Intracochlear drug delivery in combination with cochlear implants : Current aspects.

Local drug application to the inner ear offers a number of advantages over systemic delivery. Local drug therapy currently encompasses extracochlear administration (i. e., through intratympanic injection), intracochlear administration (particularly for gene and stem cell therapy), as well as various combinations with auditory neurosensory prostheses, either evaluated in preclinical or clinical studies, or off-label. To improve rehabilitation with cochlear implants (CI), one focus is the development of drug-releasing electrode carriers, e. g., for delivery of glucocorticosteroids, antiapoptotic substances, or neurotrophins to the inner ear. The performance of cochlear implants may thus be improved by protecting neuronal structures from insertion trauma, reducing fibrosis in the inner ear, and by stimulating growth of neuronal structures in the direction of the electrodes. Controlled drug release after extracochlear or intracochlear application in conjunction with a CI can also be achieved by use of a biocompatible, resorbable controlled-release drug-delivery system. Two case reports for intracochlear controlled release drug delivery in combination with cochlear implants are presented. In order to treat progressive reduction in speech discrimination and increased impedance, two cochlear implant patients successfully underwent intracochlear placement of a biocompatible, resorbable drug-delivery system for controlled release of dexamethasone. The drug levels reached in inner ear fluids after different types of local drug application strategies can be calculated using a computer model. The intracochlear drug concentrations calculated in this way were compared for different dexamethasone application strategies.

Topical application of the antiapoptotic TAT-FNK protein prevents aminoglycoside-induced ototoxicity.

We previously demonstrated that an artificial protein, TAT-FNK, has antiapoptotic effects against cochlear hair cell (HC) damage caused by ototoxic agents when applied systemically. To examine the feasibility of topical protein therapy for inner ear disorders, we investigated whether gelatin sponge soaked with TAT-FNK and placed on the guinea pig round window membrane (RWM) could deliver the protein to the cochlea and attenuate aminoglycoside (AG)-induced cochlear damage in vivo. First, we found that the immunoreactivity of TAT-myc-FNK was distributed throughout the cochlea. The immunoreactivity was observed from 1-24 h after application. When Tat-FNK was applied 1 h before ototoxic insult (a combination of kanamycin sulfate and ethacrynic acid), auditory brainstem response threshold shifts and the extent of HC death were significantly attenuated. When cochlear organotypic cultures prepared from P5 rats were treated with kanamycin, TAT-FNK significantly reduced the extent of caspase-9 activation and HC death. These findings indicate that TAT-FNK topically applied on the RWM can enter the cochlea by diffusion and effectively prevent AG-induced apoptosis of cochlear HCs by suppressing the mitochondrial caspase-9 pathway.

Efficacy and safety of zinc supplementation for adults, children and pregnant women with HIV infection: systematic review.

OBJECTIVES: To determine the efficacy and safety of zinc supplementary in children, adults and pregnant women with HIV infection. METHODS: We conducted a comprehensive search in Medline, Embase, the Cochrane Library, CBM, VIP and CNKI. Only randomized controlled trials conducted subsequent to the introduction of zinc supplementation were included in this systematic review. Two reviewers assessed and extracted data for analysis. RESULTS: Six trials with a total of 1009 participants were included. The findings in this review suggested a benefit of zinc supplementation in reducing opportunistic infection for both adults and children with HIV infection. In terms of increase in zinc level and CD4 counts, however, only adults with HIV infection benefited. For other outcomes, such as viral load, mortality, mother-to-child transmission of HIV and foetal outcomes, zinc supplementation conferred no benefit over placebo. No adverse event related to zinc supplementation was found in all the included trials. CONCLUSION: Based on the current evidence, zinc supplementation seems to be beneficial in adult patients with HIV infection in some aspects. More research is needed in children and pregnant women. The influence of zinc dose, duration and usage of antiretroviral medicine also requires further investigation.

FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity.

