Physical findings in the upper airways related to obstructive sleep apnea in men and women.

UNLABELLED: CONCLUSIONS, There are gender differences when it comes to the risk factors for sleep apnea. Large tonsils, a high tongue and a wide uvula are risk factors for sleep apnea in men, while large tonsils and a retrognathic mandible are risk factors in women. Upper airway abnormalities including mandibular retrognathia are, however, unable to predict sleep apnea among snorers being investigated for suspected sleep apnea. OBJECTIVES: To identify gender-specific risk factors for obstructive sleep apnea and the diagnostic performance from physical upper airway examinations among snoring men and women investigated because of suspected sleep apnea. PATIENTS AND METHODS: The dimensions of the uvula, tonsils, velopharynx and tongue, and nasal septal deviation, mandibular position, neck circumference, weight, and height were systematically scored in 801 consecutive snoring patients (596 men and 205 women), who had been referred for a primary sleep apnea recording. RESULTS: In men, large tonsils, a high tongue, and a wide uvula were independent factors associated with an apnea-hypopnea index of >15. In women, large tonsils and mandibular retrognathia were independent factors associated with an apnea-hypopnea index of >15. The positive predictive values for upper airway abnormalities ranged between 0.20 and 0.25 in men and between 0.09 and 0.15 in women.

Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.

Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common malignancy in the world, is associated with smoking and has a low 5-year survival rate. Various changes have been described at different stages of SCCHN tumour development, including overexpression of p63, a protein important for development of normal epidermal structures. p63 has been suggested to activate beta-catenin, and nuclear accumulation of beta-catenin is an important event in many cancers. Elevated COX-2 activity and overexpression of EGFR protein has been shown in a variety of human cancers, including SCCHN. An important question for the pathogenesis of SCCHN is when the genetic changes take place during the natural course of the disease, and whether they appear in clinically normal oral mucosa to predispose tumour development. We mapped the expression of p63, COX-2, EGFR, beta-catenin, and PP2A in oral mucosa from smokers/non-smokers and from patients with SCCHN. We also considered if changes occurring in tumours are present in the clinically normal tissue adjacent to the tumour. No direct influence of heavy smoking on the levels of the proteins studied could be seen. Tumours and clinically normal non-neoplastic tissue from SCCHN patients showed increased expression of COX-2 and PP2A. Interestingly, non-neoplastic tissue adjacent to SCCHN also showed increased beta-catenin, although this was not seen in tumours. The data support the notion that pre-existing alterations in clinically normal epithelium exist in patients with SCCHN and could be important for the pathogenesis of the disease and for local recurrences.

Antigen challenge induces a supraglottic but not a subglottic edema in the rat larynx.

OBJECTIVE: To examine the reaction of mast cells in the larynx of sensitized rats after allergen challenge and determine whether a type I hypersensitivity reaction can elicit a supraglottic and subglottic edema. STUDY DESIGN: Rats were sensitized with ovalbumin (OA) and challenged 3 weeks later by intravenous injection of either OA or NaCl and perfused with glutaraldehyde. The larynges were removed and processed for light and electron microscopy. Sections from the epiglottis and subglottic region were examined. RESULTS: In challenged animals, the connective tissue mast cells (CTMC) in the epiglottic submucosa, but not the mucosal mast cells (MMC) in epithelium, were significantly reduced compared with the case of controls, and the connective tissue was edematous. In the subglottic region, the number of both MMC and CTMC was reduced (albeit not significantly), and there was no edema in the lamina propria. CONCLUSIONS: Allergen challenge induces a marked edema in the epiglottis but not in the subglottic area. SIGNIFICANCE: The results indicate that the supraglottic and subglottic regions react differently to allergen challenge.

Function and importance of p63 in normal oral mucosa and squamous cell carcinoma of the head and neck.

BACKGROUND/AIMS: Squamous cell carcinoma of the head and neck (HNSCC) is the 6th most common malignancy worldwide with a 5-year survival that has not improved over the last 20-25 years. Factors of prognostic significance for this tumour type include the presence of regional lymph node metastasis and amplification of chromosome 3q21-29, where the p63 gene is located. This gene encodes 6 proteins and is crucial for formation of the oral mucosa, teeth, salivary glands and skin. Each of the 6 different p63 proteins has different characteristics and functions, where some resemble the tumour suppressor protein p53, whilst others have functions that oppose p53. METHODS: To understand the function and importance of p63 in oral mucosa and tumour development we have studied protein as well as mRNA expression in normal oral mucosa and tumours. RESULTS/CONCLUSION: Expression of p63 proteins differs between the cell layers in normal oral mucosa, and primary HNSCC has a high expression level of p63 isoforms normally expressed in basal cells. Data suggest that p63 expression in HNSCC influences tumour cell differentiation.

Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck.

The human p63 gene encodes a series of protein isoforms that differ in their N- and/or C-terminal sequences and possess widely varying activities in promoting or repressing p53-related functions and in regulating the proliferation and differentiation of epithelial cells. To gain further information on the role of p63 expression in human tumours, we used quantitative real-time RT-PCR to study individual p63 isoforms in squamous cell carcinomas of the head and neck (SCCHN). In keeping with previous reports, expression of the deltaN- and p63alpha-isoforms predominated and deltaNp63 mRNA was expressed at significantly higher levels in tumours compared to matched normal tissues. Some tumours also expressed the highly efficient transactivator TA- and p63beta-isoforms, and p63beta was significantly increased in tumours compared to matched normal tissue. We could not identify any correlations between different p63-isoform expression patterns and proliferation, p53 status, or telomerase expression. All p63 isoforms could be identified in normal surface epithelium, and micro-dissection showed that the high levels present in basal layers were similar to those seen in tumour tissues. Thus, high-level expression of deltaNp63 in tumour cells may represent maintained expression by the basal cells from which the tumour arose, rather than representing a true over-expression of p63 during tumourigenesis. Tobacco usage, a genotoxic predisposing factor for SCCHN, had no effect on p63 expression in oral epithelium. Taken together, our data indicate that SCCHN maintain expression of high levels of deltaNp63alpha in combination with varying levels of other p63 isoforms, some of which are highly efficient transcriptional activators. The complexity of these p63 expression patterns seen in primary SCCHN indicates that p63 has multifaceted roles in tumour biology.

Viscoelasticity of rabbit vocal folds after injection augmentation.

OBJECTIVES/HYPOTHESIS: Vocal fold function is related to the viscoelasticity of the vocal fold tissue. Augmentation substances used for injection treatment of voice insufficiency may alter the viscoelastic properties of vocal folds and their vibratory capacity. The objective was to compare the mechanical properties (viscoelasticity) of various injectable substances and the viscoelasticity of rabbit vocal folds, 6 months after injection with one of these substances. STUDY DESIGN: Animal model. METHODS: Cross-linked collagen (Zyplast), double cross-linked hyaluronan (hylan B gel), dextranomers in hyaluronan (DHIA), and polytetrafluoroethylene (Teflon) were injected into rabbit vocal folds. Six months after the injection, the animals were killed and the right- and left-side vocal folds were removed. Dynamic viscosity of the injected substances and the vocal folds was measured with a Bohlin parallel-plate rheometer during small-amplitude oscillation. RESULTS: All injected vocal folds showed a decreasing dynamic viscosity with increasing frequency. Hylan B gel and DiHA showed the lowest dynamic viscosity values, and vocal folds injected with these substances also showed the lowest dynamic viscosity (similar to noninjected control samples). Teflon (and vocal folds injected with Teflon) showed the highest dynamic viscosity values, followed by the collagen samples. CONCLUSION: Substances with low viscoelasticity alter the mechanical properties of the vocal fold to a lesser degree than substances with a high viscoelasticity. The data indicated that hylan B gel and DiHA render the most natural viscoelastic properties to the vocal folds. These substances seem to be appropriate for preserving or restoring the vibratory capacity of the vocal folds when glottal insufficiency is treated with augmentative injections.

Prediction and risk of dysphagia after uvulopalatopharyngoplasty and uvulopalatoplasty.

OBJECTIVE: To test the hypothesis that preoperative asymptomatic pharyngeal swallowing dysfunction predisposes for the development of symptoms of dysphagia after uvulopalatopharyngoplasty (UPPP) and uvulopalatoplasty (UPP). MATERIAL AND METHODS: A total of 42 patients who snored were scheduled to undergo UPPP (n = 20) or UPP (n = 22). UPP was performed using either a CO2 laser or a conventional steel scalpel. Preoperatively and 1 year postoperatively all patients were examined videoradiographically to assess pharyngeal swallowing function. They also completed a questionnaire pre- and postoperatively concerning their snoring problems and swallowing function as well as the outcome of surgery. RESULTS: Preoperatively, 7 (17%) patients reported dysphagia. Pharyngeal swallowing dysfunction was demonstrated in 6/7 patients with preoperative dysphagia while pharyngeal swallowing dysfunction was evident preoperatively in 18/35 non-dysphagic patients. Of the 35 patients without preoperative dysphagia, 10 (29%/) developed dysphagia after surgery. There was no significant risk of development of postoperative dysphagia for patients with compared to patients without preoperative pharyngeal swallowing dysfunction. Only one of the seven patients with preoperative dysphagia experienced worsening of the problem. A total of 93% of the patients reported a decrease in snoring and 95% reported a decrease in daytime sleepiness. CONCLUSIONS: Preoperative pharyngeal swallowing dysfunction was not proven to predict the development of dysphagia after UPPP or UPP. The surgical method did not influence the frequency of postoperatively acquired dysphagia. The results do not indicate that patients with preoperative dysphagia should be excluded from treatment with UPPP or UPP.

