Faculty Bibliography

Glycinergic transmission shapes the coding properties of the lateral superior olivary nucleus (LSO). We investigated intracellular pH responses in the LSO to glycine using BCECF-AM in brain slices. With extracellular bicarbonate, glycine produced an alkalinization followed by an acidification while, in the nominal absence of bicarbonate, glycine produced acidifications. Separately, in whole-cell recordings from LSO neurons, glycine caused hyperpolarization followed by long-lasting depolarization. While the bicarbonate-dependent intracellular alkalinization could be related to chloride/bicarbonate exchange, bicarbonate-independent acidification may be triggered by depolarization

We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression

CONTEXT: A number of therapies have been proposed for the long-term management of corticosteroid-responsive, rapidly progressive, bilateral sensorineural hearing loss (autoimmune inner ear disease [AIED]). Methotrexate has emerged as the benchmark agent but has not been rigorously evaluated for hearing improvement in patients with AIED. OBJECTIVE: To assess the efficacy of long-term methotrexate in maintaining hearing improvements achieved with glucocorticoid (prednisone) therapy in patients with AIED. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial conducted from February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive, bilateral sensorineural hearing loss at 10 tertiary care centers in the United States. INTERVENTION: Randomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up examinations, including audiometric evaluation, were performed at 4, 8, 12, 24, 36, 48, and 52 weeks, or until hearing loss was documented. MAIN OUTCOME MEASURE: Maintenance of hearing improvement achieved from prednisone treatment. RESULTS: Sixty-seven patients (57.8%) enrolled in the prednisone challenge experienced hearing improvement. Twenty-five patients (37%) experienced hearing improvements in both ears. Of the individuals who reached study end points, 24 (80%) of 30 end points were because of measured hearing loss in the methotrexate group and 29 (93.5%) of 31 end points were because of measured hearing loss in the placebo group (P =.15). Methotrexate was no more effective than placebo in maintaining the hearing improvement achieved with prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P =.30). CONCLUSION: Methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy in patients with AIED

Although several modalities have been discussed, a comprehensive intraoperative program should have IOERT, IOHDR, and perioperative brachytherapy facilities available to treat all sites. Interstitial brachytherapy is preferable for the treatment of gross residual tumor; IORT (IOERT for accessible sites and IOHDR for poorly accessible sites) is added to irradiate intraoperatively the surrounding margins after gross resection; and fractionated EBRT could be used in moderate doses post-operatively to irradiate the entire area of potential microscopic disease. Depending on the volume and location of the tumor, and the available expertise and equipment, IOERT, IOHDR, or perioperative brachytherapy could be used along with EBRT and surgery for the optimal management of malignancies. Finally, the best results of IOHDR are obtained when used as a conformal boost to the tumor bed after resection in conjunction with supplementary EBRT.

BACKGROUND: Distraction osteogenesis is an established technique for the lengthening of long bones and correction of selected craniofacial deformities. Regenerate osteoid bone matrix formed during the distraction phase is malleable and can recreate the three-dimensional form of native bones. Animal experiments and early clinical experience have confirmed that distraction osteogenesis can be used for the reconstruction of segmental bony defects. Herein we discuss the principles of distraction osteogenesis in reference to reconstruction of segmental bony defects and report its clinical application of the mandible continuity defects. PATIENTS AND METHODS: Four patients (age, 7-83 years) with critical segmental mandibular defects (range, 3.5 cm-6.5 cm), resulting from ablative oncologic head and neck surgery underwent primary mandibular reconstruction by transport distraction osteogenesis. Two defects were at the angle and body region, one at the body, and the other at the parasymphysis and body region. Synthes Titanium Multi-vector and Leibinger Multi-guide distractors in bifocal (n = 2) and trifocal (n = 2) architecture were used after the stabilization of the segmental continuity defect using a defect-bridging mandibular reconstruction plate. Osteodistraction was carried out at a rate of 1 mm per day, with once or twice a day rhythm, after a 1-week latency period. The consolidation period was equal to the period of distraction. RESULTS: All patients tolerated the distraction procedure. Satisfactory bone formation was observed in two patients, and partial bone formation was seen in one patient. Treatment failure was encountered in one patient who had a second oral cavity primary tumor observed during the consolidation period, requiring interruption of the treatment sequence. CONCLUSIONS: Mandibular reconstruction with distraction osteogenesis is a potentially useful technique in selected patients with segmental mandibular continuity defects after ablative head and neck cancer surgery

