Faculty Bibliography

In humans, auditory perception reaches maturity over a broad age range, extending through adolescence. Despite this slow maturation, children are considered to be outstanding learners, suggesting that immature perceptual skills might actually be advantageous to improvement on an acoustic task as a result of training (perceptual learning). Previous non-human studies have not employed an identical task when comparing perceptual performance of young and mature subjects, making it difficult to assess learning. Here, we used an identical procedure on juvenile and adult gerbils to examine the perception of amplitude modulation (AM), a stimulus feature that is an important component of most natural sounds. On average, Adult animals could detect smaller fluctuations in amplitude (i.e., smaller modulation depths) than Juveniles, indicating immature perceptual skills in Juveniles. However, the population variance was much greater for Juveniles, a few animals displaying adult-like AM detection. To determine whether immature perceptual skills facilitated learning, we compared naive performance on the AM detection task with the amount of improvement following additional training. The amount of improvement in Adults correlated with naive performance: those with the poorest naive performance improved the most. In contrast, the naive performance of Juveniles did not predict the amount of learning. Those Juveniles with immature AM detection thresholds did not display greater learning than Adults. Furthermore, for several of the Juveniles with adult-like thresholds, AM detection deteriorated with repeated testing. Thus, immature perceptual skills in young animals were not associated with greater learning

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment

Mediators involved in the generation of pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer pain. This previously unrecognized cancer pain pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer pain

OBJECTIVES: To observe the extent of nasal polyposis endoscopically in a cystic fibrosis population before the first surgical intervention and to grade the extent using a modified Malm scale, to observe patients prospectively and record the need for revision endoscopic sinus surgery (ESS), and to compare this among the individual polyp grading groupings. DESIGN: Retrospective medical record review of data collected prospectively. SETTING: Tertiary care hospital. PATIENTS: Forty-nine consecutive patients with a clinical preoperative diagnosis of cystic fibrosis and sinusitis. MAIN OUTCOME MEASURES: Using a modified Malm scale, the extent of polyps was prospectively graded into 3 groups before the first surgical intervention. The number of patients needing revision ESS and the mean time to revision ESS were compared among the 3 groups. RESULTS: Forty-nine consecutive patients underwent ESS between 1992 and 2007. We used a 3-stage system for extent of polyposis: 16 patients were noted to have no polyps (grade A), 14 had mild polyposis (grade B), and 19 had extensive polyposis (grade C). During the study, 14 patients required revision surgery: 3 with mild polyps and 11 with extensive polyps. Mean time to revision surgery was 39.7 months for those with grade B and 23.8 months for those with grade C. In the overall statistical analysis, the rate of revision ESS was significantly different among the 3 groups (P < .001). In pairwise comparisons, there were significant differences between those with grades A and C (P < .001) and between those with grades B and C (P = .04) and a trend toward significance between those with grades A and B (P = .052). There were no complications from ESS. CONCLUSION: Preoperative grading of nasal polyposis in patients with cystic fibrosis can help assess the future likelihood of revision ESS

PURPOSE: To conduct an evidence-based systematic review and provide an estimate of the effects of oral motor interventions (OMIs) on feeding/swallowing outcomes (both physiological and functional) and pulmonary health in preterm infants. METHOD: A systematic search of the literature published from 1960 to 2007 was conducted. Articles meeting the selection criteria were appraised by 2 reviewers and vetted by a 3rd for methodological quality. RESULTS: Twelve studies were included and focused on 3 OMIs-nonnutritive sucking (NNS), oral/perioral stimulation, and NNS plus oral/perioral stimulation. Six studies addressed the effects of OMI on the feeding/swallowing physiology outcomes of feeding efficiency or sucking pressures. Ten studies addressed the functional feeding/swallowing outcomes of oral feeding or weight gain/growth. No studies reported data on pulmonary health. Methodological quality varied greatly. NNS alone and with oral/perioral stimulation showed strong positive findings for improvement in some feeding/swallowing physiology variables and for reducing transition time to oral feeding. Prefeeding stimulation showed equivocal results across the targeted outcomes. None of the OMIs provided consistent positive results on weight gain/growth. CONCLUSIONS: Although some OMIs show promise for enhancing feeding/swallowing in preterm infants, methodological limitations and variations in results across studies warrant careful consideration of their clinical use

