Dynamic laryngotracheal closure for aspiration: a preliminary report.

OBJECTIVES/HYPOTHESIS: An estimated 500,000 patients per year in the United States. are affected by stroke-related dysphagia. Approximately half experience aspiration, which can lead to pneumonia or death. Aspiration may result from many factors, including delayed transport of the bolus, faulty laryngeal elevation, and poor coordination or inappropriate timing of vocal cord closure. Interventions carried out to protect the lungs are usually irreversible, destructive to the upper airway, and rarely prevent the need for enteral tube feeding. STUDY DESIGN: We present a report of the first implantations of a new device in an FDA-approved study to restore dynamic laryngotracheal separation. Two stroke patients needing tracheostomy were selected based on chronic aspiration verified by clinical and radiologic criteria (modified barium swallow [MBS]). METHODS: The left recurrent laryngeal nerve was exposed and electrically stimulated to verify vocal fold adduction. Huntington Medical Research Institute Bipolar Helical Electrodes were then implanted around the nerve. The leads were tunneled and linked to a NeuroControl Implantable Receiver-Stimulator placed subcutaneously on the chest wall. Activation of the stimulator was performed through an external transmitter linked by induction. RESULTS: The device was successfully triggered intra- and postoperatively. Serial flexible fiberoptic endoscopies and MBS demonstrate that aspiration is systematically arrested using low levels of electrical stimulation (42 Hz, 48-100 microsec, 1 mA). DISCUSSION: This pioneering work has shown that aspiration can be controlled without airway damage for a wide population of neurologically impaired patients because it appears more physiological than standard therapies. CONCLUSION: Based on the first two patients, paced laryngotracheal separation is clinically effective in controlling aspiration.

Direct autogenous fat implantation for augmentation of the vocal folds.

This report examines the results of autogenous fat implantation into paralyzed or flaccid vocal folds in 23 patients. No complications were encountered in any of these patients and very satisfactory voice improvement was achieved in every case. The voice improvement achieved initially has been sustained for one to four years in all patients but one, whose underlying disease process progressed and worsened the voice.

Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition.

Tissue plasminogen (plgn) activator (tPA) modulates neuronal death in models of stroke, excitotoxicity, and oxidative stress. Amyloid-beta (Abeta) appears central to Alzheimer's disease and is neurotoxic to neurons in vitro. Here, we evaluate tPA effects on Abeta toxicity. We report that tPA alone had no effect on Abeta toxicity. However, in combination with plgn, tPA reduced Abeta toxicity in a robust fashion. Moreover, the combined tPA and plgn treatment markedly inhibited Abeta accumulation. The addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to a sample of tPA, plgn, and Abeta resulted in a marked reduction of Abeta degradation. We interpret the actions of tPA and plgn within the context of the ability of plasmin to degrade Abeta.

The plasmin system is induced by and degrades amyloid-beta aggregates.

Amyloid-beta (Abeta) appears critical to Alzheimer's disease. To clarify possible mechanisms of Abeta action, we have quantified Abeta-induced gene expression in vitro by using Abeta-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the Abeta precursor (AbetaP). Here, we report that aggregated, but not nonaggregated, Abeta increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AbetaP overexpressing mice. Because others have reported that Abeta aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPA induction by Abeta would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate Abeta in vitro toxicity or, alternatively, that plasmin activation may lead to Abeta degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades Abeta with physiologically relevant efficiency, i.e., approximately 1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves Abeta at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades Abeta fibrils. Moreover, exogenously added plasmin blocks Abeta neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated Abeta, which can lead to Abeta degradation and inhibition of Abeta actions.

c-Jun contributes to amyloid beta-induced neuronal apoptosis but is not necessary for amyloid beta-induced c-jun induction.

The role of gene expression in neuronal apoptosis may be cell- and apoptotic stimulus-specific. Previously, we and others showed that amyloid beta (Abeta)-induced neuronal apoptosis is accompanied by c-jun induction. Moreover, c-Jun contributes to neuronal death in several apoptosis paradigms involving survival factor withdrawal. To evaluate the role of c-Jun in Abeta toxicity, we compared Abeta-induced apoptosis in neurons from murine fetal littermates that were deficient or wild-type with respect to c-Jun. We report that neurons deficient for c-jun are relatively resistant to Abeta toxicity, suggesting that c-Jun contributes to apoptosis in this model. When changes in gene expression were quantified in neurons treated in parallel, we found that Abeta treatment surprisingly led to an apparent activation of the c-jun promoter in both the c-jun-deficient and wild-type neurons, suggesting that c-Jun is not necessary for activation of the c-jun promoter. Indeed, several genes induced by Abeta in wild-type neurons were also induced in c-jun-deficient neurons, including c-fos, fosB, ngfi-B, and ikappaB. In summary, these results indicate that c-Jun contributes to Abeta-induced neuronal death but that c-Jun is not necessary for c-jun induction.

