Simplified bone-anchored hearing aid insertion using a linear incision without soft tissue reduction.

BACKGROUND: Numerous techniques have been described to manage the skin and other soft tissues during bone-anchored hearing aid insertion. Previously, generally accepted techniques have sometimes led to distressing alopecia and soft tissue defects. Now, some surgeons are rejecting the originally described split skin flap in favour of a less invasive approach. OBJECTIVE: To investigate bone-anchored hearing aid placement utilising a single, linear incision with either no or minimal underlying soft tissue reduction. PATIENTS AND METHODS: Thirty-four adults were prospectively enrolled to undergo single-stage bone-anchored hearing aid placement with this modified technique. A small, linear incision was used at the standard position and carried down through the periosteum. Standard technique was then followed with placement of an extended length abutment. Patients were reviewed regularly to assess wound healing, including evaluation with Holgers' scale. RESULTS: Only 14.7 per cent of patients had a reaction score of 2 or higher. Most complications were limited to minor skin reactions that settled with silver nitrate cautery and/or antibiotics. None required revision surgery for tissue overgrowth, and there were no implant failures. CONCLUSION: Our results suggest this to be a simple and effective insertion technique with favourable cosmesis and patient satisfaction.

Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer's disease.

The Cdc2/cyclin B kinase is a critical regulator of mitosis that is normally absent from terminally differentiated neurons of adult brain. However, unscheduled expression and activation of Cdc2/cyclin B has been seen in neurons undergoing degeneration in Alzheimer's disease. The presence of this mitotic kinase correlates with accumulation of mitotic phosphoepitopes in protein components of the hallmark neurofibrillary tangles. Of importance to the pathogenic mechanism of Alzheimer's disease is the striking appearance of Cdc2/cyclin B and mitotic phosphoepitopes prior to neurofibrillary tangle formation, which has suggested that a misappropriate mitotic cascade initiates and mediates the neurodegenerative process. To explain the atypical activation of Cdc2/cyclin B in degenerating neurons we have investigated the enzyme responsible for Cdc2/cyclin B activation in mitotic cells, i.e. the Cdc25B tyrosine phosphatase, in Alzheimer's disease brain. Although the enzyme appeared abundant in affected neurons, it was also evident in unaffected neurons of Alzheimer's disease and control brain. Thus, we have found, surprisingly, that Cdc25B is a normal constituent of adult brain neurons, with detectable basal levels of activity. In Alzheimer's disease the levels and activity of the enzyme are elevated, and the active enzyme predominates in the cytoplasmic compartment of neurons. Consistent with these M phase-type changes, Cdc25B displays increased immunoreactivity towards the MPM-2 mitotic phosphoepitope antibody. We propose that aberrant expression of Cdc2/cyclin B in Alzheimer's disease leads to potentiation of mitotic activation mediated by constitutive neuronal Cdc25B activity. As a result, various downstream indices of mitotic events are generated, eventually culminating in neurodegeneration. Our data also suggest that Cdc25B is functional in normal post-mitotic neurons lacking the mitotic Cdc2/cyclin B, but it does not appear to influence the activity of Cdk5, a Cdc2-like kinase that is particularly enriched in brain.

Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease.

Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease. During mitosis cdc2 phosphorylates and inhibits the major transcriptional regulator RNA polymerase II (RNAP II). We therefore investigated cdc2 phosphorylation of RNAP II in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated sites in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation and neurofibrillary tangle formation. Our data support the hypothesis that inappropriate activation of the cell cycle cdc2 kinase in differentiated neurons contributes to neuronal dysfunction and degeneration in part by inhibiting RNAP II and cellular processes dependent on transcription.

Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases.

Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation. The convergence of various degenerative schemes into a unified mitotic kinase-driven pathway provides a common target for therapeutic treatment of these different disorders.

The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer's disease.

The Cdc25 phosphatases play key roles in cell-cycle progression by activating cyclin-dependent kinases. The latter are absent from neurons that are terminally differentiated in adult brain. However, accumulation of mitotic phosphoepitopes, and re-expression and activation of the M phase regulator, Cdc2/cyclin B, have been described in neurons undergoing degeneration in Alzheimer's disease (AD). To explain this atypical mitotic activation in neurons we investigated the Cdc2-activating Cdc25A phosphatase in human brain. The structural hallmarks of AD neurodegeneration, neurofibrillary tangles and neuritic plaques, were prominently immunolabeled with Cdc25A antibodies. In addition numerous neurons without visible structural alterations were also intensely stained, whereas control brain was very weakly positive. After immunoprecipitation from control and AD tissue, we found that the tyrosine dephosphorylating activity of Cdc25A against exogenous Cdc2 substrate was elevated in AD. Accordingly, Cdc25A from AD tissue displayed increased immunoreactivity with the mitotic phosphoepitope-specific antibody, MPM-2, and co-localized with MPM-2 immunoreactivity in AD neurons. These data suggest that Cdc25A participates in mitotic activation during neurodegeneration. The involvement of Cdc25A in cellular transformation, modulation of the DNA damage checkpoint, and linkage of mitogenic signaling to cell cycle machinery, also implicates one of these cell-cycle pathways in AD pathogenesis.