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International audience; Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8–32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

International audience; Introduction: There remains no standard imaging method that allows computer-assisted surgery of the cochlea in real time. However, recent evidence suggests that high-frequency ultrasound (HFUS) could permit real-time visualization of cochlear architecture. Registration with an imaging modality that suffers neither attenuation nor conical deformation could reveal useful anatomical landmarks to surgeons. Our study aimed to address the feasibility of an automated three-dimensional (3D) HFUS/microCT registration, and to evaluate the identification of cochlear structures using 2D/3D HFUS and microCT.Methods: MicroCT, and 2D/3D 40 MHz US in B-mode were performed on ex vivo guinea pig cochlea. An automatic rigid registration algorithm was applied to segmented 3D images. This automatic registration was then compared to a reference method using manual annotated landmarks placed by two senior otologists. Inter- and intrarater reliabilities were evaluated using intraclass correlation coefficient (ICC) and the mean registration error was calculated.Results: 3D HFUS/microCT automatic registration was successful. Excellent levels of concordance were achieved with regards intra-rater reliability for both raters with micro-CT and US images (ICC ranging from 0.98 to 1, p < 0.001) and with regards inter-rater reliability (ICC ranging from 0.99 to 1, p < 0.001). The mean HFUS/microCT automated RE for both observers was 0.17 ± 0.03 mm [0.10-0.25]. Identification of the basilar membrane, modiolus, scala tympani, and scala vestibuli was possible with 2D/3D HFUS and micro-CT.Conclusions: HFUS/microCT image registration is feasible. 2D/3D HFUS and microCT allow the visualization of cochlear structures. Many potential clinical applications are conceivable.

Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin‐induced ototoxicity remains unclear, and hearing preservation during cisplatin‐based chemotherapy in patients is lacking. We found activation of the ATM‐Chk2‐p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin‐induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient‐derived triple‐negative breast cancer protected auditory function, without compromising the anti‐tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin‐based chemotherapy.

Deposition of perirenal adipose tissue has been associated with adverse renal and cardiovascular events. We compared various methods to measure perirenal adipose tissue using computerized tomography (CT)-scan and performed correlations with anthropometric measures associated with renal and cardiovascular events. Voluntary overweight and obese subjects undergoing a CT-scan for diagnostic purposes were included in the study. Perirenal adipose tissue volume, adipose tissue area of the renal sinus and perirenal fat thickness were manually measured bilaterally. The intra- and inter-observer coefficient correlations and the correlation between the diverse measures of renal adipose tissue, subcutaneous (SC-)fat and anthropometrics measures were analyzed using Pearson's correlation tests. The forty included patients (24 men, 16 women) had a mean age of 57.6 ± 18.1 years and a mean body mass index of 28.9 ± 2.9 kg/m2. Despite comparable waist circumference, women had a greater SC-fat thickness compared to men, and therefore a smaller amount of visceral fat, as well as smaller perirenal fat volumes. Perirenal fat thickness was better correlated with perirenal fat volume than adipose area of the renal sinus (p

Objectives: We describe the various molecular and cellular pathways that lead to early and delayed loss of residual hearing after cochlear implantation. Methods: We performed a systematic review using the Medline database with the key words cochlear implant, residual hearing, inflammation, apoptosis, and necrosis. Results: The mechanisms underlying the loss of residual hearing after cochlear implantation are multiple. Early hearing loss may be provoked by the surgical access to the inner ear spaces and by trauma caused by insertion of the electrode array. After the initial trauma, an acute inflammatory response promotes elevated levels of cytokines and reactive oxygen species, which in turn promote sensory cell loss by apoptosis, necrosis, and necrosis-like programmed cell death. Treatments that counteract such an inflammatory reaction, production of reactive oxygen species, and apoptosis are effective at preventing hair cell degeneration. However, delayed hearing loss appears to be a consequence of chronic inflammation with development of fibrotic tissue. The mechanisms that lead to fibrosis are poorly understood, and standard anti-inflammatory drugs are insufficient for preventing its development. Conclusions: Cochlear implantation is followed by an inflammatory response involving several pathways that lead to either short-term or long-term sensory hair cell degeneration. Future studies should focus on revealing the precise molecular mechanisms induced by cochlear implantation to allow the discovery of new targets for the effective prevention and treatment of loss of residual hearing.

International audience; Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3 Y260X homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3 Y260X mice by using rotating rod and vestibular behavioral tests. Tmprss3 Y260X mice effectively displayed mild vestibular syndrome that correlated histologi-cally with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.

Regenerating islet-derived1a(Reg-1a) /lithostathine, a member of a family of secreted proteins containing a C-type lectin domain, is expressed in various organs and plays a role in proliferation, differentiation, inflammation and carcinogenesis of cells of the digestive system. We previously reported that Reg-1α is over-expressed during the very early stages of Alzheimer disease and Reg-1α deposits were detected in the brain of patients with Alzheimer disease. However, the physiological function of Reg-1α in neural cells remains unknown. Here, we show that Reg-1α is expressed in neuronal cell lines (PC12 and Neuro-2a) and in rat primary hippocampal neurons (E17.5). Reg-1α is mainly localized around the nucleus and at the membrane of cell bodies and neurites. Transient over-expression of Reg-1α or addition of recombinant Reg-1α significantly increases the number of cells with longer neurites by stimulating neurite outgrowth. These effects are abolished upon down-regulation of Reg-1α by siRNA and following inhibition of secreted Reg-1α by antibodies. Moreover, Reg-1α colocalizes with Exostosin tumor- like 3 (EXTL3), its putative receptor, at the membrane of these cells. Over-expression of EXTL3 increases the effect of recombinant Reg-1α on neurite outgrowth, and Reg-1α is not effective when EXTL3 over-expression is down-regulated by shRNA. Our findings indicate that Reg-1α regulates neurite outgrowth and suggest that this effect is mediated by its receptor EXTL3.