Faculty Bibliography

OBJECTIVES/HYPOTHESIS: Inflammation and its role in a coordinated fibroplastic response, which disrupts the structure of the vocal folds following injury, is critical. Cyclooxygenase-2 (COX-2) is an important enzyme involved in both inflammation and fibrosis; in addition, it is a prime target for therapeutic intervention. We sought to study this pathway in vocal fold fibroblasts to provide a foundation for future interventional studies. STUDY DESIGN: In vitro. METHODS: Human vocal fold fibroblasts were incubated with IL-1 beta to determine the effects on COX-2 signaling, along with upstream regulatory mechanisms and downstream mediators of wound healing. In vitro methods to assess mRNA expression, as well as intracellular and secreted protein (sodium dodecyl sulfate polyacrylamide gel electrophoresis and enzyme-linked immunosorbent assay) were employed. RESULTS: IL-1 beta regulation of COX-2 mRNA and protein levels was dose and time dependent and IL-1 beta altered PGE(2) metabolism, via regulation of both synthetic and degradative enzymes. IL-1 beta increased nuclear factor (NF)-kappaB activation and nuclear translocation. Inhibition of the p50 and p65 subunits of NF-kappaB decreased IL-1 beta-induced COX-2 transcription. IL-1 beta also altered mRNA expression of four cell-surface prostaglandin receptors. CONCLUSIONS: Inflammation and fibrosis are important in the vocal fold pathophysiologic response to injury. Our data suggest that COX-2 and PGE(2) are inducible in human vocal fold fibroblasts, and this response appears to be NF-kappaB-dependent. We purport this fundamental investigation will lead to increased insight regarding injury and repair in the vocal folds, with the ultimate goal of developing novel clinical care paradigms

OBJECTIVES/HYPOTHESIS: Although the diagnostic accuracy of paradoxical vocal fold movement disorder and chronic cough has improved, the underlying pathophysiology remains relatively unknown. We hypothesize that one potential etiological factor in these patients is an aberrant laryngeal sensory response and sought to determine if respiratory retraining in addition to antireflux therapy alters this aberrant response. STUDY DESIGN: Retrospective, outcomes. METHODS: Sixteen patients who had been on at least 3 months of twice-daily proton pump inhibitors with no subjective improvement in their primary complaint of cough, self-reported symptoms of gastroesophageal and laryngopharyngeal reflux, and concurrent paradoxical vocal fold movement (PVFM) were included in the current study. In addition to continuing twice daily pharmacological therapy, subjects underwent a course of respiratory retraining. Outcome measures including the Reflux Symptom Index (RSI), transnasal flexible laryngoscopy, and laryngopharyngeal sensory discrimination thresholds were obtained prior to and following a course of respiratory retraining. RESULTS: Mean bilateral laryngeal sensory response improved significantly after combined respiratory retraining and aggressive proton pump inhibitor therapy (P = .01). In addition, mean RSI score decreased significantly following treatment (P = .02). Specifically, 13 of 16 patients experienced improved sensory response, corresponding with patient reports of improved PVFM symptoms following treatment. CONCLUSIONS: Aberrant laryngeal sensation was identified in patients with PVFM and chronic cough. This response, however, normalized following a limited course of respiratory retraining, corresponding with improved patient symptoms

BACKGROUND: Radiation therapy (RT) to the head and neck often results in damage to the vocal folds (VF) and surrounding structures. Characterization and treatment of these sequelae is limited, likely due to the lack of experimental models. METHODS: Larynges from rats exposed to 2 fractionation schedules (40 Gy total) were analyzed histologically. In vitro, reactive oxygen species (ROS) synthesis, and transcription of select genes associated with ROS, inflammation, and fibrosis were examined in VF fibroblasts after single-dose radiation. RESULTS: Although radiation-induced histologic alterations are made to VF architecture, 1 fractionation schedule was accompanied by significant morbidity and mortality. In vitro, radiation increased ROS synthesis and inflammatory and profibrotic gene expression. CONCLUSION: Our data suggest that hyperfractionated RT is more tolerable. Utilizing this model, RT-induced histologic aberrations are made to the VF mucosa. In addition, a relationship between radiation, ROS, and inflammatory and fibrotic gene expression was observed in vitro

To review existing patient reported outcomes measures (PROMs) used in dysphonic populations to assess the procedures used in their development and the extent to which these meet current development standards for content generation and psychometric evaluation. The study is a systematic review. A systematic review of Medline, Cumulative Index to Nursing & Allied Health, and Health and Psychosocial Instruments databases was completed using voice, quality of life, and PROMs as keywords. We identified all patient or parent-reported questionnaires measuring quality of life associated with voice disorders from the review findings. Questionnaires were appraised for adherence to international guidelines for the development and evaluation of PROMs as outlined by the Scientific Advisory Committee of the Medical Outcome Trust. Nine PROMs fulfilled the inclusion criteria. The quality of these questionnaires was variable with regard to instrument development and none met all of the current, recommended criteria. Of the nine questionnaires, the Voice Symptom Scale underwent the most rigorous development process. Furthermore, many instruments have been augmented to allow for proxy administration, failing to address quality of life-related issues specific to the target population. Instrument development is often overlooked when attempting to quantify patient reported outcomes in dysphonic patients. Careful instrument development procedures are required to ensure that PROMs are valid, reliable, and responsive. Our review suggests that the deficits in psychometric properties of the current voice-related PROMs may be, at least in part, due to deficits in the development process. Furthermore, these data suggest the potential utility of a novel PROM adhering to rigorous international standards to better ensure that clinicians appreciate the variables most relevant to patients with voice disorders and address some of the psychometric shortcomings of the currently used questionnaires

We present the unique opportunity to correlate videostroboscopic findings with histologic examination. An immunocompromised patient with hoarseness because of ulcerative lesions of both vocal folds of uncertain cause died within a few weeks of initial presentation, and the larynx was donated for postmortem examination. Relevant history, as well as endoscopic and histopathologic findings, is presented

OBJECTIVE: Dehydration challenges can increase the chemical composition of surface fluid overlying vocal fold epithelia (hypertonic surface fluid). The vocal fold epithelium is posited to act as a barrier, shielding the lamina propria from perturbations in the airway lumen. However, the effects of hypertonic surface fluid on the barrier functions of vocal fold epithelia have not been quantified. We, therefore, sought to investigate whether hypertonic surface fluid compromises epithelial barrier function. We examined the effects of hypertonic surface fluid on vocal fold epithelial resistance, paracellular pathway morphology, and tight junction protein integrity. STUDY DESIGN: Ex vivo, between group design. SETTING: Laboratory. METHODS: Porcine vocal folds (n = 24) were exposed to hypertonic or isotonic challenge and examined by electrophysiology, transmission electron microscopy, and Western blot analyses. RESULTS: Hypertonic, but not isotonic, challenge significantly reduced transepithelial resistance. This decrease in resistance was observed immediately after the challenge and was consistent with the appearance of dilated paracellular pathway morphology. However, hypertonic challenge did not alter protein levels of occludin, zona occludens-1, E-cadherin, or beta-catenin. CONCLUSION: Hypertonic surface fluid alters epithelial barrier function in the vocal folds. Specifically, exposure to hypertonic challenges increases epithelial permeability. Given the important role of the vocal fold epithelium in shielding the underlying mucosa from inhaled pathogens and pollutants, our data provide the impetus for future studies on pharmacological treatments aimed at restoring the hydration level and chemical composition of vocal fold surface fluid

OBJECTIVES/HYPOTHESIS: The potassium titanyl phosphate (KTP) laser is emerging as a potentially effective treatment for various vocal fold pathologies. To date, the precise mechanism(s) of action of this wavelength on the layered microarchitecture of the vocal fold remains unknown. The purpose of this study is to develop an in vivo model for the use of the KTP laser in the rat vocal fold and to characterize the potential of this model for future studies. STUDY DESIGN: In vivo survival surgery. METHODS: A model for videoendoscopic visualization and injury to the rat vocal fold was established using a microlaryngoscope and rigid telescope. Unilateral vocal fold injury was induced with the KTP laser at 10 Watts (W) 20 milliseconds (ms) pulse width. Animals were euthanized at 1 day post-treatment. Larynges were subjected to gross visual analysis and histological analyses via hematoxylin and eosin and trichrome staining. RESULTS: Consistent endoscopic visualization and injury was obtained without significant operative morbidity or mortality. The KTP laser caused superficial blanching and minor edema in the vocal fold, which resolved grossly by 24 hours postinjury. A modest inflammatory cell infiltrate was observed 1 day following injury. However, no remarkable alterations to the vocal fold microarchitecture were observed in the acute period. CONCLUSIONS: We propose that this novel model simulates the clinical scenario of laser use for the vocal folds. Use of this model will allow us to further characterize effects, mechanisms, and therapeutic efficacy of this wavelength

OBJECTIVE/HYPOTHESIS: Oxidative damage mediates the lower airway response to cigarette smoke (CS). In the vocal folds, the tissue phenotype is both distinct and largely uncharacterized. We sought to investigate the effects of CS on the oxidative status and fibroblast phenotype in the vocal folds. Specifically, we hypothesized that CS would induce a hypermetabolic fibroblast phenotype and altered oxidative metabolism potentially providing insight into the relationship among CS, Reinke's edema (RE), and malignancy. STUDY DESIGN: In vivo/in vitro. METHODS: Heme oxygenase (HO)-1 gene expression was examined in human tissue. In vitro, the effects of cigarette smoke condensate (CSC) on HO-1 gene expression and secretion was assayed. In addition, CS-mediated intracellular reactive oxygen species synthesis was quantified, and compared to the response in pulmonary fibroblasts (HFL). We then examined the effects of CSC on migration and proliferation in human vocal fold fibroblasts (HVOX). RESULTS:: HO-1 expression was approximately 4-fold higher in RE samples versus vocal fold polyps. CSC induced HO-1 gene expression and secretion in a time- and dose-dependent fashion in vitro. CSC also increased intracellular ROS in both HVOX and HFL. CSC decreased HVOX proliferation and migration in a dose-dependent manner. CONCLUSIONS: These data suggest that the fibroblast phenotype is influenced by smoke. Our data suggest that the antioxidant response in the vocal fold tissue may be one mechanism of chemoprotection, a putative explanation for the observation that RE rarely transforms to malignancy. In addition, CSC does not appear to induce a hypermetabolic fibroblast phenotype as expected

The objectives of this study are to describe central nervous system modulation associated with voice improvement following Type I thyroplasty in a patient with glottic insufficiency secondary to unilateral vocal fold paralysis. Serial functional magnetic resonance imaging scans were performed before as well as one and six months after thyroplasty. Paradigms consisting of four voice production tasks and a motor control task were completed. Volumes of activation within regions activated during each task were measured. Acoustic and aerodynamic measures were also obtained. A widespread network of neural activations was shown for all tasks. Differences in volumes of activation 1-month postsurgery positively correlated with acoustic and aerodynamic improvements. Sixth months following medialization, lesser volumes of activation were observed in all regions. Prior to this session, however, the patient's mediastinal disease progressed, leading to a significant deterioration in voice. Functional differences between patient brain maps yield new information about the central nervous system's ability to reorganize sensorimotor representations associated with voice improvement following Type I thyroplasty in a patient with glottic insufficiency secondary to unilateral vocal fold paralysis (UVFP)