Faculty Bibliography

To investigate the etiology of hole formation in the gerbil and rat central auditory system, organotypic cultures were grown in control and veratridine-containing media. The latter condition is known to increase neuronal activity. Tissue was obtained at postnatal day 6 and grown for 6-9 days in vitro, a period prior to the formation of holes in vivo. In both rats and gerbils, veratridine led to the appearance of large numbers of holes, and these were phenotypically similar to those found in vivo. These results support the idea that hole formation is an activity-dependent phenomenon, and suggest that it is not restricted to the mature gerbil auditory system

English-language skills were evaluated in two groups of profoundly hearing-impaired children with the Reynell Developmental Language Scales, Revised. The first group consisted of 89 deaf children who had not received cochlear implants. The second group consisted of 23 children wearing Nucleus multichannel cochlear implants. The subjects without implants provided cross-sectional language data used to estimate the amount of language gains expected on the basis of maturation. The Reynell data from the group without implants were subjected to a regression by age. On the basis of this analysis, deaf children were predicted to make half or less of the language gains of their peers with normal hearing. Predicted language scores were then generated for the subjects with implants by using the children's preimplant Reynell Developmental Language Scale scores. The predicted scores were then compared with actual scores achieved by the subjects with implants 6 and 12 months after implantation. Twelve months after implantation, the subjects demonstrated gains in receptive and expressive language skills that exceeded by 7 months the predictions made on the basis of maturation alone. Moreover, the average language-development rate of the subjects with implants in the first year of device use was equivalent to that of children with normal hearing. These effects were observed for children with implants using both the oral and total-communication methods

Leptospirosis is the most widespread zoonosis in the world. It is mostly an occupational disease especially in rural areas. Kolenchery is in the midlands of Kerala. The landscape consists of marshy land and dry land interspersed by rivulets and ponds. Irrigation of dry lands for cultivation during the summer months started in mid 1980s after the irrigation projects were commissioned. Cases of leptospirosis were rarely diagnosed in Kolenchery before 1987. Since then a yearly increase in incidence is observed. No major study on either epidemiology or clinical picture has been done on human leptospirosis in Kerala so far. The aim of this study was to define the major clinical presentations, epidemiology of the infection and demonstrate the predominant serogroups and serovars causing the illness in this limited geographical area. The study involves 976 cases of leptospirosis confirmed by culture and/or serological tests. Serogroups Autumnalis, Australis and Icterohaemorrhagiae were the commonest. Mortality rate was 5.32%. The increase in incidence is probably due to the geographical characteristics, continuous moisture of the soil due to irrigation in summer and year-round cultivation making food and cover available to host rodents. Close interaction of humans, animals, soil and water in this region make the spread of leptospirosis to humans easy. Confirmation of cases has been done by enzyme linked immunosorbent assay (ELISA) and/or microscopic agglutination test (MAT) and/or by culture. Serovar identification has been done in 21 cultures isolated from patients. One new serovar belonging to serogroup Australis has been identified from a patient and named serovar Australis bharathy

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.

Early cochlear implantation is desirable to effect maximal development of receptive and expressive language. Factors to consider in implanting before the age of 2 years include anatomic considerations, temporal bone growth and device extrusion or migration, the sequela of otitis media, and the accuracy of early diagnosis. Clinical experience and laboratory data indicate that cochlear implantation before the age of 2 years is possible

Analysis of the amino acid sequence encoded by the familial breast and ovarian cancer susceptibility gene, BRCA1 [Miki et al. (1994) Science 266, 66-71], revealed the presence of an amino-terminal RING finger domain, a zinc binding motif found in a variety of proteins. Previously determined structures of two RING finger peptides from other proteins revealed that each RING finger sequence forms a single domain that includes two interleaved metal binding sites. One is a four-cysteine site comprised of metal binding residues 1, 2, 5, and 6 (in terms of position along the amino acid sequence) (site 1) and the other is a three-cysteine, one-histidine site involving metal binding residues 3, 4, 7, and 8 (site 2). We have characterized the metal binding and metal-dependent folding properties of peptides encompassing the BRCA1 RING finger. Using cobalt(II) as a spectroscopic probe, we have found that metal binding is sequential, with site 1 becoming nearly fully occupied prior to metal binding to site 2. More detailed thermodynamic analysis as well as studies of a variant peptide revealed that metal binding appears to be anticooperative with dissociation constants of 3 x 10(-8) M for site 1, 5 x 10(-7) M for site 2 with site 1 unoccupied, and 8 x 10(-6) M for site 2 when site 1 is occupied. Circular dichroism spectroscopic studies revealed that the BRCA1 RING finger peptide is somewhat structured at pH 7 in the absence of metal ions, with further structural changes occurring after the metal binding

Recent studies demonstrate calcium ion influx at the tips of hair cell stereocilia during mechano-transduction. These ions must be either pumped from the cytosol into the extracellular space or endoplasmic envelope, or else sequestered by binding to specific proteins. A plasma membrane calcium pump (ATPase-type) was analysed in whole-mounts of rat organ of Corti using a monoclonal antibody to a large cytoplasmic loop of this protein. The reactivity was particularly high on the tips of longer stereocilia and was found along the shafts. Inner hair cell stereocilia had much less reactivity than outer hair cells. The reactivity lined the plasma membrane of inner hair cell bodies while a higher reactivity appeared in the cytoplasm of outer hair cells. Supporting cells were unreactive. Ultrastructural examination confirmed the plasma membrane calcium pump location on stereocilia and along the endolymph surface of receptor cells. Reaction product lined the plasma membrane of stereocilia as intense puncta. More reactive puncta occurred near the distal ends of stereocilia and the number decreased toward the ciliary base. The endolymph plasma membrane over the cuticular notch was especially reactive. The finding of more intense pump reactivity at the tips of stereocilia than the base is consistent with the hypothesis that during transduction, calcium ions enter stereocilia, distally, and the ATPase plasma membrane calcium pump rapidly extrudes these ions to the extracellular space

We review our experience treating patients with medically refractory frontal sinusitis that could not be relieved with endoscopic intranasal surgery alone. Fourteen combined external and intranasal endoscopic frontal sinusotomies were performed on a consecutive sample of 11 patients presenting over a 38-month period of study. Postoperative results were classified as cured, improved, unchanged, or worse, based on patient symptoms and physical findings. At a mean postoperative follow-up of 19 months (range 4-36), 100% of these patients had benefited from this technique (7 cured, 4 improved, 0 unchanged, 0 worse). There were no major complications and natural sinus physiology was preserved. We conclude that a combined external and endoscopic intranasal frontal sinusotomy is an effective alternative to frontal sinus obliteration