The use of amikacin (AMK) in present treatment strategies results in severe ototoxicity; however, the underlying molecular mechanisms of this toxicity remain unclear. In this study, we investigated the effectiveness of orally administered pomegranate peel extract (PPE), a strong antioxidant, as a protective agent against AMK-induced ototoxicity. To this end, PPE was orally administered to adult BALB/c mice for 5 days, and the mice were then concurrently treated with AMK (500 mg/kg/day for 15 consecutive days). Auditory threshold shifts induced by AMK were significantly attenuated. The results of immunohistochemical staining and western blot analysis revealed that PPE exerted its protective effects by by downregulating the phosphorylation of Forkhead box O3a (FoxO3a), an important transcription factor which is involved in the responses to oxidative stress. The results also showed that PPE treatment inhibited mitogen-activated protein kinase phosphorylation, prevented the activation of pro-apoptotic protein caspase-3, decreased the levels of apoptosis-inducing Bax protein, and increased the levels of the anti-apoptotic mediator, Bcl-2, induced by AMK in the mouse cochlea. Taken together, our experimental findings suggest that phosphorylated FoxO3a mediates AMK-induced apoptosis in BALB/c mice cochlea. PPE effectively attenuated oxidative stress and ototoxicity by regulating FoxO3a, and may thus prove to be beneficial in protecting auditory cells from ototoxic drugs.

MR safety issues particular to women.

Because of its lack of ionizing radiation, MR imaging is increasingly used for patients with cardiovascular disease, including young women. However, the risks related to the MR environment need to be acknowledged and prevented. For women, there are unique gender-related safety issues that are important to address in cardiovascular MR examinations. This article familiarizes radiologists with MR safety issues and current, evidence-based recommendations for specific situations such as pregnancy or lactation and imaging of women who have pelvic gynecologic devices such as intrauterine devices. Practical algorithms to minimize risk and increase MR safety for these women are suggested.

Robot-assisted stapedotomy: micropick fenestration of the stapes footplate.

OBJECTIVE: Micropick fenestration of the stapes footplate, a difficult step in stapedotomy, was selected for trials evaluating the potential for robotic assistance (RA) to improve clinical measures of surgical performance. STUDY DESIGN: In a surgical model of stapedotomy, we measured accuracy of fenestration to a desired point location and force applied to the stapes footplate. Performance variables were measured for 3 experienced and 3 less-experienced surgeons. RESULTS: RA significantly reduced the maximum force applied to the stapes footplate. For fenestration targeting, RA significantly improved accuracy for less-experienced surgeons and significantly worsened targeting for more-experienced surgeons. CONCLUSIONS: RA significantly improves performance for micropick fenestration in a surgical model of stapedotomy. For certain tasks, RA differentially affects performance for users of different experience levels. CLINICAL SIGNIFICANCE: These are the first results showing quantitative improvements in performance during simulated ear surgery using RA and differential effects of RA on performance for users of different experience levels.

The effects of superoxide dismutase in gerbils with bacterial meningitis.

BACKGROUND: Inflammatory products, such as oxygen radicals generated during the course of bacterial meningitis, can damage nerve endings, hair cells, and/or supporting cells in the cochlea. Superoxide dismutase (SOD), an O2-scavenger, has been shown to play an important role in the protection against radical toxicity in various animal experiments. OBJECTIVE: To study the antioxidant effects of SOD on the inflammatory response of gerbils with bacterial meningitis. STUDY DESIGN: Meningitis was induced in three groups of 10 gerbils by intrathecal (IT) injection of Streptococcus pneumoniae into the cisterna magna. Group 1 received IT SOD, group 2 received intramuscular (IM) SOD, and group 3, the control group, received IM normal saline. Histologic data and auditory brainstem responses (ABR) were obtained from each gerbil. RESULTS: Fibrosis and/or neo-ossification were near absent in the IT SOD group and significantly less fibrosis occurred in the IM group (IT vs. IM: P = 0.010; IT vs. control group: P = 0.001). The amount of surviving spiral ganglion cells correlated inversely with the extent of fibrosis (r = -0.753, P < 0.00001). CONCLUSIONS: IT injection of SOD significantly reduced cochlear fibrosis and neo-ossification, reduced the spiral ganglion cell loss, and decreased damage of the cochlear components following bacterial meningitis.