Cross-linked hyaluronan versus collagen for injection treatment of glottal insufficiency: 2-year follow-up.

OBJECTIVES: To evaluate the long-term (24 months) clinical performance (vocal fold function) and safety of hylan B gel as compared with bovine cross-linked collagen in the treatment of patients with glottal insufficiency. MATERIAL AND METHODS: In a prospective trial, 70 patients with glottal insufficiency due to unilateral vocal fold paresis (n =35) or atrophy (n =35) were randomized to received either hylan B gel (n =47) or collagen (n =23) injections into 1 vocal fold. Forty-two of the patients were examined 24 months after treatment. Evaluations were made based on patients' subjective ratings, digitized videostroboscopic measurements, maximum phonation time and phonation quotient. RESULTS: The patients' self-ratings were significantly improved in both the hylan B gel and collagen groups. Videostroboscopic measurements of glottal closure were significantly improved for both groups. The hylan B gel group showed a trend towards less resorption at the injected vocal fold edge in comparison with the collagen group (p =0.05). No serious adverse events were observed. Twenty-eight patients dropped out of the study after 12 months: 18 had been re-injected or operated on with medialization laryngoplasty due to insufficient voice and 10 had either died of causes unrelated to the study or refused to attend follow-up. CONCLUSIONS: No long-term side-effects were found for either the hylan B gel or collagen groups after injection treatment. Both treatments resulted in significantly improved voice as rated by the patients and significantly improved glottal closure. Some resorption was noted for both substances, and approximately 25%, of the patients chose re-treatment 2 years after the initial treatment.

Viscoelastic properties of rabbit vocal folds after augmentation.

BACKGROUND: Vocal fold function is closely related to tissue viscoelasticity. Augmentation substances may alter the viscoelastic properties of vocal fold tissues and hence their vibratory capacity. OBJECTIVES: We sought to investigate the viscoelastic properties of rabbit vocal folds in vitro after injections of various augmentation substances. STUDY DESIGN AND SETTING: Polytetrafluoroethylene (Teflon), cross-linked collagen (Zyplast), and cross-linked hyaluronan, hylan b gel (Hylaform) were injected into the lamina propria and the thyroarytenoid muscle of rabbit vocal folds. Dynamic viscosity of the injected vocal fold as a function of frequency was measured with a Bohlin parallel-plate rheometer during small-amplitude oscillation. RESULTS: All injected vocal folds showed a decreasing dynamic viscosity with increasing frequency. Vocal fold samples injected with hylan b gel showed the lowest dynamic viscosity, quite close to noninjected control samples. Vocal folds injected with polytetrafluoroethylene showed the highest dynamic viscosity followed by the collagen samples. CONCLUSIONS: The data indicated that hylan b gel in short-term renders the most natural viscoelastic properties to the vocal fold among the substances tested. This is of importance to restore/preserve the vibratory capacity of the vocal folds when glottal insufficiency is treated with injections.

Sleep apnea and Down's syndrome.

OBJECTIVE: Obstructive sleep apnea has been reported to occur in 20-50% of children with Down's syndrome in case series of patients referred for evaluation of suspected sleep apnea. In this population-based controlled study, we aimed to investigate whether sleep apnea is related to Down's syndrome. MATERIAL AND METHODS: Every child aged 2-10 years with Down's syndrome residing in the Umeå healthcare district (n = 28) was invited to participate in the study, with their siblings acting as controls. Successful overnight sleep apnea recordings and echocardiography were performed in 17/21 children with Down's syndrome and in 21 controls. RESULTS: Obstructive sleep apnea could not be diagnosed, either in children with Down's syndrome or in the control children. The apnea-hypopnea index in the children with Down's syndrome was 1.2 +/- 1.5 and did not differ from that in controls. Snoring and hypertrophy of the tonsils were more common in children with Down's syndrome than in controls. Children with Down's syndrome slept for a shorter time (p < 0.001) and changed body position more often (p < 0.05) than the control children. CONCLUSIONS: Snoring, restless sleep and hypertrophy of the tonsils were common among children with Down's syndrome. Obstructive sleep apnea was, however, not related to Down's syndrome in the present population-based controlled study.

