Hoarseness--current concepts on etiologies and treatment alternatives.

The care of the human voice has challenged medical practitioners for centuries. Over the last 25 years we have seen significant advancements in the diagnosis and treatment of vocal disorders. This article is an overview of the more common voice disorders encountered in clinical practice and the diagnostic and management alternatives currently available. A thorough understanding of these conditions can lead to a prompt diagnosis and improved clinical outcomes in all patients, especially professional voice users. The insights presented are compiled through the eyes of a clinician and the heart of a performer.

Human nasal mucosal carboxypeptidase: activity, location, and release.

BACKGROUND: Carboxypeptidases (CPs), such as carboxypeptidase N (CPN) (kininase I, E.C.3.4.17.3), may regulate peptide-mediated vasodilation and vascular permeability in respiratory mucosa by degrading proinflammatory peptides such as bradykinin, anaphylatoxins, and neuropeptides during allergic and nonallergic inflammation. The sources of CP activity in human nasal secretions were investigated. METHODS: Well-characterized human nasal provocation and secretion analysis methods were used. Potential sources of CPN in human nasal mucosa were identified by immunohistochemistry. CP activity was defined as DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid inhibitable Bz-Gly-Lys degradation. CP activity was measured in nasal mucosal homogenates and nasal lavage fluids induced by methacholine, histamine, and allergen nasal provocation. RESULTS: CPN-immunoreactive material was localized to the glycocalyx of the epithelium, some vessels, and gland ducts near the epithelial basement membrane but not to submucosal gland cells. CP activity in human nasal lavage fluid after saline nasal provocation was 0.10 +/- 0.04 U/L. Histamine provoked secretion of significantly more CP activity (3.84 +/- 0.99 U/L; p < 0.01 vs saline). Methacholine did not significantly increase secretion (0.54 +/- 0.22 U/L). After nasal allergen challenge, CP activity was at a maximum between 11 and 20 minutes, and CP activity correlated with IgG concentration (r = 0.91, p < 0.01), a marker for proteins of plasma origin, suggesting that CP activity originated in plasma. CONCLUSIONS: These data suggest that plasma is the predominant source of CP activity secreted from human nasal mucosa and that plasma extravasation and interstitial fluid exudation across the epithelium are the primary processes regulating its appearance in nasal secretions.

Angiotensin-converting enzyme in the human nasal mucosa.

Angiotensin-converting enzyme (ACE; EC 3.4.15.1) may participate in respiratory inflammatory diseases by regulating levels of inflammatory peptides such as bradykinin. The presence of ACE in the human nasal mucosa and in nasal secretions was determined by immunohistochemistry, measures of enzyme activity, and immunoblot. ACE activity was significantly more abundant in the membrane-rich fraction than in the soluble cytosolic fraction of nasal mucosal extracts (74.18 +/- 24.50 versus 3.99 +/- 1.83 pmol/min/mg protein, respectively, P < 0.01 by an enkephalin degradation assay; 89.16 +/- 16.17 versus 2.30 +/- 0.89 mU/mg protein, P < 0.01 by colorimetric assessment of Bz-Gly-Gly-Gly degradation). Topical application of histamine stimulated secretion of ACE activity into nasal lavage fluid (2.90 +/- 0.88 versus 1.53 +/- 0.45 U/liter after saline provocation, P < 0.05 by Bz-Gly-Gly-Gly assay). Allergen challenge also induced nasal secretion of ACE. In both histamine and allergen challenges, ACE release correlated closely with that of the vascular proteins IgG and albumin. Methacholine, a stimulant of glandular secretions, failed to augment ACE levels above baseline. ACE-immunoreactive material was localized by the immunogold technique with silver enhancement to the glycocalyx, between epithelial cells, and to interstitial, extracellular sites in the superficial lamina propria, with the highest intensity of staining immediately beneath the basement membrane. Some ACE was detectable in the mucus material of gland and duct lumens but not in gland cells themselves. Endothelial cells and some interstitial mononuclear cells also stained for ACE. ACE was identified by immunoblotting as a 150 kD band on SDS-PAGE.(ABSTRACT TRUNCATED AT 250 WORDS)

Human nasal mucosal neutral endopeptidase (NEP): location, quantitation, and secretion.

