Evaluation of masking effects on speech perception in patients with unilateral chronic tinnitus using the hearing in noise test.

OBJECTIVE: To verify that tinnitus itself could disturb speech perception and to evaluate the effects of masking noise on speech perception ability in the patients with normal hearing but unilateral chronic tinnitus using the hearing in noise test. STUDY DESIGN: Prospective, nonrandomized study. MATERIALS AND METHODS: Between June 2009 and May 2011, we enrolled 20 patients with normal hearing and subjective unilateral tinnitus that had persisted for more than 12 months, along with 20 healthy controls of the same age. All subjects were evaluated using audiologic examinations, the tinnitus handicap inventory, and the Korean version of the Hearing in Noise Test (K-HINT) to assess characteristics of tinnitus and speech perception ability in various noisy situations. RESULTS: Reception threshold for speech (RTS) in a quiet environment and signal-to-noise ratio (SNR) in various conditions of noise were significantly higher in the tinnitus than in the control group, regardless of whether noise came from the front, right, or left (p < 0.05). When the tinnitus group was subdivided according to the site of noise exposure, the mean SNR of the contralateral noise group was -7.9 ± 1.4 dB, which was significantly higher than the ipsilateral noise (-9.1 ± 1.8 dB) or control group (right, -10.0 ± 0.6 dB; left, -10.1 ± 0.5 dB) (p < 0.05). In addition, there was no significant difference between ipsilateral noise and control groups. CONCLUSION: From this study, we showed that tinnitus itself could adversely affect speech perception ability by increasing both RTS and SNR in the tinnitus patients in comparison with healthy controls. In addition, we suggest that proper level of noise on the site of tinnitus might be helpful to increase speech perception in the patients who experience chronic subjective tinnitus.

Modafinil inhibits K(Ca)3.1 currents and muscle contraction via a cAMP-dependent mechanism.

Modafinil has been used as a psychostimulant for the treatment of narcolepsy. However, its primary mechanism of action remains elusive. Therefore, we examined the effects of modafinil on K(Ca)3.1 channels and vascular smooth muscle contraction. K(Ca)3.1 currents and channel activity were measured using a voltage-clamp technique and inside-out patches in mouse embryonic fibroblast cell line, NIH-3T3 fibroblasts. Intracellular adenosine 3',5'-cyclic monophosphate (cAMP) concentration was measured, and the phosphorylation of K(Ca)3.1 channel protein was examined using western blotting in NIH-3T3 fibroblasts and/or primary cultured mouse aortic smooth muscle cells (SMCs). Muscle contractions were recorded from mouse aorta and rat pulmonary artery by using a myograph developed in-house. Modafinil was found to inhibit K(Ca)3.1 currents in a concentration-dependent manner, and the half-maximal inhibition (IC(50)) of modafinil for the current inhibition was 6.8 ± 0.7 nM. The protein kinase A (PKA) activator forskolin also inhibited K(Ca)3.1 currents. The inhibitory effects of modafinil and forskolin on K(Ca)3.1 currents were blocked by the PKA inhibitors PKI(14-22) or H-89. In addition, modafinil relaxed blood vessels (mouse aorta and rat pulmonary artery) in a concentration-dependent manner. Modafinil increased cAMP concentrations in NIH-3T3 fibroblasts or primary cultured mouse aortic SMCs and phosphorylated K(Ca)3.1 channel protein in NIH-3T3 fibroblasts. However, open probability and single-channel current amplitudes of K(Ca)3.1 channels were not changed by modafinil. From these results, we conclude that modafinil inhibits K(Ca)3.1 channels and vascular smooth muscle contraction by cAMP-dependent phosphorylation, suggesting that modafinil can be used as a cAMP-dependent K(Ca)3.1 channel blocker and vasodilator.

Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease.

AIMS: Excessive endothelial globotriaosylceramide (Gb3) accumulation is associated with endothelial dysfunction and impaired endothelium-dependent relaxation in Fabry disease. In endothelial cells, K(Ca)3.1 channels contribute to endothelium-dependent relaxation. However, the effect of Gb3 on K(Ca)3.1 channels and the underlying mechanisms of Gb3-induced dysfunction are unknown. Herein, we hypothesized that Gb3 accumulation induces K(Ca)3.1 channel dysfunction and aimed to clarify the underlying mechanisms. METHODS AND RESULTS: The animal model of Fabry disease, α-galactosidase A (Gla) knockout mice, displayed age-dependent K(Ca)3.1 channel dysfunction. K(Ca)3.1 current and the channel expression were significantly reduced in mouse aortic endothelial cells (MAECs) of aged Gla knockout mice, whereas they were not changed in MAECs of wild-type and young Gla knockout mice. In addition, K(Ca)3.1 current and the channel expression were concentration-dependently reduced in Gb3-treated MAECs. In both Gb3-treated and aged Gla knockout MAECs, extracellular signal-regulated kinase (ERK) and activator protein-1 (AP-1) were down-regulated and repressor element-1 silencing transcription factor (REST) was up-regulated. Gb3 inhibited class III phosphoinositide 3-kinase and decreased intracellular levels of phosphatidylinositol 3-phosphate [PI(3)P]. In addition, endothelium-dependent relaxation was significantly attenuated in Gb3-treated mouse aortic rings. CONCLUSION: Gb3 accumulation reduces K(Ca)3.1 channel expression by down-regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes K(Ca)3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease.