Joel Lavinsky

Genome-Wide Association Study Identifies Nox3 as a Critical Gene for Susceptibility to Noise-Induced Hearing Loss

In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

Effectiveness of hypopharyngeal packing during nasal and sinus surgery in the prevention of PONV

Objective Evaluate the hypopharyngeal packing effectiveness on prevention of postoperative nausea and vomiting (PONV) in nasal surgery. Study Design and Setting A randomized clinical trial was conducted from July 2004 to October 2005. The intervention group was submitted to hypopharyngeal packing after orotracheal tube placement. The control group had no hypopharyngeal packing. Occurrence of nausea, vomiting, use of antiemetic drugs, and throat pain were checked blindly on recovery period. Results One hundred forty-four patients were included in the study. There was no difference related to postoperative nausea (RR 1.34; CI 0.72–2.48), vomiting (RR 0.52; CI 0.19–1.47), use of anti-emetic drugs (RR 1.54; CI 0.80–2.95), and throat pain (RR 0.91; 0.62–1.34) between both groups. A beta error could not be excluded. CONCLUSION: Results suggest there is no benefit in hypopharyngeal packing on PONV prevention in nasal surgery. New studies with a greater number of patients should be carried out in order to confirm these results.

Transcanal Cochleostomy in Cochlear Implantation: Experience with 50 Cases

Abstract The traditional access route for cochlear implantation was initially proposed by William House in 1961. Alternatives to this surgical approach have been suggested by many authors. The combined approach technique (CAT) is a variation of the traditional mastoidectomy-posterior tympanotomy method, which uses a transcanal approach to cochleostomy combined with a small mastoidectomy and an equally small posterior tympanotomy for the insertion of electrodes. This paper presents a detailed description of this alternative procedure, reporting our experience with 50 cases, and adds our contribution regarding possible advantages and implications of using a transcanal cochleostomy. The subjects had profound and severe bilateral hearing loss and had not benefited from external hearing aids. They underwent cochlear implantation at Hospital de Clinicas de Porto Alegre from May 2003. The median follow-up was 29 months. All cases were successfully implanted using CAT. No major complications, such as facial paralysis or paresis, meningitis, cholesteatoma, or cerebrospinal fluid leaks, were observed in any patient. The CAT is a safe and efficient variation of cochlear implantation surgery, which is especially appropriate if cochlear calcification or malformations are present, or whenever cochleostomy has to be performed anteriorly, and when the position of the facial nerve prevents an adequate posterior tympanotomy.

The Genetic Architecture of Hearing Impairment in Mice: Evidence for Frequency-Specific Genetic Determinants.

Genome-wide association studies (GWAS) have been successfully applied in humans for the study of many complex phenotypes. However, identification of the genetic determinants of hearing in adults has been hampered, in part, by the relative inability to control for environmental factors that might affect hearing throughout the lifetime, as well as a large degree of phenotypic heterogeneity. These and other factors have limited the number of large-scale studies performed in humans that have identified candidate genes that contribute to the etiology of this complex trait. To address these limitations, we performed a GWAS analysis using a set of inbred mouse strains from the Hybrid Mouse Diversity Panel. Among 99 strains characterized, we observed approximately two-fold to five-fold variation in hearing at six different frequencies, which are differentiated biologically from each other by the location in the cochlea where each frequency is registered. Among all frequencies tested, we identified a total of nine significant loci, several of which contained promising candidate genes for follow-up study. Taken together, our results indicate the existence of both genes that affect global cochlear function, as well as anatomical- and frequency-specific genes, and further demonstrate the complex nature of mammalian hearing variation.

Large-scale phenotyping of noise-induced hearing loss in 100 strains of mice.

A cornerstone technique in the study of hearing is the Auditory Brainstem Response (ABR), an electrophysiologic technique that can be used as a quantitative measure of hearing function. Previous studies have published databases of baseline ABR thresholds for mouse strains, providing a valuable resource for the study of baseline hearing function and genetic mapping of hearing traits in mice. In this study, we further expand upon the existing literature by characterizing the baseline ABR characteristics of 100 inbred mouse strains, 47 of which are newly characterized for hearing function. We identify several distinct patterns of baseline hearing deficits and provide potential avenues for further investigation. Additionally, we characterize the sensitivity of the same 100 strains to noise exposure using permanent thresholds shifts, identifying several distinct patterns of noise-sensitivity. The resulting data provides a new resource for studying hearing loss and noise-sensitivity in mice.