The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer's disease.

In this study, changes of the expression of two mitochondrial and two nuclear genes encoding the subunits of cytochrome c oxidase (CO) and NADH dehydrogenase (ND) were studied in the hippocampus, inferior parietal lobule, and cerebellum of 10 Alzheimer's disease (AD) and 10 age-matched control subjects. The altered proportion between CO II and CO IV mRNAs was observed in the AD brain. Changes of the proportion between CO II and CO IV transcripts may contribute to the kinetic perturbation of CO documented in AD. A coordinated decrease of ND4 and ND15 mRNAs was found in the AD hippocampus and inferior parietal lobule, but not in cerebellum. The decrease of ND4 gene expression may lead to the inhibition of normal ubiquinone oxidoreductase activity of ND. This study suggests that changes of the expression of mitochondrial and nuclear genes, encoding parts of ND and CO enzyme complexes, may contribute to alterations of oxidative metabolism in AD.

Long-term preservation of voice improvement following surgical medialization and reinnervation for unilateral vocal fold paralysis.

In June of 1996, we reported improved functional voice results when reinnervation was combined with surgical medialization for unilateral vocal fold paralysis. In addition, it was noted that further wasting of the reinnervated vocal fold was prevented in 96% of these patients beyond 2 years' follow-up. The study reported here compares the long-term preservation of voice improvement achieved by surgical medialization alone with that resulting from combined medialization and nerve-muscle pedicle reinnervation. Further significant wasting of the paralyzed vocal fold with voice deterioration from that achieved by surgical medialization alone was noted between 6 months and 2 years postoperatively in 28% of patients, while only 4% of those undergoing combined reinnervation demonstrated this finding at a minimum of 2 years' follow-up.

Adenoid cystic carcinoma of the trachea.

OBJECTIVE: Primary tracheal tumors are rare, occurring in 0.2 per 100,000 persons per year. Adenoid cystic carcinoma (ACC) is the second most common histologic type of tracheal malignancy. Its clinical behavior is different from the other tracheal neoplasms and thus should be studied separately. STUDY DESIGN/METHODS: Retrospective review of the medical records of six patients with tracheal ACC who were treated at University Hospitals of Cleveland between 1971 and 1996 and literature review. RESULTS/CONCLUSION: Tracheal ACC is an indolent tumor that affects people at any age but has a peak incidence in the fifth decade. There is a nearly equal male-to-female ratio. Almost half of tracheal ACCs occur in the proximal trachea, accounting for the most common presenting symptoms: dyspnea, cough, and hoarseness. Because of the hoarseness, patients are often referred to an otolaryngologist. Complete resection provides the best chance for increased survival. Neutron beam radiotherapy holds promise for adjuvant therapy.

Human amylin induces "apoptotic" pattern of gene expression concomitant with cortical neuronal apoptosis.

Amylin forms large beta-pleated neurotoxic oligomers but shows only 38% sequence similarity to A beta. As patterns of gene expression during neuronal apoptosis appear stimulus and cell type specific, we compared the pattern of amylin-induced gene expression in rat cortical neurons with that shown previously to be induced by A beta in order to evaluate whether these two peptides with different primary but similar secondary structure induce apoptosis similarly. Morphologic and quantitative measures of cell death show widespread apoptotic death after amylin treatment. Amylin treatment results in time- and concentration-dependent inductions of oxidative stress genes, such as cox-2 and IkappaB-alpha. "Apoptotic" genes are also induced in a time- and concentration-dependent manner, including c-jun, junB, c-fos, and fosB, followed temporally by a gene known to be modulated by these transcription factors, i.e., transin. In situ hybridization analyses show that c-fos expression is restricted largely to neurons with condensed chromatin, a hallmark of apoptosis. As these genes are not induced in all models of apoptosis, that amylin-induced neuronal death is genetically similar to that of A beta suggests that these peptides may be neurotoxic through a common mechanism.

"Exploratory" surgery for advanced carcinoma of the larynx: a relatively safe approach.

