Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy.

Cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is a widely used, highly effective, oncolytic agent that has serious ototoxic side-effects. To test the effectiveness of local delivery, of L-methionine (L-Met) as an otoprotective agent against CDDP ototoxicity, we used a rat model of a highly metastatic breast cancer tumor, i.e. Fisher 344 rats implanted with MTLn3 breast cancer cells. Four experimental groups were evaluated--I: untreated; II: CDDP-treated (three dosages); III: systemically-delivered L-Met + CDDP-treated; IV: locally delivered L-Met + CDDP-treated. The integrity of the outer hair cells (OHCs) was determined using scanning electron microscopy (SEM); hearing was assessed by recording auditory brainstem responses (ABRs) at multiple frequencies. The chemotherapeutic effectiveness of CDDP was quantified by measuring changes in tumor mass and the presence of tumor metastasis. L-Met provided otoprotection of the OHCs against CDDP toxicity in the cochleae of rats following either systemic (III) or local (IV) administration. The ABRs were unchanged in each of the L-Met protection Groups (III and IV) and in the untreated animals of Group I. Treatment with CDDP only (II) induced significant hearing losses at both 16 and 18 kHz when compared to ABRs of untreated rats(I). CDDP was effective in controlling the MTLn3 initiated breast cancer tumors in the CDDP-treated (II) and the local L-Met protection, CDDP-treated (IV) Groups. In contrast, the tumors in the systemic L-Met protection, CDDP-treated Group (III) were not controlled by the CDDP treatment regime. This study demonstrates that local delivery of L-Met to the scala tympani of the cochlea via the round window membrane (IV) provides effective protection against CDDP ototoxicity without compromising its ability to control a highly metastatic form of cancer.

Neurophysiological indices of language impairment in children.

Recent investigations of children with specific language impairment (SLI) have found deviant anatomical asymmetry of the perisylvian cortex. These studies argue that this deviant anatomical asymmetry is linked to the language disorders of SLI children. To date no studies have examined whether deviant functional asymmetry underlies the processing of spoken language in these children. In the current study, brain-electrical activity was recorded from 31 scalp sites while children with SLI listened to auditorally presented stories and two different nonsense contexts. Electrical activity was time-locked to the grammatical word "the" in these contexts. The SLI children showed reversed asymmetry compared to control children from 200 ms to 400 ms in processing "the" in all contexts. More specifically, they showed depressed processing at the left temporal scalp site (T7) and enhanced processing at the right temporal site (T8). The second spatial derivative (the Laplacian) of the voltage activity was calculated to remove constant voltage potential and uniform changes in voltage potential across the scalp. The Laplacian analysis indicated that the sources of the positive electrical activity seen at the temporal electrode sites T7 and T8 are the lateral surfaces of the temporal cortices. A comparison of the scalp topography of the voltage potentials and Laplacian also suggests that children with SLI lack some contribution from a deep neural generator, possibly in the hippocampus or basal ganglia. This investigation is the first to demonstrate a direct link between deviant neurophysiological asymmetry and the processing of spoken language in children with SLI.

Efficacy of ofloxacin and other otic preparations for otitis externa.

Ofloxacin otic is as effective in curing otitis externa in children (<12 years of age) as is the preparation combining polymyxin/neomycin plus hydrocortisone and as ciprofloxacin otic. Furthermore ofloxacin otic, as it requires less frequent dosing, is likely to encourage greater patient adherence and consequently to achieve a better cure rate than both of these treatment options. Because a number of cases of otitis externa are complicated by an undiagnosed tympanic membrane perforation, the lack of ototoxicity associated with ofloxacin otic makes it a particularly safe option for use in these patients.

Redefining the survival of the fittest: communication disorders in the 21st century.

OBJECTIVES: To determine the economic effect on the US economy of the cost of caring for people with communication disorders as well as the cost of lost or degraded employment opportunities for people with such disorders, including disorders of hearing, voice, speech, and language. STUDY DESIGN: Survey of available historical and contemporary governmental and scholarly data concerning work force distribution and the epidemiology of disorders of hearing, voice, speech, and language. METHOD: Analysis of epidemiological and economic data for industrialized countries, North America, and the United States. RESULTS: Communication disorders are estimated to have a prevalence of 5% to 10%. People with communication disorders may be more economically disadvantaged than those with less severe disabilities The data suggest that people with severe speech disabilities are more often found to be unemployed or in a lower economic class than people with hearing loss or other disabilities. Communication disorders may cost the United States from $154 billion to $186 billion per year, which is equal to 2.5% to 3% of the Gross National Product. CONCLUSIONS: Communication disorders reduce the economic output of the United States, whose economy has become dependent on communication-based employment. This trend will increase during the next century. The economic cost and the prevalence rates of communication disorders in the United States indicate that they will be a major public health challenge for the 21st century.