The Genetic Architecture of Noise-induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.

The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5–6-wk-old female mice from the HMDP (4–5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a “genetical genomics” approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL.

Cocleostomia transcanal: resultados em longo prazo de um estudo de coorte

UNLABELLED The combined approach technique (CAT) is a variation of the classical the mastoidectomy-posterior tympanotomy technique (MPTA) that combines a transcanal approach to cochleostomy with a reduced posterior tympanotomy for insertion of electrodes. AIM To compare and evaluate long-term safety and effectiveness outcomes obtained with the CAT and with MPTA approach in patients submitted to cochlear implant (CI) surgery. DESIGN series study. METHODS Patients who underwent CI using CAT or MPTA at a Brazilian center were followed in a cohort study. Main outcomes were complications,audiometric performance and radiological evaluation of electrode position. RESULTS Fourty-four patients were implanted using CAT and 31 MPTA. There were no cases of facial nerve paralysis, mastoiditis, cholesteatoma or cerebrospinal fluid leaks after 3.4±1.0 years. Radiological evaluation of electrode position revealed that the median number of electrodes outside the cochlea was 0 in CAT and 3 in MPTA groups (p < 0.001). There were no differences between both surgical approaches in terms of mean pure-tone thresholds with CI at all frequencies. CONCLUSION Long-term follow-up data showed that the transcanal route to cochleostomy, combined with a reduced posterior tympanotomy, is a safe alternative approach in cochlear implant surgery, with no related major complications and fewer cases of electrode migration when compared with the MPTA. These findings encourage the use of the transcanal route to cochleostomy as an alternative approach option.

Effect of hyperinsulinism on sensorineural hearing impairment in Ménière's disease: a cohort study.

Objective To compare the degree of sensorineural hearing loss in patients with Ménière’s disease (MD) with and without hyperinsulinism by different methods of assessment. Study Design Historical cohort study. Setting Ménière’s Disease Care and Research Clinics of Hospital de Clinicas de Porto Alegre, a tertiary care university hospital in Southern Brazil. Patients Patients with a definite diagnosis of MD based on the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) guidelines. Intervention Patients were assessed by glucose overload tests (5-h glucose and insulin curves) and under baseline physiological conditions (Homeostasis Model Assessment/Insulin Resistance [HOMA-IR], Quantitative Insulin Sensitivity Check Index [QUICKI], and glucose/insulin ratio). These patients underwent annual pure-tone audiometry and were analyzed using 4-tone average (FTA), that is, arithmetic mean of 500, 1,000, 2,000, and 3,000 Hz, during the third, fourth, and fifth years of disease progression. Main Outcome Measure Hearing loss assessed by FTA and classified in Stages I to IV (AAO-HNS). Results Forty-nine (76.6%) patients were defined as hyperinsulinemic and 15 (23.4%) as normoinsulinemic. Impairment on FTA was higher in the hyperinsulinemic group (52.04 ± 17.5 versus 39.75 ± 9.20, p = 0.027) when assessed by the 5-hour insulin curve. Hyperinsulinemic subjects were 3.5 times more likely to develop hearing damage greater than 40 dB (i.e., Stages III and IV) than normoinsulinemic subjects (OR = 3.52; 95% CI, 1.05–11.76). A moderate correlation between the insulin curve and the HOMA-IR was found (r = 0.524, p = 0.001). Conclusion Hyperinsulinism in MD is associated with greater clinical hearing damage.

Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea

Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL.

Solitary Plasmacytoma in the Internal Auditory Canal and Cerebellopontine Angle Mimicking Meningioma.

Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Department of Otolaryngology, Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California; yDepartment of Otolaryngology–Head and Neck Surgery; zDepartment of Neurosurgery; §Department of Radiology; and Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, U.S.A.