OBJECTIVES: We compared estimated blood loss (EBL) in patients who underwent surgical excision of carotid body tumors (CBTs) after preoperative superselective angiography with embolization (PSE) with that in patients who underwent excision of CBTs without PSE. METHODS: We performed a retrospective chart review of a consecutive case series in a single surgeon's practice within an academic tertiary care medical center. Twenty-five patients underwent surgical resection of a CBT from 1989 to 2009. From 1989 to 1996, 10 consecutive patients had PSE of the CBT, whereas the subsequent 15 patients (1996 to 2009) had no PSE. Demographic data including age, sex, and tumor size were collected. The EBL was obtained from intraoperative records and operative notes dictated at the time of surgery. Tumor size was based on preoperative radiographic measurements by a senior radiologist and the surgeon. RESULTS: In the 10 patients with PSE, the mean age was 41 years (range, 22 to 72 years) and the mean tumor size was 4.8 cm (range, 2.9 to 8.3 cm). The mean EBL was 305 mL (range, 50 to 1,000 mL); 2 patients had an EBL of more than 400 mL. In the 15 patients without PSE, the mean age was 43.7 years (range, 20 to 75 years) and the mean tumor size was 4.4 cm (range, 2.8 to 7.9 cm). The mean EBL was 265.6 mL (range, 40 to 900 mL); 2 patients had an EBL of more than 400 mL. There were no significant differences between the 2 groups with regard to age, tumor size, or EBL. CONCLUSIONS: Preoperative superselective angiography with embolization of a CBT does not lead to a significant reduction in intraoperative EBL

OBJECTIVES: The specialty of otolaryngology in the United States has changed dramatically over the past century, and this is particularly true in the field of bronchoesophagology, which has evolved from a new specialty at the beginning of the 20th century to one that is now multidisciplinary and further subspecialized. The purpose of this report was to trace the evolution of bronchoesophagology over the past 60 years by examining and quantitating the scientific subject matter of the annual meetings of the American Broncho-Esophagological Association (ABEA). METHODS: The Transactions of the ABEA annual meetings from the 1940s to the present day were examined in depth for subject matter, and articles were categorized by topic. Each decade was represented by 3 years. Data were sorted into 3 domains: 1) anatomic area, 2) adult versus pediatric, and 3) subject matter, including neoplasms, infectious diseases, foreign bodies, technologies, function, and trauma. The overall changes were quantified to outline the direction and interests of the ABEA. RESULTS: We reviewed 483 scientific articles from the 1940s into the present decade, with a mean of 69.7 papers (SD, 32.4) representing each decade. Bronchology and pulmonology decreased in percentage of papers, from 43% and 17.9% in 1940 to 1.7% and 2.6%, respectively, in the 2000s. Laryngology evolved from 12.5% to 58.1%. Esophagology peaked in the 1950s at 35.7%, dropped to 4% in the 1980s, and then rose to its present-day level of 15.4%. Trends were also discernible in gastric and tracheal areas. Pediatric topics rose to 26.7% in the 1980s, then declined to their present level of 12.8%. Topics related to aerodigestive tract function increased from 3.6% to 34.2%, and presentation of technology declined from 23.2% in the 1940s to nil in the 2000s. Trends in neoplasms, infectious diseases, foreign bodies, and trauma were less significant. CONCLUSIONS: Analysis of the data reveals changing trends in the focus of the ABEA. The changing focus of the ABEA has paralleled scientific advances in our field, as well as the rise of other subspecialties such as interventional pulmonology and gastroenterology

