely serious photosensitive disorders in which patients easily develop multiple skin cancers if they are not completely protected from ultraviolet radiation. XP patients thus need to be strictly shielded from sunlight throughout their lives, and they often experience idiopathic neurodegenerative complications that markedly reduce the quality of life for both the patients and their families. Hospitals in Japan often see cases of XP as severely photosensitive in children, and as advanced pigmentary disorders of the sun-exposed area with multiple skin cancers in adults (aged in their 20-40s), making XP an important disease to differentiate in everyday clinical practice. It was thus decided that there was a strong need for clinical practice guidelines dedicated to XP. This process led to the creation of new clinical practice guidelines for XP.

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Acoustic overstimulation increases Ca(2+) concentration in auditory hair cells. Because calcineurin is known to activate cell death pathways and is controlled by Ca(2+) and calmodulin, this study assessed the role of calcineurin in auditory hair cell death in guinea pigs after intense noise exposure. Immediately after noise exposure (4-kHz octave band, 120 dB, for 5 hr), a population of hair cells exhibited calcineurin immunoreactivity at the cuticular plate, with a decreasing number of positive-stained cells on Days 1-3. By Day 7, the levels of calcineurin immunoreactivity had diminished to near control, non-noise exposed values, concomitant with an increasing loss of hair cells. Staining of hair cell nuclei with propidium iodide (PI), restricted to calcineurin-immunopositive cells, indicated breakdown of cell membranes symptomatic of incipient cell death. The local application of the calcineurin inhibitors, FK506 and cyclosporin A, reduced the level of noise-induced auditory brain stem response threshold shift and hair cell death, indicating that calcineurin is a factor in noise-induced hearing loss. The results suggest that calcineurin inhibitors are of potential therapeutic value for long-term protection of the morphologic integrity and function of the organ of Corti against noise trauma.

The results of our study indicate that CCRT with TPF for locally advanced temporal bone cancer is an effective and promising regimen. © 2015 Wiley Periodicals, Inc. Head Neck 38: E949-E953, 2016.