Polarity Sensitivity as a Potential Correlate of Neural Degeneration in Cochlear Implant Users.

Cochlear implant (CI) performance varies dramatically between subjects. Although the causes of this variability remain unclear, the electrode-neuron interface is thought to play an important role. Here we evaluate the contribution of two parameters of this interface on the perception of CI listeners: the electrode-to-modiolar wall distance (EMD), estimated from cone-beam computed tomography (CT) scans, and a measure of neural health. Since there is no objective way to quantify neural health in CI users, we measure stimulus polarity sensitivity, which is assumed to be related to neural degeneration, and investigate whether it also correlates with subjects' performance in speech recognition and spectro-temporal modulation detection tasks. Detection thresholds were measured in fifteen CI users (sixteen ears) for partial-tripolar triphasic pulses having an anodic or a cathodic central phase. The polarity effect was defined as the difference in threshold between cathodic and anodic stimuli. Our results show that both the EMD and the polarity effect correlate with detection thresholds, both across and within subjects, although the within-subject correlations were weak. Furthermore, the mean polarity effect, averaged across all electrodes for each subject, was negatively correlated with performance on a spectro-temporal modulation detection task. In other words, lower cathodic thresholds were associated with better spectro-temporal modulation detection performance, which is also consistent with polarity sensitivity being a marker of neural degeneration. Implications for the design of future subject-specific fitting strategies are discussed

Role of Interaction and Nucleoside Diphosphate Kinase B in Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Function by cAMP-Dependent Protein Kinase A

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia