Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear.

Biological membranes organize and compartmentalize cell signaling into discrete microdomains, a process that often involves stable, cholesterol-rich platforms that facilitate protein-protein interactions. Polarized cells with distinct apical and basolateral cell processes rely on such compartmentalization to maintain proper function. In the cochlea, a variety of highly polarized sensory and non-sensory cells are responsible for the early stages of sound processing in the ear, yet little is known about the mechanisms that traffic and organize signaling complexes within these cells. We sought to determine the prevalence, localization, and protein composition of cholesterol-rich lipid microdomains in the cochlea. Lipid raft components, including the scaffolding protein caveolin and the ganglioside GM1, were found in sensory, neural, and glial cells. Mass spectrometry of detergent-resistant membrane (DRM) fractions revealed over 600 putative raft proteins associated with subcellular localization, trafficking, and metabolism. Among the DRM constituents were several proteins involved in human forms of deafness including those involved in ion homeostasis, such as the potassium channel KCNQ1, the co-transporter SLC12A2, and gap junction proteins GJA1 and GJB6. The presence of caveolin in the cochlea and the abundance of proteins in cholesterol-rich DRM suggest that lipid microdomains play a significant role in cochlear physiology. BIOLOGICAL SIGNIFICANCE: Although mechanisms underlying cholesterol synthesis, homeostasis, and compartmentalization in the ear are poorly understood, there are several lines of evidence indicating that cholesterol is a key modulator of cochlear function. Depletion of cholesterol in mature sensory cells alters calcium signaling, changes excitability during development, and affects the biomechanical processes in outer hair cells that are responsible for hearing acuity. More recently, we have established that the cholesterol-modulator beta-cyclodextrin is capable of inducing significant and permanent hearing loss when delivered subcutaneously at high doses. We hypothesize that proteins involved in cochlear homeostasis and otopathology are partitioned into cholesterol-rich domains. The results of a large-scale proteomic analysis point to metabolic processes, scaffolding/trafficking, and ion homeostasis as particularly associated with cholesterol microdomains. These data offer insight into the proteins and protein families that may underlie cholesterol-mediated effects in sensory cell excitability and cyclodextrin ototoxicity.

A meta-analysis of clinical screening tests for obstructive sleep apnea.

The purpose of this meta-analysis is to compare clinical screening tests for obstructive sleep apnea and establish an evidence base for their preoperative use. Diagnostic odds ratios were used as summary measures of accuracy, and false-negative rates were used as measures of missed diagnosis with each screening test in this review. Metaregression revealed that clinical models, logarithmic equations, combined techniques, cephalometry, and morphometry are significant characteristics, whereas body mass index, history of hypertension, and nocturnal choking are significant test elements associated with higher diagnostic accuracy. Test accuracy in repeated validation studies of the same screening test is variable, suggesting an underlying heterogeneity in either the clinical presentation of obstructive sleep apnea or the measured clinical elements of these models. Based on the false-negative rates, it is likely that most of the clinical screening tests will miss a significant proportion of patients with obstructive sleep apnea.

Cushing's Syndrome: An Unusual Presentation of Olfactory Neuroblastoma.

A 48-year-old man presented with symptoms consistent with Cushing's syndrome. Subsequent laboratory studies revealed markedly elevated adrenocorticotropic (ACTH) and cortisol levels, as well as a hypoklemic metabolic alkalosis. A pituitary MRI was performed, which revealed a normal pituitary; however, a large mass was seen centered in the ethmoid and paranasal sinuses with a significant amount of extension into surrounding structures. A biopsy was performed and pathology of the specimen was consistent with esthesioneuroblastoma. Immunohistochemical staining further defined the tumor as an ACTH-secreting esthesioneuroblastoma. After total resection of the mass and further treatment with adjuvant radiation therapy, the patient's symtoms completely resolved and the ACTH and cortisol levels were also greatly reduced. This case demonstrates the successful diagnosis and treatment of a rare neoplasm. Ectopic ACTH syndrome due to esthesioneuroblastoma is extremely uncommon with only five other cases being discussed in the literature.