Tinnitus suppression in patients with cochlear implants.

OBJECTIVE: To determine the degree of tinnitus suppression provided by currently available multichannel cochlear implants and to determine factors that can influence this process. STUDY DESIGN: Prospective cohort. SETTING: Tertiary-care referral center. PATIENTS: Thirty-eight adult patients (18 years of age or older) with severe-to-profound hearing loss and tinnitus who met criteria for cochlear implantation. INTERVENTION: Cochlear implantation with a multichannel cochlear implant device. MAIN OUTCOME MEASURES: Patients rated the intensity of their tinnitus using a semiquantitative scale before and after cochlear implantation. These data were analyzed to determine the significance of the reduction of tinnitus after implantation. Tinnitus levels after implantation were also analyzed to determine whether the level of speech recognition, patient gender, or the implant type influenced the degree of tinnitus reduction. RESULTS: Statistical analysis revealed a significant reduction in tinnitus intensity in patients using cochlear implants, with 35 of 38 patients (92%) experiencing a reduction in tinnitus intensity. All multichannel implants studied afforded similar degrees of tinnitus suppression. The degree of tinnitus reduction was not correlated with speech recognition, as measured by CID Everyday Sentence scores. Female patients had significantly greater degrees of tinnitus before implantation, but both male and female patients demonstrated similar levels of tinnitus after implantation. No patient experienced greater levels of tinnitus after implantation. CONCLUSION: All currently available multichannel cochlear implant devices provide effective and similar levels of tinnitus suppression when activated. Exacerbation of tinnitus as a result of cochlear implantation does not represent a significant risk. The mechanisms by which cochlear implants exert tinnitus suppression are, as yet, unclear.

Regulation of glycogen synthase kinase 3beta and downstream Wnt signaling by axin.

Axin is a recently identified protein encoded by the fused locus in mice that is required for normal vertebrate axis formation. We have defined a 25-amino-acid sequence in axin that comprises the glycogen synthase kinase 3beta (GSK-3beta) interaction domain (GID). In contrast to full-length axin, which has been shown to antagonize Wnt signaling, the GID inhibits GSK-3beta in vivo and activates Wnt signaling. Similarly, mutants of axin lacking key regulatory domains such as the RGS domain, which is required for interaction with the adenomatous polyposis coli protein, bind and inhibit GSK-3beta in vivo, suggesting that these domains are critical for proper regulation of GSK-3beta activity. We have identified a novel self-interaction domain in axin and have shown that formation of an axin regulatory complex in vivo is critical for axis formation and GSK-3beta activity. Based on these data, we propose that the axin complex may directly regulate GSK-3beta enzymatic activity in vivo. These observations also demonstrate that alternative inhibitors of GSK-3beta can mimic the effect of lithium in developing Xenopus embryos.

Xenopus axin interacts with glycogen synthase kinase-3 beta and is expressed in the anterior midbrain.

Axin is encoded by the fused locus in mice and is required for normal vertebrate axis formation. It has recently been shown that axin associates with APC, beta-catenin and glycogen synthase kinase-3 (GSK-3) in a complex that appears to regulate the level of cytoplasmic beta-catenin. We have identified the Xenopus homologue of axin through its interaction with GSK-3b. Xenopus axin (Xaxin) is expressed maternally and throughout early development with a low level of ubiquitous expression. Xaxin also shows remarkably high expression in the anterior mesencephalon adjacent to the forebrain-midbrain boundary.

Activation of the Wnt signaling pathway: a molecular mechanism for lithium action.

Glycogen synthase kinase-3 beta (GSK-3 beta/zeste-white-3/shaggy) is a negative regulator of the wnt signaling pathway which plays a central role in the development of invertebrates and vertebrates; loss of function and dominant negative mutations in GSK-3 beta lead to activation of the wnt pathway in Drosophila and Xenopus. We now provide evidence that lithium activates downstream components of the wnt signaling pathway in vivo, leading to accumulation of beta-catenin protein. Our data indicate that this activation of the wnt pathway is a consequence of inhibition of GSK-3 beta by lithium. Using a novel assay for GSK-3 beta in oocytes, we show that lithium inhibits GSK-3 beta from species as diverse as Dictyostelium discoideum and Xenopus laevis, providing a biochemical mechanism for the action of lithium on the development of these organisms. Lithium treatment also leads to activation of an AP-1-luciferase reporter in Xenopus embryos, consistent with previous observations that GSK-3 beta inhibits c-jun activity. Activation of the wnt pathway with a dominant negative form of GSK-3 beta is inhibited by myo-inositol, similar to the previously described effect of coinjecting myo-inositol with lithium. The mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and lithium remains uncertain.

Polyethylene glycol enhanced refolding of bovine carbonic anhydrase B. Reaction stoichiometry and refolding model.

Polyethylene glycol (PEG) inhibited aggregation during refolding of bovine carbonic anhydrase B (CAB) through the formation of a nonassociating PEG-intermediate complex. Stoichiometric concentrations of PEG were required for complete recovery of active protein during refolding at aggregating conditions. For example, a PEG (Mr = 3350) to CAB molar ratio ([PEG]/[CAB]) of 2 was sufficient to inhibit aggregation during refolding at 1.0 mg/ml (33.3 microM) protein and 0.5 M guanidine hydrochloride. In addition, the PEG concentration required for enhancement was dependent upon the molecular weight and only molecular weights between 1000 and 8000 were effective in inhibiting aggregation. In the presence of PEG, the rate of refolding was the same as that observed for refolding without the formation of associated species. Refolding in the presence of PEG resulted in the rapid formation of a PEG complex with the molten globule first intermediate, and this PEG-intermediate complex did not aggregate. The CAB refolding kinetics in the presence of PEG were determined and used to develop a model of the PEG enhanced refolding pathway. The mathematical model was validated by independent activity measurements of CAB refolding. This model predicted that PEG enhanced refolding of CAB occurred by a specific interaction of PEG with the molten globule first intermediate to form a nonassociating complex which continued to fold at the same rate as the first intermediate. The predicted pathway and binding properties of PEG indicate that PEG enhanced refolding may be analogous to chaperonin mediated protein folding.

Color flow and image-directed Doppler ultrasound evaluation of iatrogenic arteriovenous fistulas in the groin.

Color flow image-directed Doppler ultrasound was used to image 9 iatrogenic arteriovenous (AV) fistulas in the groin following femoral artery catheterization. Characteristic findings in the color images and spectral waveforms seen in most patients included (1) visible connection between the artery and vein (8 cases); (2) a multicolored speckled mass at the fistula site (7 cases); (3) spreading of color pixels into the extraluminal soft tissues (7 cases); (4) high diastolic flow in the arterial waveform proximal to the fistula site (7 cases); (5) decreased flow in the artery caudal to the fistula (5 cases); and (6) high velocity turbulent flow, sometimes with a pulsatile component, in the vein near the fistula (9 cases). The authors conclude that color flow imaging is useful in differentiating an AV fistula from other complications of femoral artery catheterization, such as pseudoaneurysm or hematoma.