BACKGROUND: Chlamydia pneumoniae infection is a frequent cause of lower respiratory disease in both adults and children. However, its role in upper respiratory disease, including sinusitis, is less clear. OBJECTIVE: To determine the role of infection with C. pneumoniae in chronic sinusitis in children. DESIGN: Prospective collection of specimens. SETTING: Tertiary care academic medical center. PARTICIPANTS: Children with clinical and radiologic evidence of chronic sinusitis unresponsive to medical management undergoing adenoidectomy, maxillary sinus lavage, or endoscopic sinus surgery for treatment. Intervention Nasopharyngeal and middle meatal swabs and portions of surgical specimens were obtained and cultured for C. pneumoniae. RESULTS: Specimens were obtained from 20 children (14 boys and 6 girls) aged 3 through 16 years. Thirteen bilateral endoscopic ethmoidectomies with maxillary antrostomies, 10 adenoidectomies, and 3 bilateral maxillary sinus lavages were performed. Chlamydia pneumoniae was isolated from the nasopharyngeal swab and adenoid tissue of 1 child (aged 6 years); however, his middle meatal swabs and maxillary sinus aspirates were negative. After 10 days of treatment with clarithromycin, repeat nasopharyngeal cultures were negative for C. pneumoniae. CONCLUSIONS: With the use of sensitive culture methods, C. pneumoniae was not isolated from sinus specimens of children enrolled in this study. This preliminary study suggests that C. pneumoniae does not play a significant role in chronic sinusitis in children

We investigated how frequently the imaging procedure we use immediately prior to radiosurgery--triple-dose gadolinium-enhanced MR performed with the patient immobilized in a nonrelocatable head frame and 1-mm-thick MPRAGE (magnetization-prepared rapid gradient echo) images (SRS3xGado)-identifies previously unrecognized cerebral metastases in patients initially imaged by conventional MR with single-dose gadolinium (1xGado). Between July 1998 and July 2000, the diagnoses established for 47 patients who underwent radio-surgical procedures for treatment of cerebral metastases at The Gamma Knife Center of New York University were based initially on the 1xGado protocol. In July 1998, we began using SRS3xGado as our routine imaging protocol in preparation for targeting lesions for radio-surgery, using triple-dose gadolinium and acquisition of contiguous 1-mm Tl-weighted axial images. Because our SRS3xGado scans sometimes unexpectedly revealed additional metastases, we sought to learn how frequently the initial 1xGado scans would underestimate the number of metastases. We therefore reviewed the number of brain metastases identified on the SRS3xGado studies and compared the results to the number found by the 1xGado protocol, which had initially identified the brain metastases. Additional metastases, ranging from 1 to 23 lesions per patient, were identified on the SRS3xGado scan in 23 of 47 patients (49%). In 57% of the 23 patients, only one additional lesion was identified. The mean time interval between the 1xGado and the SRS3xGado scans was 20.6 days (range, 4-83 days), and the number of additional lesions detected and the time interval between two scans were negatively correlated (-0.11). The number of lesions detected on the SRS3xGado was associated only with the number of lesions on the 1xGado and not with any other patient or tumor pretreatment characteristics such as age, gender, largest tumor volume on the 1xGado, or number of days between the 1xGado and the SRS3xGado or prior surgery. The identification of additional lesions with SRS3xGado MR may have implications for patients who are treated with stereotactic radiosurgery alone (without whole-brain irradiation) with single-dose gadolinium imaging, in that unidentified lesions may go untreated. As a result of these findings we continue to use and advocate SRS3xGado scans for radiosurgery

OBJECTIVE: Most reports in the literature focus on the efficacy of a single procedure for obstructive sleep apnea (OSA). We review the overall efficacy of a surgical methodology based on localizing the level of anatomic obstruction for each patient and surgical correction of the nasal, oropharyngeal, or hypopharyngeal obstruction.Study design and setting Retrospective review of cases performed by a single practitioner using a systematic approach to surgery for OSA with preoperative and postoperative sleep studies. RESULTS: Forty-two patients with a respiratory disturbance index (RDI) greater than 15 were included in the study. Surgery involved at least 2 levels of obstruction usually performed in 2 stages. All patients reported symptomatic improvement. Overall, 83.3% (35 of 42) of patients were cured according to the accepted RDI criteria of more than 50% reduction and final RDI of less than 20. All 21 patients with mild OSA (RDI, <29), 73% of patients with moderate OSA (RDI, 30 to 49), and 50% of patients with severe OSA (RDI, >50) were cured. CONCLUSION: The use of an anatomically based methodology in approaching patients with OSA seems to offer a higher efficacy than a single procedure as reported in the literature

Expression of beta 3 integrins is increased in invasive melanoma. In this study we show that K1735 cell proliferation is enhanced by the expression of either beta 3 or a constitutively active Src. We investigated possible modulators of FN matrix assembly and found that matrix metalloproteinase 2 (MMP2) was activated by alpha v beta 3. alpha v beta 3 integrin was localized to focal contacts whereas alpha v beta 5 was peripherally distributed. MMP2 was also activated by expression of CASrc. MMP2 activation inversely correlated with FN matrix assembly, in that it dramatically reduced the organization of a FN matrix. K1735 cell migration on VN and invasion through a reconstituted basement membrane were decreased in the presence of anti-MMP2 antibodies. These results demonstrate that the expression of the alpha v beta 3 complex modulates melanoma cell behavior including activation of Src, organization of the cytoskeleton, assembly of the extracellular matrix, cell motility, and activation of MMP2.