Reversible sensorineural hearing loss following administration of muromonab-CD3 (OKT3) for cadaveric renal transplant immunosuppression.

This prospective study is a follow-up to a case report noting reversible sensorineural hearing loss after administration of OKT3 for immunosuppression in a steroid-resistant renal cadaveric transplant patient who was rejecting his transplant. The objective is to determine the interval estimate for incidence of sensorineural hearing loss following treatment with OKT3. Seven patients were admitted to the Renal Transplant Service at Montefiore Medical Center from July 1996 to July 1997 with steroid-resistant rejection of renal cadaveric transplants and received OKT3 as an immunosuppressant. All 7 patients received 3 audiograms: the first, prior to the administration of the first dose of OKT3, the second, 48 to 72 hours after administration of OKT3, and the third, approximately 2 weeks after administration of OKT3. Five of the 7 patients (71%) demonstrated a sensorineural hearing loss of 15 dB or greater at frequencies of 8 to 12 kHz. Four of the 5 patients with audiographic changes had near-complete to complete recovery of their high-frequency thresholds after discontinuation of the drug regimen. In conclusion, OKT3 can cause sensorineural hearing loss. This side effect is mainly reversible after 2 weeks following discontinuation of the drug. Patients receiving OKT3 should be forewarned of this possible side effect prior to the administration of OKT3.

Persistency of an effect: otitis media during the first year of life with nine years follow-up.

A cohort of lower socioeconomic-economic children who experienced multi and prolonged episodes of otitis media during their first year of life and followed for 9 years showed that all of the children had poorer performance in linguistic tasks than did the control group. Differences were found in all of the OM + children at all ages. The effect of the otitis media and its accompanying hearing loss was noted in eight measures throughout the 9-year period of observation.

Speech perception and verbal memory in children with and without histories of otitis media.

Two groups of children, with (n = 7) and without (n = 7) first-year histories of otitis media, were participants in a longitudinal study that included periodic audiological and medical evaluations during the first year of life. At age 9, these children were tested on a series of speech perception and verbal short-term memory tasks using stimuli of varying degrees of phonetic contrast. Although the otitis-positive group performed less accurately than the otitis-free group, the pattern of errors was the same for the two groups. The performances of the children with and without positive histories of otitis media were negatively affected by an increase in phonetic similarity of the stimulus items. The two groups, however, did not differ on identification or on temporal-order recall when the speech sounds were differentiated by multiple features. These findings provide evidence of subtle, long-term effects of early episodes of otitis media on phonological representations and on working memory.

Necessity versus sufficiency: the role of input in language acquisition.

There is data which indicates that the critical/sensitive period(s) for language development begins in the 6th month of fetal life and may be most susceptible to impairment during the first 2 years of life. There are observations which would indicate that the linguistic abilities which develop are dependent upon the amount of linguistic information available to the infant and are not dependent upon any particular receptive sensory mode. The challenge for the cochlear implant is to be able to transmit sufficient linguistic information--flux of information--during this period so that the resultant language is optimal. Language must be the primary outcome measure of the cochlear implant in the infant and young child.

A time frame of critical/sensitive periods of language development.

By a focus on three essential elements of language, phonology, semantics, and syntax, a time frame for critical/sensitive periods of language development is presented as a model of central auditory nervous system flexibility. Several studies support the hypothesis that the critical/sensitive period of phonology is from the sixth month of fetal life through the 12th month of infancy. Data indicates that the critical/sensitive periods for syntax runs through the fourth year of life, and for semantics through the 15th or 16th year of life. The data indicate that there is a time dependent series of functions in sequence that is based on responsive adaptations made by the CNS to psychophysical and electrophysiological stimuli.

Mammalian auditory hair cell regeneration/repair and protection: a review and future directions.