Between the years 1970 and 1986, the author managed 132 patients with T3 glottic carcinoma. Over half of these patients were explored in an effort to safely perform subtotal laryngectomy. Twenty-seven of them were found to have extension of tumor that required immediate conversion to total laryngectomy. Five-year survival rates were essentially the same for all three groups: immediate total laryngectomy, subtotal laryngectomy, and total laryngectomy following attempted subtotal laryngectomy. I conclude that carefully selected patients with T3 glottic cancer may be candidates for subtotal laryngectomy after surgical exploration, since conversion to total laryngectomy yields local control rates as satisfactory as those of initial total laryngectomy. When subtotal laryngectomy is possible, local control of tumor and recurrence rates are as satisfactory as those of total laryngectomy.

Structural stability of the rotary door myocutaneous flap.

This canine study examines the structural stability of extensive laryngotracheal reconstruction with the sternohyoid myocutaneous rotary door flap (RDF) and modifications of the RDF with subdermal collagen and collagen hydroxyapatite matrix. The postreconstruction stability of the RDF and these modifications were tested and compared by measuring immediate postmortem airway stability during application of negative intraluminal pressures. Comparisons between controls and experimental specimens demonstrated that the RDF provides structural stability to secure airway patency under physiologic pressures. Biocompatible matrix adds further structural support in maintenance of the reconstructed lumen. This study validates that the RDF provides adequate rigid support for extensive laryngotracheal reconstruction without the requirement of skeletal support.

The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease.

Alzheimer's disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the "marker genes" (beta-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the "oxidative stress-handling gene/beta-actin" ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/beta-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/beta-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS-mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain.

Aggregated amyloid-beta protein induces cortical neuronal apoptosis and concomitant "apoptotic" pattern of gene induction.

To gain a molecular understanding of neuronal responses to amyloid-beta peptide (Abeta), we have analyzed the effects of Abeta treatment on neuronal gene expression in vitro by quantitative reverse transcription-PCR and in situ hybridization. Treatment of cultured rat cortical neurons with Abeta1-40 results in a widespread apoptotic neuronal death. Associated with death is an induction of several members of the immediate early gene family. Specifically, we (1) report the time-dependent and robust induction of c-jun, junB, c-fos, and fosB, as well as transin, which is induced by c-Jun/c-Fos heterodimers and encodes an extracellular matrix protease; these gene inductions appear to be selective because other Jun and Fos family members, i.e., junD and fra-1, are induced only marginally; (2) show that the c-jun induction is widespread, whereas c-fos expression is restricted to a subset of neurons, typically those with condensed chromatin, which is a hallmark of apoptosis; (3) correlate gene induction and neuronal death by showing that each has a similar dose-response to Abeta; and (4) demonstrate that both cell death and immediate early gene induction are dependent on Abeta aggregation state. This overall gene expression pattern during this "physiologically inappropriate" apoptotic stimulus is markedly similar to the pattern we previously identified after a "physiologically appropriate" stimulus, i.e., the NGF deprivation-induced death of sympathetic neurons. Hence, the parallels identified here further our understanding of the genetic alterations that may lead neurons to apoptosis in response to markedly different insults.

Combined surgical medialization and nerve-muscle pedicle reinnervation for unilateral vocal fold paralysis: improved functional results and prevention of long-term deterioration of voice.

Including those patients that were the subject of our previous report in 1990 (1) a total of 52 patients with unilateral vocal fold paralysis have been managed by combined surgical medialization and nerve-muscle pedicle reinnervation. The technique has been modified only slightly since 1985, when the first such surgery was performed. Short- and long-term voice results determined by a panel of sophisticated listeners are reported, as well as details of patient selection and complications. Better functional results were noted than were observed with surgical medialization alone, and long-term deterioration of the voice improvement initially achieved was prevented with this technique.

The superiorly based flap long-term tracheostomy in pediatric patients.

PURPOSE: Tracheostomy is commonly used to provide control of the upper airway in pediatric patients. The traditional approach, which uses a midline vertical incision in the anterior tracheal wall, is associated with relatively high rates of complications when it is used on a long-term basis. Alternative approaches, such as removing tracheal window or creating tracheal flaps, have been avoided in the pediatric patient because of the risk of tracheal stenosis and the potential for the subsequent effect on tracheal growth. The superiorly based flap tracheostomy (SBFT) has greatly reduced these risks in adults and offers better stomal maintenance, safety, and patient acceptance, but it has not been widely evaluated in pediatric patients. METHODS: We reviewed 21 superiorly based flap tracheostomies performed in children at our institution between 1986 and 1993. Routine follow-up assessments included fixed and flexible laryngotracheoscopy. Average follow-up was 17 months. RESULTS: The most common indication for performing the SBFT was bilateral vocal cord paralysis. Short-term complications included wound infection and granuloma in 2 patients. Long-term complications were not observed. One patient died from lower respiratory tract causes. Five of the patients were eventually decannulated, and the stoma closed without laryngotracheal stenosis. Morbidity rates were less and mortality was comparable to those of traditional tracheostomy. CONCLUSION: We conclude that the SBFT is promising a technique for establishing long-term control of the airway in pediatric patients.

