Nasal septal deviation in the pediatric and adult populations.

A significant proportion of the population has nasal septal deviation of varying degrees. Recent reports of such deviation occurring at younger ages suggest a congenital etiology. To the best of our knowledge, no previous clinical studies have compared the septal deviation of adult and pediatric populations with a uniform measure that focuses on the degree of deviation. We retrospectively analyzed computed tomography (CT) and magnetic resonance imaging (MRI) scans obtained from 81 patients who had undergone head and neck imaging for a variety of reasons. These subjects were divided into four age groups: younger than 4 months; 4 months to less than 5 years; 5 to 15 years; and more than 15 years. We used a measure of tortuosity to examine and compare nasal septal deviation among the different age groups. The tortuosity of the septum was measured at four precise points along the length of the septum on thin-section sinus CT and MRI. Tortuosity was defined as the ratio of the "actual" length of the septum to the "ideal" length of the septum, which was defined as the length of a straight line drawn from the superior to the inferior aspect of the septum. We found that subjects younger than 5 years of age exhibited significantly less tortuosity (p ≤ 0.017459) than did the older children and the adults. Therefore, we conclude that nasal septal deviation occurs at a higher frequency in older children and in adults when calculations of tortuosity are used as a measure. Our data may suggest that a noncongenital etiology is responsible for nasal septal deviation. However, given that the growth of the septum continues throughout childhood, our results do not preclude the possibility of a genetic predisposition to the later development of a deviated nasal septum.

Small vestibular schwannomas with no hearing: comparison of functional outcomes in stereotactic radiosurgery and microsurgery.

OBJECTIVES: To date, numerous studies have compared functional outcomes between stereotactic radiosurgery (SRS) and microsurgery (MS) in the treatment of vestibular schwannomas (VS). However, most of them involve tumors of difference sizes, radiation dosages, and surgical approaches. Few have systematically compared issues of dysequilibrium. By studying only patients with small tumors and no hearing, we sought to minimize confounding variables. STUDY DESIGN: A retrospective chart review and telephone questionnaire. METHODS: From 1998-2006, 31 patients with small (<1.5 cm) VS and nonserviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery [AAO-HNS] Class C or D) were treated at our institution. Twenty-two were available for follow-up and telephone questionnaire, including the University of California Los Angeles Dizziness Questionnaire (UCLA-DQ). Twelve underwent SRS and 10 underwent MS. All MS patients underwent the translabyrinthine approach to their tumors. Outcomes measurements included tumor control, facial nerve function, tinnitus, trigeminal function, and imbalance. RESULTS: Patients undergoing SRS had comparable rates of tumor control, facial nerve function, tinnitus, and trigeminal function to MS patients. However, SRS did result in statistically significantly worse long-term imbalance when compared with MS patients. Detailed comparisons of the two modalities are made. CONCLUSIONS: In our study population, patients with small tumors and no serviceable hearing, these data suggest that MS results in comparable minimal morbidity with SRS, though posttreatment dysequilibrium is significantly decreased. While the authors recommend translabyrinthine resection of small VS with no hearing in patients able to tolerate surgery, the need for further prospective investigation is clear.

Identification of domains in gag important for prototypic foamy virus egress.

Sequence motifs (L domains) have been described in viral structural proteins. Mutations in these lead to a defect at a late stage in virus assembly and budding. For several viruses, recruitment of an endosomal sorting complexes required for transport 1 subunit (Tsg101), a component of the class E vacuolar protein sorting (EVPS) machinery, is a prerequisite for virion budding. To effect this, Tsg101 interacts with the PT/SAP L domain. We have identified candidate L-domain motifs, PSAP, PPPI, and YEIL, in the prototypic foamy virus (PFV) Gag protein, based on their homology to known viral L domains. Mutation of the PSAP and PPPI motifs individually reduced PFV egress, and their combined mutation had an additive effect. When PSAP was mutated, residual infectious PFV release was unaffected by dominant negative Vps4 (an ATPase involved in the final stages of budding), and sensitivity to dominant negative Tsg101 was dramatically reduced, suggesting that the PSAP motif functions as a conventional class E VPS-dependent L domain. Consistent with this notion, yeast two-hybrid analysis showed a PSAP motif-dependent interaction between PFV Gag and Tsg101. Surprisingly, PFV release which is dependent on the PPPI motif was Vps4-independent and was partially inhibited by dominant negative Tsg101, suggesting that PPPI functions by an unconventional mechanism to facilitate PFV egress. Mutation of the YEIL sequence completely abolished particle formation and also reduced the rate of Gag processing by the viral protease, suggesting that the integrity of YEIL is required at an assembly step prior to budding and YEIL is not acting as an L domain.

Identification of human VPS37C, a component of endosomal sorting complex required for transport-I important for viral budding.

Endosomal sorting complex required for transport-I (ESCRT-I) is one of three defined protein complexes in the class E vacuolar protein sorting (VPS) pathway required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. In yeast, ESCRT-I is composed of three proteins, VSP23, VPS28, and VPS37, whereas in mammals only Tsg101(VPS23) and VPS28 were originally identified as ESCRT-I components. Using yeast two-hybrid screens, we identified one of a family of human proteins (VPS37C) as a Tsg101-binding protein. VPS37C can form a ternary complex with Tsg101 and VPS28 by binding to a domain situated toward the carboxyl terminus of Tsg101 and binds to another class E VPS factor, namely Hrs. In addition, VPS37C is recruited to aberrant endosomes induced by overexpression of Tsg101, Hrs, or dominant negative form of the class E VPS ATPase, VPS4. Enveloped viruses that encode PTAP motifs to facilitate budding exploit ESCRT-I as an interface with the class E VPS pathway, and accordingly, VPS37C is recruited to the plasma membrane along with Tsg101 by human immunodeficiency virus, type 1 (HIV-1) Gag. Moreover, direct fusion of VPS37C to HIV-1 Gag obviates the requirement for a PTAP motif to induce virion release. Depletion of VPS37C from cells does not inhibit murine leukemia virus budding, which is not mediated by ESCRT-I, however, if murine leukemia virus budding is engineered to be ESCRT-I-dependent, then it is inhibited by VPS37C depletion, and this inhibition is accentuated if VPS37B is simultaneously depleted. Thus, this study identifies VPS37C as a functional component of mammalian ESCRT-I.

HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway.

Many enveloped viruses exploit the class E vacuolar protein-sorting (VPS) pathway to bud from cells, and use peptide motifs to recruit specific class E VPS factors. Homologous to E6AP COOH terminus (HECT) ubiquitin ligases have been implicated as cofactors for PPXY motif-dependent budding, but precisely which members of this family are responsible, and how they access the VPS pathway is unclear. Here, we show that PPXY-dependent viral budding is unusually sensitive to inhibitory fragments derived from specific HECT ubiquitin ligases, namely WWP1 and WWP2. We also show that WWP1, WWP2, or Itch ubiquitin ligase recruitment promotes PPXY-dependent virion release, and that this function requires that the HECT ubiquitin ligase domain be catalytically active. Finally, we show that several mammalian HECT ubiquitin ligases, including WWP1, WWP2, and Itch are recruited to class E compartments induced by dominant negative forms of the class E VPS ATPase, VPS4. These data indicate that specific HECT ubiquitin ligases can link PPXY motifs to the VPS pathway to induce viral budding.