Neutral endopeptidase (E.C.3.4.24.11, enkephalinase, NEP) is a potentially important enzyme capable of regulating the activity of neuropeptides released in the respiratory mucosa. In order to confirm the existence of NEP in the human respiratory mucosa, inferior nasal turbinate mucosae obtained at surgery and nasal secretions induced by topical provocations with methacholine, histamine, and allergen were analyzed for: (1) NEP activity (pmol product/min/ml) by enzymatic degradation of [3H]leu-enkephalin, (2) the presence of NEP-immunoreactive material by Western blot analysis, and (3) cellular localization of NEP distribution by immunohistochemistry. NEP activity in human nasal secretions obtained after normal saline challenge was 0.15 +/- 0.06 pmol/min/ml. Secretion increased to 0.86 +/- 0.26 pmol/min/ml after methacholine provocation and 1.69 +/- 0.74 pmol/min/ml after histamine provocation. The increase in NEP activity in methacholine-induced secretions was prevented by atropine (0.13 +/- 0.06 pmol/min/ml). After methacholine, histamine, and antigen nasal provocation, the kinetics of NEP appearance correlated more closely to the glandular marker, lactoferrin, than with the vascular markers albumin and IgG. In homogenates of nasal mucosa, the membrane fraction contained significantly more NEP on a per mg protein basis than did the soluble fraction (227.6 +/- 50.52 versus 9.61 +/- 3.18 pmol/min/mg protein, respectively, P < 0.01, n = 6). NEP in the membrane fraction was detected as a single band migrating at 97 kD on Western blots using antibodies specific for NEP and the common acute lymphoblastic leukemia antigen (CALLA). Immunoreactive NEP was localized to serous cells of the submucosal glands, epithelial cells, and endothelial and myoepithelial cells of small vessels. Staining for NEP in the serous cells was of the same intensity as that in epithelial cells. These results indicate that 97 kD NEP-immunoreactive material exists in discrete locations in the nasal mucosa, including the epithelium, serous cells of the submucosal glands, and vessel walls, and that NEP activity is detected as a minor component in nasal secretions enriched by glandular products. In addition to the modulating functions of NEP on neuropeptide-mediated activities on vessels and glands, it is possible that NEP in secretions plays a role in regulating mucosal responses to luminal neuropeptides or other as yet uncharacterized NEP substrates.

Quantification of resident inflammatory cells in the human nasal mucosa.

BACKGROUND: To define the normal resident inflammatory cell population in the nasal mucosa, surgical specimens of human nasal turbinates were immunohistologically stained for various cell markers. METHODS: Freeze-dried paraffin-embedded sections were stained for lymphocyte cell-surface markers, and Carnoy's fixed sections were stained for mast cells and immunoglobulins. The numbers of stained cells were microscopically counted. RESULTS: T cells (CD3+ cells) were abundant in the lamina propria, and the number of CD4+ cells and CD8+ cells accounted for two thirds and one third of CD3+ cell number, respectively. Cells that stained for the alpha-chain of the interleukin-2 receptor (activated cells, CD25+) were limited and accounted for only 0.6% of CD3+ cell number. B cells (CD22+ cells) and monocytes and macrophages (CD14+ cells) were observed less frequently than T cells. Many immunoglobulin-producing cells were found in close proximity to the submucosal glands, and those cells were predominantly IgA+. Mast cells were widely distributed in the nasal mucosa, and about one third of these cells were stained for IgE molecules. Nonmast cells bearing IgE were rarely observed. CONCLUSION: Thus the dominant cell in the nasal mucosa is a CD3+, CD4+, CD25-lymphocyte.

Endothelin in human nasal mucosa.