Sequence requirements in the reactive-center loop of plasminogen-activator inhibitor-1 for recognition of plasminogen activators.

Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin superfamily of proteins and is the fast acting inhibitor of both urinary plasminogen activator and tissue-type plasminogen activator. We have assessed the functional significance of reactive center residues on the carboxy-terminal side of the cleavage site of recombinant human PAI-1. Using site-directed mutagenesis, the P1'-P5' residues (P1' is the first residue on the carboxy-terminal side of the protease cleavage site) of the wild-type PAI-1 reactive center sequence were replaced with the corresponding sequences of plasminogen activator inhibitor-2, antithrombin, alpha 2-antiplasmin and protease nexin I. Rate constants of inhibition of the serine proteases urinary plasminogen activator, tissue-type plasminogen activator, plasmin and thrombin by the variants were determined. The results suggest a crucial role for both reactive center length and sequence in the inhibition of plasminogen activators by PAI-1. Analysis of substitutions at positions P4' and P5' both confirms and extends our previous work demonstrating a favorable electrostatic interaction between these residues and tissue-type plasminogen activator. None of the variants show dramatic increases in the rate constants of inhibition of other serine proteases, suggesting that these residues alone are not sufficient to confer protease specificity on PAI-1. Apparently, the determinants of the rapid inhibitory specificity of PAI-1 are localized to the P1'-P5' region of the reactive center and these residues act synergistically to produce the exquisite specificity of PAI-1 for plasminogen activators.

Vocal fold medialization using autologous cartilage in a canine model: a preliminary study.

Unilateral vocal fold paralysis can alter phonation. Medialization of the vocal fold using cartilage augmentation dates to the early 1950s. Improved phonation after cartilage chordal augmentation has been reported, but no study has as yet documented cartilage viability or size in this setting over time. The authors of this study evaluated thyroid alar cartilage as a medializing material in three mongrel dogs. Grafts were inserted lateral to the inner thyroid perichondrium at the vocal fold level via a window in the thyroid cartilage. Changes in weight, size, and volume were assessed 6 months after implantation. The average graft weight declined by 15%, and the average square area declined by 3%. Importantly, the average volume maintained was 87%. The grafts remained rigidly fixed to the thyroid cartilage in their placement positions. Histologic examination documented minimal resorption. The data suggest that thyroid alar cartilage is a viable filler in type I thyroplasty procedures.

Long-term flap tracheostomy in a pediatric animal model.

OBJECTIVE: To investigate the short- and long-term complications of pediatric tracheostomy, emphasizing posttracheostomy tracheal stenosis in an animal model. DESIGN: Twenty-five New Zealand white rabbits were randomly assigned to three groups: flap tracheostomy, traditional vertical tracheostomy, and control. Interactive image analysis was used to compare the tracheal cross-section area and circumference between groups 16 weeks after surgery. The incidence of peristomal infections and accidental decannulations was also compared. RESULTS: The vertical tracheostomy group had a smaller circumference (P = .01) and smaller cross-sectional area (P = .006) than the control or flap tracheostomy groups. A 30% decrease in tracheal cross-sectional area occurred in the vertical tracheostomy group. The flap tracheostomy group had fewer problems with accidental decannulation and peristomal infection compared with the vertical tracheostomy group. CONCLUSIONS: We found no significant risk of tracheal stenosis or adverse effects on tracheal growth for the flap tracheostomy in a developing animal model. This tracheostomy technique may be useful in the management of pediatric patients who require long-term bypass of the upper airway.

G. Paul Moore Lecture--1993. New voices for old.

Otolaryngology and voice science have entered the era of "phonosurgery." Several techniques allow voice professionals to intervene to restore or modify the voice in patients with immobile vocal folds and other problems related to voice production. It is necessary and appropriate that physicians and speech and language pathologists critically examine what has been accomplished and what may yet be possible for further voice improvement.