Regeneration/repair and protection of auditory hair cells and auditory neurons is an exciting, rapidly evolving field. Simultaneous developments in the fields of otobiology and surgical otology have led to new and exciting possibilities in inner ear medicine and surgery; specifically, the treatment or prevention of a variety of types of hearing losses in the foreseeable future. Sensorineural hearing loss in humans is commonly associated with a loss of auditory hair cells. It has been generally accepted that hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury. An organ of Corti explant study has shown that it is possible to initiate the regeneration/repair of mammalian hair cells. In this study, ototoxin-damaged organ of Corti explants from juvenile rats were treated with a combination of retinoic acid (10-8M) and fetal calf serum (10%). TGF-alpha has been identified as a growth factor capable of evoking auditory hair cell regeneration/repair in ototoxin-damaged organ of Corti explants. Preliminary in vitro experiments with juvenile rat organ of Corti explants and in vivo studies in the cochleae of adult guinea pigs indicate that pretreatment followed by continuous treatment of the inner ear with a combination of retinoic acid and TGF-alpha can protect the auditory hair cells from the ototoxic effects of aminoglycosides. Because the integrity of spiral ganglion neurons is also essential for normal auditory function, there is a parallel series of in vitro and in vivo studies of the effects of neurotrophic factors on the survival of auditory neurons and the regeneration of injured neuronal processes. Clinical studies have demonstrated that it is now possible to perform surgeries on the inner ear, i.e., partial or total labyrinthectomies, and maintain hearing. The field of cochlear implantation has also provided insights into both the short- and long-term effects of cochlear fenestration on inner ear function. Administration of growth factors to the inner ears of animals is now possible with the use of implanted catheters and miniature infusion pumps. These advances suggest that localized application of drugs to the human inner ear may be feasible. The aim of this paper has been to provide an overview of advances in the study of the biology of auditory hair cells and auditory neurons, as well as recent relevant surgical advances. Taken together, these advances in otobiology and surgery will, in the future, be combined to devise new and innovative treatments for inner ear disorders.

Use of organotypic cultures of Corti's organ to study the protective effects of antioxidant molecules on cisplatin-induced damage of auditory hair cells.

HYPOTHESIS: Cisplatin causes the generation of reactive oxygen species (ROS), which interferes with the antioxidant defense system of Corti's organ and results in damage to the hair cells. BACKGROUND: Cisplatin is a widely used chemotherapeutic agent with the dose-limiting side effect of ototoxicity. Evidence is accumulating that cisplatin interferes with the antioxidant defense system of Corti's organ. METHODS: Organotypic explants of P-3 rat organ of Corti were the in vitro model system. Presence of intact auditory hair cells and stereocilia bundle integrity was assayed by phalloidin-FITC staining. Fluorescent dye probes detected H2O2 and intracellular thiol [e.g., glutathione (GSH)]. Spectrophotometric analysis determined antioxidant enzyme levels. RESULTS: There was a rapid dose-dependent cisplatin cytotoxicity in the explants after 48 h of exposure. An accumulation of H2O2 and a reduction of GSH levels were observed within cisplatin-exposed hair cells. L-buthionine sulfoximine, an inhibitor of GSH formation, enhanced cisplatin ototoxicity, whereas N6-(2-phenylisopropyl) adenosine, an adenosine agonist, elevated antioxidant enzyme levels and ameliorated cisplatin toxicity. The following molecules protected hair cells from cisplatin-induced damage: GSH; glutathione diethyl ester (GSHe); ebselen (EBS); 4-methylthiobenzoic acid (MTBA); and D-methionine (D-MET). EBS, MTBA, and D-MET in vitro protection correlates with in vivo protection in rats. CONCLUSIONS: Organotypic culture of Corti's organ has been validated as a model for studying cisplatin toxicity and for screening otoprotective molecules. Some of the events that contribute to cisplatin's ability to damage auditory hair cells are generation of ROS (e.g., H2O2), depletion of intracellular GSH, and interference with antioxidant enzymes within the cochlea. Agents that bolster the cochlea's antioxidant system can prevent cisplatin destruction of auditory hair cells. Identified protective agents may prove to be clinically useful in limiting or completely protecting from cisplatin ototoxicity.

Eradication of communicative disorders: preventive medicine in the 21st century.