Endothelin (ET), a potent vasoconstrictor and bronchoconstrictor peptide synthesized by endothelial and epithelial cells, was examined for its potential functions in human inferior turbinate nasal mucosal tissue by four techniques: (1) immunoreactive ET was localized in the mucosa by immunohistochemistry; (2) receptors for ET were identified by autoradiography employing [125I]ET; (3) ET-1 mRNA was localized by in situ hybridization; and (4) the secretory functions of ET were examined by the release of mucous and serous cell products after the addition of ET to human nasal turbinates in short-term cultures. Specific ET-1-immunoreactive material was found most extensively in small muscular arteries and in serous cells in submucosal glands. ET-1 was also found to a lower extent in the walls of venous sinusoids. [125I]ET-1 binding sites were localized by autoradiography to submucosal glands and to venous sinusoids and small muscular arterioles. mRNA for ET-1 was found most extensively in the venous sinusoids and to a lesser extent in small muscular arteries. In mucosal explant cultures, ET-1 and ET-2 stimulated lactoferrin and mucous glycoprotein release from serous and mucous cells, but ET-3 was inactive. The observations indicate that in the human nasal mucosa, ET is present in the vascular endothelium and the serous cells in submucosal glands and acts on glandular ET receptors to induce both serous and mucous cell secretion. It is also likely that ET plays a role in the regulation of vasomotor tone.

Muscarinic receptor subtypes in human nasal mucosa: characterization, autoradiographic localization, and function in vitro.

Muscarinic receptors play important roles in the regulation of glandular secretion and vasomotor tone in human nasal mucosa. M1, M2, and M3 muscarinic receptor subtypes were pharmacologically characterized in human inferior turbinates by receptor-binding assays using [3H](-)quinuclidinyl benzilate (QNB, identifies total muscarinic receptors) and [3H]-pirenzepine (PZ). Receptors were localized by autoradiography, and their function examined in vitro by assaying mucus secretion from cultured nasal mucosal explants. In competition assays, PZ was employed as a selective muscarinic antagonist for M1 receptors, gallamine and AF-DX 116 for M2 receptors, and 4-DAMP for M3 receptors. These ligands are selective at low nanomolar concentrations, but can interact with other muscarinic receptors at higher concentrations. It is not known if they can interact with putative M4 and M5 muscarinic receptor subtypes. Using [3H](-)QNB, total muscarinic receptor binding was 688.4 +/- 49.6 fmol/mg protein (Bmax), with a Kd of 1.47 +/- 0.13 nM. [3H]-PZ bound to 45% of the total QNB binding sites. In competition experiments, 4-DAMP displaced [3H](-)QNB with the lowest IC50, followed by PZ and AF-DX 116. Autoradiograms demonstrated that [3H](-)QNB binding was completely displaced by 4-DAMP, partially displaced by PZ, but not displaced by gallamine or AF-DX 116, and suggested that M1 and M3 subtypes coexist in submucosal glands. The localization of M1 receptors on submucosal glands was confirmed by direct labeling with [3H]-PZ. [3H]-PZ also labeled vessels, but with a low silver grain density. Autoradiographic [3H]-QNB binding was displaced by 4-DAMP and atropine, but not by PZ, gallamine, or AF-DX 116. In studies of mucus secretion in vitro, 4-DAMP significantly inhibited methacholine-induced secretion. Although less effective, PZ also had significant inhibitory effects. Neither gallamine nor AF-DX 116 had any inhibitory effect. M1 receptors (PZ binding sites) may regulate glandular secretion while M3 receptors (4-DAMP binding sites) may regulate glandular secretion and vasomotor tone in human nasal mucosa.

Characterization and autoradiographic localization of histamine H1 receptors in human nasal turbinates.

To examine the localization of histamine H1 receptors (H1R) in human nasal mucosa, the autoradiographic distribution of H1R was studied in human nasal inferior turbinates. Cryostat sections were incubated with various concentration of [3H]pyrilamine in saturation-binding studies and with 1 nmol/L of [3H]pyrilamine for autoradiography. Nonspecific binding was determined by adding 2 mumol/L of pyrilamine. Scatchard analysis demonstrated high-affinity binding sites with a maximum binding capacity of H1R of 193 +/- 46 fmol/mg of protein, and dissociation constant was 0.6 +/- 0.1 nmol/L. Autoradiograms indicated H1R exist exclusively on the endothelium of vessels. No specific labeling could be observed in the submucosal glands or epithelium. These results extend and support our previous finding that histamine directly causes vascular permeability through H1R and stimulates nasal glandular secretion indirectly through reflexes.