Cochlear implantation: strategies to protect the implanted cochlea from middle ear infection.

A cochlear implant for use in children must take into account the high incidence of middle ear infection in this age group. A scala tympani electrode that traverses the middle ear and round window will likely act as a conduit by which infection can spread to the inner ear and potentially to the CNS. In this study an attempt was made to reestablish a separation of the cochlea from the middle ear by developing a seal around the implant at the level of the round window. A series of cats were implanted with simulated cochlear prostheses consisting of either a plain Silastic cylinder, a Silastic cylinder wrapped with autogenous fascia, or a Silastic cylinder with a cuff of bioactive ceramic. Middle ear infection was induced, followed by histologic examination. Bioactive ceramic appears to have some merit as a round window sealing material, while fascia was shown to be of no value. Intracochlear infection, when it did occur, was limited to the basal regions of the cochlea.

[These vestibular problems in the absence of gravity...]. / Ces problèmes vestibulaires sans gravité....

For a few years, more and more astronauts complain to endure space motion sickness during the two or three first days of their mission. This is due to the repetition of shifting and sudden head movements, which becomes possible by the increasing of volume of the new space stations. To avoid that payload specialists onboard be obliged to renounce to conduct planned experiments, it has been necessary to find effective solutions to detect by ground based tests the candidates sensitive to space motion sickness and perfect therapeutic means able to avoid unexpected arrival of these symptoms, and even to treat them. The best results are undeniably obtained by the "Biofeedback" and the "tolerance" training, but we base wide hopes on ginger roots and on tolerance with sensorial deprivation lockers. However, we must not disregard the trigger action of emotional factors and anxiety in space motion sickness. The European mission SPACELAB-1 has been marked by the display of a caloric nystagmus during the vestibular experiments in weightlessness. If no explanation is given to this phenomenon, it will be necessary to call in question the role of the thermal convection described by Barany in the appearance of the caloric nystagmus.

"In-bone" utricle cultures--a simplified, atraumatic technique for in situ cultures of the adult mouse (Mus musculus) utricle.

HYPOTHESIS: The "in-bone" method of culturing utricles described here is a reliable and atraumatic technique for culturing mature mouse hair cells and studying hair cell death and protection. BACKGROUND: The current in vitro technique for studying hair cells of the mature mouse utricle involves removal from the temporal bone and free floating culture in media. This technique can be problematic because of variability in the preservation of the sensory epithelium and a steep learning curve that results in injury of the sensory epithelium in less experienced hands. We present a new atraumatic technique of culturing the utricle in situ within the temporal bone. METHODS: Leaving the temporal bone largely intact, a window is opened in the bony vestibule overlying the mouse utricle. The entire temporal bone is then placed into culture media. Utricles were cultured in situ for several days with minimal damage to the epithelium. The utricles are then fixed in situ, removed from the temporal bone, and processed. A standardized aminoglycoside-induced hair cell damage protocol was developed. RESULTS: Mature mouse utricles maintained hair cell numbers for 3 days in culture. Exposure to neomycin resulted in significant dose-dependent hair cell toxicity (p < 0.0001, 1-way analysis of variance). Exposure to the protective drug tacrine resulted in significant protection against neomycin (p < 0.05, 3-way analysis of variance). CONCLUSION: The "in-bone" technique is a reliable and atraumatic method for culturing mature mouse utricles and studying hair cell death and protection. It is easily mastered and can make in vitro study of hair cells accessible to more research groups.

The protective effect of Ginkgo biloba extract against experimental cisplatin ototoxicity: animal research using distortion product otoacoustic emissions.

