Development of a viral vector that can infect hair cells of the cochlea without producing viral-associated ototoxic effects is crucial for utilizing gene replacement therapy as a treatment for certain forms of hereditary deafness. In the present study, cochlear function was monitored using distortion-product otoacoustic emissions (DPOAEs) in guinea pigs that received infusions of either (E1(-), E3(-)) adenovirus, or adeno-associated virus (AAV), directly into the scala tympani. Replication-deficient (E1(-), E3(-)) adenovirus-directed gene transfer, using the cytomegalovirus (CMV) promoter, drove transgene expression to inner hair cells and pillar cells of the cochlea. AAV transduction was tested with several promoters, such as platelet-derived growth factor (PDGF), neuron-specific enolase (NSE), and elongation factor 1alpha (EF-1alpha) promoters; which drove transgene expression to cochlear blood vessels, nerve fibers, and certain spiral limbus cells, respectively. AAV transgene expression was visualized by green fluorescent protein immunostaining. Immunocytochemistry to heparan sulfate confirmed the absence of proteoglycans in guinea pig hair cells, indicating that the receptor for AAV was not present on these cells. However, the heparan sulfate proteoglycan expression pattern mimicked the AAV transduction pattern. An overall finding was that cochlear function was not altered throughout the infection period using AAV titers as high as 5 x 10(8) IP/infused cochlea. In contrast, cochlear function was severely compromised by 8 days postinfection with adenoviral titers of 5 x 10(8) PFU/infused cochlea, and outer hair cells were eliminated. Thus, cochlear hair cells are amenable to in vivo gene transfer using a replication-deficient (E1(-), E3(-)) adenovirus. However, replication-defective or gutted adenovirus vectors must be employed to overcome the ototoxic effects of (E1(-), E3(-)) adenovirus vectors.

Large intersubject variabilities in acoustic injury are known to occur in both humans and animals; however, the mechanisms underlying such differences are poorly understood. The olivocochlear efferent system has been hypothesized to play a significant role in protecting the cochlea from noise overexposure. In this study, we demonstrate that a newly developed test for determining average efferent system strength can predict intersubject variations in acoustic injury. In addition, the intersubject variability in cochlear expression of the alpha9 subunit of the nicotinic acetylcholine receptor was found to be proportional to an animals average efferent strength. Therefore, the inter-animal variability in the alpha9-containing acetylcholine receptor expression may be one mechanism contributing to the inter-animal variability in acoustic injury.

Psychophysical, basilar-membrane (BM), and single nerve-fiber tuning curves, as well as suppression of distortion-product otoacoustic emissions (DPOAEs), all give rise to frequency tuning patterns with stereotypical features. Similarities and differences between the behaviors of these tuning functions, both in normal conditions and following various cochlear insults, have been documented. While neural tuning curves (NTCs) and BM tuning curves behave similarly both before and after cochlear insults known to disrupt frequency selectivity, DPOAE suppression tuning curves (STCs) do not necessarily mirror these responses following either administration of ototoxins [Martin et al., J. Acoust. Soc. Am. 104, 972-983 (1998)] or exposure to temporarily damaging noise [Howard et al., J. Acoust. Soc. Am. 111, 285-296 (2002)]. However, changes in STC parameters may be predictive of other changes in cochlear function such as cochlear immaturity in neonatal humans [Abdala, Hear. Res. 121, 125-138 (1998)]. To determine the effects of noise-induced permanent auditory dysfunction on STC parameters, rabbits were exposed to high-level noise that led to permanent reductions in DPOAE level, and comparisons between pre- and postexposure DPOAE levels and STCs were made. Statistical comparisons of pre- and postexposure STC values at CF revealed consistent basal shifts in the frequency region of greatest cochlear damage, whereas thresholds, Q10dB, and tip-to-tail gain values were not reliably altered. Additionally, a large percentage of high-frequency lobes associated with third tone interference phenomena, that were exhibited in some data sets, were dramatically reduced following noise exposure. Thus, previously described areas of DPOAE interference above f2 may also be studied using this type of experimental manipulation [Martin et al., Hear. Res. 136, 105-123 (1999); Mills, J. Acoust. Soc. Am. 107, 2586-2602 (2002)].

Cutan eous muco n nycosis is an uncomnion, life-t hreatening, opportunistic fun gal infe ction that is a distin ctly different entity from the more frequent alth ough stiil IIIl COlllmOIl rhinocerebral fo rm that is better known to otolaryngologists. We describe what to our knowledge is the only reported case ofcutaneous mu corm ycosis ofthe fa ce with parotid gland invo lvetnent, which occurred in a 56-year-old man. The diagnosis was established by tissue biopsy. The patient was treat ed with antifunga l tnedications and wide local debridement, including a total parotidectomy with sacrifice of the inferior division of the fac ial nerve. At the 2-yearfollow-lIp, he rema inedfree of disea se. Familiarity with the risk fa ctors associat ed with the developm ent of cutaneous muconnycosis is critica l to detem üning the needfor early tissue biopsy to confi rm the diagn osis. Generally favora ble clinical outcomes are associat ed with prompt and aggressive medi cal and surgical therapy.

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