Cross-linked hyaluronan used as augmentation substance for treatment of glottal insufficiency: safety aspects and vocal fold function.

OBJECTIVE: To examine safety aspects and vocal fold function after vocal fold augmentation with a cross-linked hyaluronan derivative (hylan B gel) as compared with bovine collagen. STUDY DESIGN; A prospective, randomized trial. METHODS: Eighty-three patients with glottal insufficiency were treated with injection augmentation with hylan B gel and bovine collagen and were examined at 1, 6, and 12 months after treatment. Seventy patients with unilateral vocal fold paresis (n = 35) or atrophy (n = 35) were randomly assigned to receive either hylan B gel (n = 47) or collagen (n = 23) injections into one vocal fold. Thirteen patients with glottal insufficiency caused by scar defects or paresis resulting from malignant disease were included in a nonrandomized group and were treated only with hylan B gel. Evaluations were made from patients' subjective ratings (visual analogue scales), digitized videostroboscopic measurements, phonetograms, maximum phonation time, and phonation quotients. RESULTS: Twelve months after injections, the patients' self-ratings were significantly improved for both the hylan B gel and the collagen groups. In addition, the videostroboscopic measurements showed significantly improved glottal closure for both groups. However, for the hylan B gel group, vibration amplitude and glottal area variations were preserved, and this group showed significantly less resorption at the injected vocal fold edge. Furthermore, maximum phonation time had increased significantly for the hylan B gel patients (collagen, nonsignificant). No serious adverse events were observed; three patients injected with hylan B gel had temporary inflammation at the injection site, which resolved without sequelae. CONCLUSIONS: The results showed that both hylan B gel and collagen can be safely used for injection treatment of glottal insufficiency. Both treatments resulted in significantly improved voice as rated by the patients. However, the patients treated with hylan B gel showed better vocal fold status and longer maximum phonation time at 12 months after treatment as compared with patients treated with collagen.

Cross-linked hyaluronan for augmentation of the posterior pharyngeal wall: an experimental study in rats.

Velopharyngeal insufficiency can be treated in different ways. Augmentation injections of various space-filling materials have been tried, but a substance that has the ideal properties--easy to inject, non-toxic, and not immunogenic, and having a lasting effect--has not yet been found. Hylan b gel, a double cross-linked hyaluronan solution, is a new tissue augmentor that is not immunogenic and is easy to use. The purpose of this study was to evaluate the persistence of and the tissue reaction to hylan b gel injected into the posterior pharyngeal wall of 12 rats. Six rats acted as controls. A light immediate, and no late, inflammatory reaction developed in the pharyngeal mucosa after injection. Six months after injection, the gel was still present and the substance had been invaded by and surrounded by newly-formed, loose connective tissue. These results indicate that hylan b gel may be an appropriate substance in the augmentation of mild velopharyngeal insufficiency in man. However, further studies are needed to evaluate its long-term effects.

Differential expression of p63 isoforms in normal tissues and neoplastic cells.

The p63 gene encodes at least six different proteins with homology to the tumour suppressor protein p53 and the related p53 family member p73. So far, there have been limited data concerning the expression patterns of individual p63 proteins, due to a lack of reagents that distinguish between the different isoforms. Three antibodies have been produced specifically directed against the two N-terminal isoforms (TAp63 and DeltaNp63) and the C-terminal region of the p63alpha proteins. TAp63 proteins are located suprabasally in stratified epithelia compared with the N-terminal truncated forms, which are more abundantly expressed in the basal cell layer, indicating a switch in expression of p63 isoforms during normal cellular differentiation. Analysis of squamous cell carcinomas shows DeltaNp63alpha to be the most widely expressed isoform, compatible with a role for this protein in promoting neoplastic cell growth in these tissues. DeltaNp63 protein expression is also restricted to basal cells in breast and prostate, whilst TAp63 isoforms are more widely expressed in these tissues as well as in tumours at these sites. TAp63, but not DeltaNp63 or p63alpha, is detected in normal colon and in colon carcinoma. TAp63 proteins are also expressed in the nuclei of a sub-population of lymphoid cells and in most malignant lymphomas, whereas DeltaNp63 proteins are not expressed. Taken together, a hitherto unrecognized regulation of p63 isoform expression in vivo has been uncovered, with different p63 proteins expressed during differentiation and in different cell types. The data indicate roles for specific p63 isoforms not only in maintaining epithelial stem cell populations, but also in cellular differentiation and neoplasia.