BACKGROUND: Cisplatin, an effective therapeutic agent for various human cancers, has dose-limiting side effects of ototoxicity and nephrotoxicity. Cisplatin ototoxicity is thought to result from increased amounts of toxic free radicals or cell membrane changes leading to increased intracellular calcium content. Ginkgo biloba extract prevents lipid peroxidation, decreases intracellular free oxygen radical levels, regulates the cell membrane calcium transport mechanism and prevents cell death. This study aimed to investigate the protective effect of Ginkgo biloba extract against cisplatin-induced ototoxicity in rats. METHODS: Twenty Wistar albino rats with normal hearing (confirmed by distortion product otoacoustic emission testing prior to cisplatin application) were randomly allocated to two groups. Both groups received a single intraperitoneal dose of cisplatin (12 mg/kg). Group two also received daily intraperitoneal doses of Ginkgo biloba extract (100 mg/kg) for 10 days. Distortion product otoacoustic emission measurements were repeated on days 10 and 17 and signal-to-noise ratios were compared. RESULTS: Compared with group one, group two had significantly better distortion product otoacoustic emission results at 3, 4, 6 and 8 kHz on days 10 and 17. CONCLUSION: These findings suggest that Ginkgo biloba extract protects the inner ear against cisplatin-induced ototoxicity.

Effect of cochleostomy size on perilymph fistula control.

OBJECTIVES/HYPOTHESIS: Although the overall incidence of perilymphatic gushers is approximately 1%, patients with inner ear anomalies are at an increased risk for development of perilymphatic gushers. As cochlear implantation becomes more common in patients with inner ear anomalies (e.g., Mondini defect or common cavity defect), the ability to successfully seal such leaks becomes of paramount importance to reduce the risk of subsequent meningitis. METHODS: A 1.0-mm and a 1.5-mm cochleostomy were placed superior to the round window in two respective temporal bones. Cochlear implant electrodes (Cochlear [Lane Cove NSW, Australia], Med-El [Insbruck, Austria] and Advanced Bionics [Valencia, CA]) were placed in the cochleostomy and sealed with porcine periosteum. A fixed amount of pressure was applied to the inner ear, and the presence or absence of a leak was recorded for 10 different packings of each cochleostomy diameter at 0, 10, 15, 20, and 30 cm H(2)O. RESULTS: For the Cochlear, Med-El, and Advanced Bionics electrode, no statistically significant difference was noted between the 1.0-mm and the 1.5-mm cochleostomy at 0, 10, 15, and 20 cm H(2)O. At 30 cm H(2)O, no leaks were noted with the 1.5-mm cochleostomy for any brand. For the 1.0-mm cochleostomy at 30 cm H(2)O, 6/10 of the Cochlear trials leaked (P = .004), 2/10 of the Med-El trials leaked (P = .24), and 5/10 of the Advanced Bionics trials leaked (P = .03). CONCLUSIONS: The 1.5-mm cochleostomies are associated with a decreased risk of perilymphatic fistula as compared to 1.0-mm cochleostomies at 30 cm H(2)O; this likely represents a phenomenon of packing adequacy.

Future approaches for inner ear protection and repair.

UNLABELLED: Health care professionals tending to patients with inner ear disease face inquiries about therapy options, including treatments that are being developed for future use but not yet available. The devastating outcome of sensorineural hearing loss, combined with the permanent nature of the symptoms, make these inquiries demanding and frequent. The vast information accessible online and the publicity for breakthroughs in research add to patient requests for access to advanced and innovative therapies, even before these are available for clinical use. This can sometimes be taxing on the health care provider who is in contact with the patients. Here we aim to equip the provider with information about some of the progress made for protective and reparative approaches for treating inner ears. LEARNING OUTCOMES: (1) Readers will be able to explain why hearing loss is irreversible and common, (2) readers will be able to explain the importance of protective measures and the progress made in discovery and design of novel biological protective molecules, (3) readers will be able to describe reparative approaches currently under investigation (such as tissue engineering), the main difficulties in the design of such therapies and the major hurdles that remain for making novel technologies clinically viable, and (4) readers will be able to explain to their patients some of the progress in developing new treatments without making the promise of imminent clinical use. With this information, readers will be able to guide patients to make better choices for their treatment and to guide students toward research in this exciting field.