Verification of sleep apnea using a portable sleep apnea screening device.

Sixty-seven patients referred to a sleep laboratory with a tentative diagnosis of obstructive sleep apnea were examined with a device designed for home use as an apnea screening system. Direct comparison was made between data obtained by the portable device and by data acquired simultaneously with standard polysomnographic techniques. The portable recorder measured nasal/oral airflow, chest wall movement, cardiac rhythm, and blood oxygen saturation. There was no significant difference in the number of disordered breathing events (apneas and hypopneas) recorded by the two systems. The portable device was found to have a sensitivity of 95% and a specificity of 96%. Indications and limitations for use of the portable home apnea screening test are reviewed and guidelines for normalcy suggested.

Iontophoretic treatment of oral herpes.

Recent development of pharmaceutical agents that interfere with reproduction and metabolism of the herpes virus appear to have clinical applications in the treatment of orocutaneous herpetic lesions. Use of topical medications has always been limited by skin penetration. Combining these new pharmaceutical agents with iontotransport techniques has been shown to be effective for treatment of herpetic lesions. Instrumentation and a specially designed applicator electrode are described. Use of this instrumentation and its clinical application is described in the treatment of 32 patients and the results are summarized. Combining the use of the new pharmaceuticals with the iontotransport instrumentation is described as an effective treatment of localized herpetic lesions. Similar technique offers fascinating possibilities in other areas of skin pathology.

Artificial larynx prosthesis: comparative clinical evaluation.

The work pioneered by Drs. Singer and Blom established the clinical feasibility of controlled tracheoesophageal fistula for generation of fluent esophageal speech. There have been numerous practical difficulties that have been encountered with the use of voice prosthesis. Problems encountered are: extrusion, speech initiation delay, leakage around the prosthesis, stoma obstruction, and low volume output. A second generation laryngeal prosthesis is introduced for comparison. Its design incorporates features that will significantly improve the clinical problems encountered; extrusion is minimized; and the new prosthesis allows for one size to fit all patients. A clinical trial was established to directly compare the artificial speech generated by the currently existing laryngeal prosthesis. Each laryngectomy patient was fitted with three different devices and the resulting speech was evaluated. Video recordings of patients are presented to illustrate the type of speech produced by each device. Comparisons of intelligibility, fluency, volume, and patient preference are made. Results indicate that a significant variation in the speech obtained is critically dependent on the choice of prosthesis.

Sudden airway obstruction due to pedunculated laryngeal polyps.

Acute upper airway obstruction from laryngeal polyps is uncommon. However, a large pedunculated laryngeal polyp, when unrecognized, may produce sudden airway obstruction. The importance of an early diagnosis and treatment is stressed. Primary care physicians, endoscopists, anesthesiologists, and otolaryngologists should be aware of this condition and add it to their differential diagnosis of sudden respiratory obstruction.

A biomechanical study of the ligamentous stability of the thoracic spine in man.

An in vitro study was conducted to establish the thresholds of thoracic spine stability. Flexion or extension producing horizontal forces of 43 percent body weight were applied to fresh two-vertebrae spine specimens. Spine components were transected in two different sequences until failure. Load-displacement curves were measured. Intact spine exhibited average inter-vertebral horizontal translatory displacement of 1.0 mm (s.d. = 0.4) and sagittal plane rotation of 1.4 degrees (s.d. = 0.8). Just prior to failure these average displacements increased to 2.4 mm (s.d. = 1.4) and 4.1 degrees (s.d. = 1.7). A horizontal displacement of 2.5 mm (on lateral X-ray) or 5 degrees of angulation of one vertebra with respect to the other may indicate an unstable spine. This information, together with other clinical indicators of spine instability discussed here, will be helpful in the clinical judgment regarding an injured spine.