Villin is an actin-binding protein localized in intestinal and kidney brush borders. In vitro, villin has been demonstrated to bundle and sever F-actin in a Ca2+-dependent manner. We generated knockout mice to study the role of villin in vivo. In villin-null mice, no noticeable changes were observed in the ultrastructure of the microvilli or in the localization and expression of the actin-binding and membrane proteins of the intestine. Interestingly, the response to elevated intracellular Ca2+ differed significantly between mutant and normal mice. In wild-type animals, isolated brush borders were disrupted by the addition of Ca2+, whereas Ca2+ had no effect in villin-null isolates. Moreover, increase in intracellular Ca2+ by serosal carbachol or mucosal Ca2+ ionophore A23187 application abolished the F-actin labeling only in the brush border of wild-type animals. This F-actin disruption was also observed in physiological fasting/refeeding experiments. Oral administration of dextran sulfate sodium, an agent that causes colonic epithelial injury, induced large mucosal lesions resulting in a higher death probability in mice lacking villin, 36 ± 9.6%, compared with wild-type mice, 70 ± 8.8%, at day 13. These results suggest that in vivo, villin is not necessary for the bundling of F-actin microfilaments, whereas it is necessary for the reorganization elicited by various signals. We postulate that this property might be involved in cellular plasticity related to cell injury.

Objective: The pathogenesis of idiopathic sudden sensorineural hearing loss (ISSHL) remains unknown, but vascular involvement is one of the main hypotheses. The main objective of this study was to investigate the association between ISSHL and cardiovascular and thromboembolic risk factors. Study Design: Multicentric case-control study. Methods: Ninety-six Caucasian patients with ISSHL and 179 sex- and age-matched controls were included. Patients were evaluated on the day of the inclusion and 1 week, 3 weeks and 3 months later. Clinical information concerning personal and familial cardiovascular and thromboembolic risk factors and concerning the ISSHL was collected. Blood samples were collected for genetic analysis of factor V Leiden and G20210A polymorphism in the factor II gene. The severity of the hearing loss was classified as mild (21–40 dB), moderate (41–70 dB), severe (71–90 dB) and profound or total (>90 dB). Hearing improvement was calculated as a relative improvement of hearing thresholds using the contralateral ear as baseline. Results: Systolic blood pressure was higher in patients (130 ± 1.7 mm Hg) than in controls (124 ± 1.1 mm Hg, p = 0.003). The personal/familial history of cardiovascular events was also more prevalent in patients (p = 0.023 and p = 0.014, respectively), whereas no difference was found in the prevalence of personal cardiovascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking habits). There was no correlation between the audiogram type, the hearing outcome and the presence of cardiovascular risk factors. No significant difference was observed in the personal/familial history or in the presence of thromboembolic risk factors. The prothrombin and factor V mutations were uncommon in both patients and controls. The final hearing threshold was only correlated with the severity of the initial hearing loss (p < 0.001), but not influenced by the presence of vertigo, audiogram type, time elapsed from onset of ISSHL to hospitalization or failure of a previous oral therapy. Hearing stabilization was obtained at 21 days in 92% of patients. Conclusion: These results support the theory of vascular involvement as the etiology of some cases of ISSHL. The sole predictive factor of poor final hearing is the severity of the initial hearing loss.

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Objective: To evaluate speech performance, in quiet and noise, and localization ability in adult patients who had undergone bilateral and simultaneous implantation. Study Design: Prospective multi-center study. Methods: Twenty-seven adult patients with profound or total hearing loss were bilaterally implanted in a single-stage procedure, and simultaneously activated (Med-El, Combi 40/40+). Subjects were assessed before implantation and at 3, 6 and 12 months after switch-on. Speech perception tests in monaural and binaural conditions were performed in quiet and in noise using disyllabic words, with speech coming from the front and a cocktail party background noise coming from 5 loudspeakers. Sound localization measurements were also performed in background noise coming from 5 loudspeakers positioned from –90° to +90° azimuth in the horizontal plane, and using a speech stimulus. Results: There was a bilateral advantage at 12 months in quiet (77 ± 5.0% in bilateral condition, 67 ± 5.3% for the better ear, p < 0.005) and in noise (signal-to-noise ratio +15 dB: 63 ± 5.9% in bilateral condition, 55 ± 6.9% for the better ear, p < 0.05). Considering unilateral speech scores recorded in quiet at 12 months, subjects were categorized as ‘good performers’ (speech comprehension score ≥60% for the better ear, n = 19) and ‘poor performers’ (n = 8). Subjects were also categorized as ‘asymmetrical’ (difference between their 2 unilateral speech scores ≥20%, n = 11) or ‘symmetrical’ (n = 16). The largest advantage (bilateral compared to the better ear) was obtained in poor performers: +19% compared to +7% in good performers (p < 0.05). In the group of good performers, there was a bilateral advantage only in cases of symmetrical results between the 2 ears (n = 10). In the group of poor performers, the bilateral advantage was shown in both patients with symmetrical (n = 6) and asymmetrical results (n = 2). In bilateral conditions, the sound localization ability in noise was improved compared to monaural conditions in patients with symmetrical and asymmetrical performance between the 2 ears. No preoperative factor (age, duration of deafness, use of hearing aids, etiology, etc.) could predict the asymmetrical performance, nor which ear would be the best. Conclusion: This study demonstrates a bilateral advantage (at 12 months after the implantation) in speech intelligibility and sound localization in a complex noisy environment. In quiet, this bilateral advantage is shown in cases of poor performance of both ears, and in cases of good performance with symmetrical results between the 2 ears. No preoperative factor can predict the best candidates for a simultaneous bilateral implantation.

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Plastin 1 (I-plastin, fimbrin) along with villin and espin is a prominent actin-bundling protein of the intestinal brush border microvilli. We demonstrate here that plastin 1 accumulates in the terminal web and interacts with keratin 19, possibly contributing to anchoring the rootlets to the keratin network. This prompted us to investigate the importance of plastin 1 in brush border assembly. Although in vivo neither villin nor espin is required for brush border structure, plastin 1-deficient mice have conspicuous ultrastructural alterations: microvilli are shorter and constricted at their base, and, strikingly, their core actin bundles lack true rootlets. The composition of the microvilli themselves is apparently normal, whereas that of the terminal web is profoundly altered. Although the plastin 1 knockout mice do not show any overt gross phenotype and present a normal intestinal microanatomy, the alterations result in increased fragility of the epithelium. This is seen as an increased sensitivity of the brush border to biochemical manipulations, decreased transepithelial resistance, and increased sensitivity to dextran sodium sulfate-induced colitis. Plastin 1 thus emerges as an important regulator of brush border morphology and stability through a novel role in the organization of the terminal web, possibly by connecting actin filaments to the underlying intermediate filament network.

This study demonstrates that the performance of the VSB does not deteriorate for more than 5 yr, without adverse effect. These results confirm the safety and the effectiveness of the VSB with a long-term follow-up.

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