Identification of two major loci that suppress hearing loss and cochlear dysmorphogenesis in Eya1bor/bor mice.

The Eya1(bor) mutant hypomorph contains an intracisternal A particle insertion in intron 7 of the Eya1 gene that results in a 50% reduction in wild-type mRNA levels. The homozygous mutants have middle and inner ear defects and variable kidney abnormalities. The severity of the disorder is affected by genetic background. In contrast to complete deafness and cochlear agenesis in the C3HeB/FeJ strain, F2 Eya1(bor/bor) mutants from an intercross between C3HeB/FeJ-Eya1(bor/+) and C57BL/6J showed variable auditory brain-stem responses and cochlear coiling. In this study, using these F2 Eya1(bor/bor) mutants, we have identified two major loci, Mead1 (modifier of Eya1-associated deafness 1) and Mead2, that are responsible for suppression of the original phenotypes. We have narrowed these two loci to 5.4 and 4.4 cM, respectively, in congenic lines. Quantitative PCR demonstrated that this modifying effect did not result from an increase in wild-type Eya1 mRNA, suggesting Mead1 and Mead2 are interacting directly or indirectly with Eya1 during inner ear development.

Classification of the external auditory canal cholesteatoma.

OBJECTIVES/HYPOTHESIS: The external auditory canal cholesteatoma (EACC) is a rare disease in the field of otolaryngology. Only 1 in 1,000 new otologic patients present with this entity, which was first described by Toynbee. The aim of this article is to classify EACC by different histopathologic and clinical findings of patients presenting to the Department of Otolaryngology at the University of Mannheim, Germany. METHODS: From 2000 to 2004, 17 patients presented to our clinic with EACC. The cholesteatoma were treated surgically, and the specimens were investigated histologically. Clinical findings were also recorded. We classified four stages: stage I with hyperplasia of the canal epithelium, stage II including periosteitis, Stage III including a defective bony canal, and stage IV showing an erosion of adjacent anatomic structure. RESULTS: Eight patients presented with stage II, five patients with stage III, three with stage I, and only one patient presented with erosion of the mastoid cells, which was determined as stage IV. CONCLUSION: In summary, our classification serves to describe the different histopathologic and clinical stages of EACC.

Regulation of apoptosis in external auditory canal cholesteatoma by hepatocyte growth factor/scatter factor.

OBJECTIVES: External auditory canal cholesteatomas (EACC) are characterized by focal invasion of squamous cell epithelium and accumulation of keratin debris in the apical part of the matrix. Apoptosis appears to be important in understanding the pathogenesis of EACC. Here the possible regulatory effect of the apoptosis mediated by hepatocyte growth factor (HGF)/scatter factor (SF)-c-Met-Fas in EACC is discussed. METHODS: We examined 17 EACC specimens for immunohistochemical expression of HGF/SF, c-Met, caspase 3 and Fas. The staining reaction was evaluated semiquantitatively. RESULTS: HGF/SF was detected in mesenchymal tissue below the EACC epithelium. c-Met was expressed throughout the epithelium. Fas and caspase 3 were detected at increasing levels towards the apical layers of the EACC matrix. CONCLUSIONS: High levels of HGF/SF result in binding of HGF/SF to c-Met, releasing Fas to aggregate and bind to its death-inducing signaling complex. The result is apoptosis, marked by formation of dead squamous cells and sequestered keratin debris on the apical side of the cholesteatoma.

The evolution of surgical approaches for posterior fossa meningiomas.

OBJECTIVE: To evaluate surgical outcomes for the treatment of posterior fossa meningiomas at the House Ear Clinic from 1987 to 2001. We review our current treatment algorithm and present our postoperative outcomes with attention to facial and auditory neural preservation. STUDY DESIGN: Retrospective review. SETTING: Tertiary care center. PATIENTS: Medical records of 71 patients who underwent posterior fossa meningioma surgery at the House Ear Clinic were reviewed. INTERVENTION: All patients had surgical removal of their meningioma via translabyrinthine, transcochlear, retrosigmoid, extended middle fossa, or combined petrosal approaches by House Ear Clinic neurotologists and neurosurgeons. MAIN OUTCOME MEASURES: Preoperative and postoperative auditory and facial nerve function data were collected. Patient and tumor characteristics including presenting symptoms, completion of tumor resection, and complications secondary to surgery were also recorded. RESULTS: The most common presenting symptoms in this series were otologic, with hearing loss (61%), tinnitus (58%), and imbalance (58%) as the three most common. Gross total resection was achieved in 67 (94%) patients. Hearing-preservation surgery was attempted in 37 (52%) patients (68% via extended middle fossa or combined approach). Twenty-one patients with preoperative Class A hearing had follow-up audiometric data and 18 (86%) had serviceable hearing preserved. Excluding transcochlear craniotomies, 85% of patients had normal facial nerve function postoperatively. Cerebrospinal fluid leak (6%) was the most common complication. CONCLUSIONS: Advances in microsurgical techniques have greatly changed our management of patients with posterior fossa meningiomas. These changes have reduced postoperative morbidity. Specifically, use of the anterior and posterior petrosal approaches has facilitated facial and auditory neural preservation while not compromising the extent of tumor excision.

Molecular biology of feather morphogenesis: a testable model for evo-devo research.

Darwin's theory describes the principles that are responsible for evolutionary change of organisms and their attributes. The actual mechanisms, however, need to be studied for each species and each organ separately. Here we have investigated the mechanisms underlying these principles in the avian feather. Feathers comprise one of the most complex and diverse epidermal organs as demonstrated by their shape, size, patterned arrangement and pigmentation. Variations can occur at several steps along each level of organization, leading to highly diverse forms and functions. Feathers develop gradually during ontogeny through a series of steps that may correspond to the evolutionary steps that were taken during the phylogeny from a reptilian ancestor to birds. These developmental steps include 1) the formation of feather tract fields on the skin surfaces; 2) periodic patterning of the individual feather primordia within the feather tract fields; 3) feather bud morphogenesis establishing anterio-posterior (along the cranio-caudal axis) and proximo-distal axes; 4) branching morphogenesis to create the rachis, barbs and barbules within a feather bud; and 5) gradual modulations of these basic morphological parameters within a single feather or across a feather tract. Thus, possibilities for variation in form and function of feathers occur at every developmental step. In this paper, principles guiding feather tract formation, distributions of individual feathers within the tracts and variations in feather forms are discussed at a cellular and molecular level.