BACKGROUND: Although bioethics is considered essential to the practice of medicine, medical students often view it as a 'soft' subject that is secondary in importance to the other courses in their basic science and clinical curriculum. This perspective may be a consequence of the heavy reliance on students' aptitude in the quantitative sciences as a criterion for entry into medical school and as a barometer of academic success after admission. It is exacerbated by the widespread impression that bioethics is imprecise and culturally relativistic. SUMMARY: In an effort to redress this imbalance, we propose an approach to teaching bioethics to medical students which emphasizes that the intellectual basis and the degree of certainty of knowledge is comparable in all medical subjects ranging from basic science courses to clinical rotations to bioethics tutorials. CONCLUSIONS: Adopting these pedagogical steps may promote greater integration of the various elements-bioethics and clinical science-in the medical school curriculum

Introduction: Epidemiologic observations have suggested a protective effect of soybeans against a number of epithelial cancers including oral malignancies and by inference precursor lesions such as leukoplakia. Several compounds in soybeans have shown activity in preclinical models; we have focused our studies on BBI (Bowman-Birk inhibitor), which is active against the protease chymotrypsin. Our phase I trial demonstrated a very low toxicity profile and a 31% response rate in a 1-month nonrandomized study that was associated with favorable modulation of protease activity and neu oncogene in exfoliated buccal mucosal cells (EBMC). Methods: An intent-to-treat(ITT) randomized placebo (Quaker mass harina, a corn flour)-controlled, double-blind clinical trial of a soybean concentrate (C) of BBI (600 C.I. units) was performed in a multinstitutional investigation (7 sites). The study duration was 6 months and included pre/interim/postevaluation of lesions sizes and pre/post photographic assessments and oral mucosa biopsies(with post central pathology review) of the involved area(s). Intermediate biomarkers (IBM) included serial measurements of EBMC neu protein (ng/mg) and protease (Delrfu/min/ug protein) and serum neu protein (ng/ml). 325 patients underwent preliminary screening and 148 per protocol eligible were enrolled. Of these, 132 were randomized and 105 completed 6 months on study. All data on lesion sizes, photo judgments, and pathology indications of degree of abnormality or change in abnormality were entered into SAS datasets and subjected to 100% verification against the crf forms by the statistician. The several IBM measurements were converted from the original Microsoft Excel sheets into SAS data sets, and subject to spot checks against the original spreadsheets. Similarly, host-factor information from the questionnaires was spot checked against the original records. In all cases, the primary, per-protocol analyses was ITT. The per-protocol, intent-to-treat cohort, and all other categorizations of study participants will also be described with appropriate descriptive summary measures. Results: The ITT data set is composed of all those with valid, two-dimensional measurements on all lesions observed at both the randomization and 6-month visit. 89 evaluable patients met these criteria: 43 in the treatment and 46 in the placebo group. For the BBIC group, the mean relative percent change in total lesion area was -20.6% and for the placebo group -17.1%. Clinical responses for the 89 patients were: four showed a complete response (4.5%), 22 showed a partial response (25%), 53 showed stable disease (60%), and 10 showed disease progression (11.2%). For the drug group the CR+PR(>50% change) was 27.91% and for placebo group 30.43%. Neither the lesion size nor response comparisons demonstrated differences between the two groups that were significantly different (p>0.05). Photos of the same lesion at baseline and at the 6-month exam were available for 91 participants. Five qualified reviewers made judgments of the degree of change in abnormality on a seven-point scale, blinded to study arm and timepoint of photos. For mean comparison scores, 1 was substantial improvement over time, 4 indicated no change and 7 meaning much worse decline over time. Preliminary assessments of 77% of the patients having pre/post photos indicates that there were no significant differences between the placebo and treatment groups. Conclusion: BBIC is not effective as a chemoprevention agent for the management of oral leukoplakia. Central pathology review by two reviewers is near completion, but is unlikely to affect this conclusion. Final measurements of the three biomarkers should be available by the time of presentation and subanalysis will be presented for the two groups and for the patients who seemed to have had a clinical response