Profound changes in our society occurring over the past few decades have resulted in a major shift in societal emphasis from labor to communication. The widespread use of personal computers has enhanced the importance of information-communication in daily life. People with communication disorders are at substantial risk of underemployment and lowered quality of life. Advances in medical science and hearing health care have placed us on the thresholds of being able to correct, rather than remediate, certain types of hearing loss. The finding that auditory hair cells of submammalian species regenerate has stimulated greatly the field of auditory research. A new lexicon is required to describe this emerging field. Methods exist to protect against hearing loss, repair affected structures prior to their degeneration, promote dedifferentiation-redifferentiation of undamaged structures into sensory cells, and, finally, promote regeneration of new sensory cells from precursor cells. Each of these processes has unique requirements, and all may be required to promote the restoration of hearing following damage or disease.

A time frame of critical/sensitive periods of language development.

By a focus on three essential elements of language: phonology, semantics, and syntax, a time frame for critical/sensitive periods of language development is presented as a model of central auditory nervous system flexibility. Several studies support the hypothesis that the critical/sensitive period of phonology is from the 6th month of fetal life through the 12th month of infancy. Data indicate that the critical/sensitive periods for syntax run through the 4th year of life, and for semantics through the 15th or 16th year of life. The data indicate that there is a time dependent series of functions in sequence that is based on responsive adaptations made by the CNS to pyschophysical and electrophysiological stimuli.

Long-term communication deficiencies in children with otitis media during their first year of life.

A cohort of lower socio-economic children who experienced multiple episodes of otitis media (OM) during their first year of life were compared to a group of children who were largely free of OM during their first year. Both groups were followed until 9 years of age. The data indicate that some children with positive histories of OM performed poorer on a variety of communicative tasks across the 9 year age span than the children with the negative histories of OM. The results suggest that the effect of otitis media and its accompanying hearing loss on communication skills may extend throughout childhood.

Selection of pediatric patients for use of the Passy-Muir valve for speech production.

A potential side effect of tracheotomy in the pediatric population is poor speech development. It has been well documented that children with tracheotomies have delays in expressive and receptive language out of proportion to the child's degree of intellectual functioning. While numerous methods of augmentative devices have been proposed, none are ideal for the child with a tracheotomy. Of the choices available, the Passy-Muir valve is best suited for use in the pediatric population. We present a method of selection of patients for Passy-Muir valve placement currently in use at Blythedale Children's Hospital. The criteria employed include measurement of trans-tracheal pressures. This has not previously been presented in the literature, but has been found to be of significant value in determining who will benefit most from Passy-Muir valve placement.

Auditory consequences of early mild hearing loss associated with otitis media.

Two groups of children received periodic documentation of their middle ear status by pneumatic otoscopy in the first year of life and had hearing sensitivity estimated by multiple auditory brainstem response (ABR) assessments during the same period. One group was considered otitis media (OM)-positive, with repeated bilateral episodes of OM and mild conductive hearing loss. The second group was considered OM-free with normal middle ear function bilaterally and normal hearing sensitivity in the first year of life. Children's higher-order auditory abilities were examined at 4, 6 and 9 years of age. Various measures such as speech recognition-in-competition, visual-auditory learning, sound blending, auditory memory, and masking level difference estimates were utilized to probe the children's auditory abilities. Results show that children with a first-year history of otitis media demonstrate deficits in the long term in some aspects of higher-order auditory processing. Performance appears to be associated with the mild hearing loss experienced during an important period of early development.

Effect of neurotrophic factors on the inner ear: clinical implications.

Loss of auditory neurons is commonly associated with sensorineural deafness, and may result from either direct neuronal injury or be a consequence of sensory hair cell loss (i.e. loss of source of trophic factors). Developmental studies and in vitro studies of adult neurons have begun to identify growth factors important for the development, maintenance, and rescue/repair of auditory neurons. Specific neurotrophic factors have been shown to enhance the auditory neurons' ability to withstand traumatic loss of target tissue connections and toxic injury. Promising initial in vivo studies confirm that specific neurotrophins are able to support neuronal survival and promote neuronal repair in an intact animal following injury to the cochlea. Further study into unique methods and routes of growth factor delivery will provide insights into the possibility of neurotrophic growth factors to act as drugs for the treatment of injured or stressed auditory neurons.