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Epithelial cells play an important role in maintaining the airway barrier, which is impaired in inflammatory conditions. Recently, thrombin was reported to be increased in the airway of patients with asthma, and thrombin has been shown to increase the permeability of endothelial cell monolayers. Therefore, we suspected that thrombin affects airway permeability. Calu-3 cell monolayers were established on microporous membranes of tissue culture cell inserts. We examined the effects of topically applied thrombin or thrombin receptor-activating peptide (TRAP) on: (1) transepithelial permeability (luminal to serosal transfer) of radiolabeled mannitol and albumin, (2) changes in electrical resistance, and (3) actin fiber content as assessed by fluorescence microscopy. Compared with untreated control cultures, treatment of the monolayers for 24 h with thrombin or TRAP significantly decreased the electrical resistance and increased the permeability to mannitol and albumin. In addition, these treatments enhanced the appearance of actin stress fibers, and small gaps became visible at areas of cell-cell contact. Thrombin appears to increase epithelial permeability by receptor-mediated reorganization of the actin network in airway epithelial cells. This is likely to contribute to the impairment of the airway barrier function., (Copyright 2006 S. Karger AG, Basel)

Intranasal topical steroids are commonly used for the treatment of olfactory dysfunction. Although the side effects are considered to be minimal, these have not been studied in detail. We examined the side effects of intranasal topical treatment with steroids in patients with olfactory dysfunction. We treated 62 patients with intranasal topical application of 0.1% betamethasone sodium phosphate (Rinderone) administered to the olfactory clefts. After treatment for 1 or 2 months, serum ACTH or cortisol was reduced in 42 (68% of total) patients, however, no clinical symptoms associated with steroid side effects were observed. The treatment was discontinued in 8 of these patients, who elected to withdraw from the treatment. In these patients, the serum ACTH or cortisol returned to normal a month after stopping the treatment. In the remaining 34 patients, the topical treatment was continued and in only 4 of these patients, minor steroid-associated side effects such as the sensation of facial swelling and facial hair thickening, appeared 2-5 months after beginning the treatment. These side effects disappeared within a month after stopping the treatment. Regarding the therapeutic efficacy, in 18 (78%) of the 23 patients who continued treatment for an average period of 5 months, steroid treatment significantly improved their olfactory dysfunction. In conclusion, although it is important to consider the potential side effects of long-term intranasal topical treatment with steroids for olfactory dysfunction, this treatment is a highly effective method against olfactory dysfunction with minimal side effects.

Conclusion: CD14/-159 plays a role in sensitization to Dermatophagoides pteronyssinus in Japanese patients with allergic rhinitis., Objective: An association between a polymorphism in the 5'-flanking region of the CD14 gene and atopic phenotypes has been identified in a pediatric American population and an adult Dutch population. The aim of this study was to determine whether the CD14/-159 polymorphism is associated with specific IgE levels in allergic rhinitis patients in a Japanese population., Material and Methods: The CD14/-159 genotypes of 81 unrelated patients with allergic rhinitis and 78 healthy subjects were determined and compared. The total IgE level and the specific IgE levels for three aeroallergens were determined. The IgE levels for each genotype were compared., Results: The frequencies of CD14/-159 genotypes did not differ between the two groups. Among the allergic rhinitis patients, TT homozygotes had significantly fewer positive CAP-radioallergosorbent tests (CAP-RASTs) than CC homozygotes and CT heterozygotes, suggesting that the C allele is dominant. TT homozygotes also had significantly lower CAP-RAST scores for Dermatophagoides pteronyssinus, but not for Cryptomeria japonica or Dactylis glomerata, than CC homozygotes and CT heterozygotes. There was no significant association between total serum IgE levels and CD14/-159 genotypes in the allergic rhinitis patients.

Purpose: For identification of CTL epitopes useful for cancer vaccines, it is crucial to determine whether cognate epitopes are presented on the cell surface of target cancer cells through natural processing of endogenous proteins. For this purpose, we tried to use the cellular machinery of both mice and human to define naturally processed CTL epitopes derived from two "cancer germ line" genes, MAGE-A4 and SAGE., Experimental Design: We vaccinated newly produced HLA-A2402 transgenic mice with DNA plasmids encoding target antigens. Following screening of synthesized peptides by splenic CD8(+) T cells of vaccinated mice, we selected candidate epitopes bound to HLA-A2402. We then examined whether human CD8(+) T cells sensitized with autologous CD4(+) PHA blasts transduced by mRNA for the cognate antigens could react with these selected peptides in an HLA-A2402-restricted manner., Results: After DNA vaccination, murine CD8(+) T cells recognizing MAGE-A4(143-151) or SAGE(715-723) in an HLA-A2402-restricted manner became detectable. Human CTLs specific for these two peptides were generated after sensitization of HLA-A2402-positive CD8(+) T cells with autologous CD4(+) PHA blasts transduced with respective mRNA. CTL clones were cytotoxic toward tumor cell lines expressing HLA-A2402 and cognate genes. Taken together, these CTL epitopes defined in HLA-A24 transgenic mice are also processed and expressed with HLA-A2402 in human cells. The presence of SAGE(715-723)-specific precursors was observed in HLA-A2402-positive healthy individuals., Conclusions: Two novel HLA-A2402-restricted CTL epitopes, MAGE-A4(143-151) and SAGE(715-723), were identified. Our approach assisted by cellular machinery of both mice and human could be widely applicable to identify naturally processed CTL epitopes.

Pranlukast is a selective cysteinyl leukotriene(1 )(cysLT(1)) receptor antagonist, and is now widely used in the treatment of asthma. The anti-asthmatic effect of pranlukast may be rendered not only by antileukotriene activity, but also by other pharmacological activity. This study was designed to investigate whether pranlukast had inhibitory effects on nuclear factor-kappaB (NF-kappaB) activation and mucin gene expression in cultured human epithelial cells. Luciferase assay was mainly used for analysis. Cultured epithelial cells were transfected with NF-kappaB luciferase vector, MUC2 or MUC5AC luciferase vectors. Lipopolysaccharide (LPS) significantly increased NF-kappaB activation in NCI-H292 cells, which was inhibited by the pretreatment by pranlukast in a dose-dependent manner. Either LTD(4) or pranlukast alone did not increase NF-kappaB activation in NCI-H292 cells. Pranlukast also inhibited NF-kappaB activation induced by phorbol 12-myristate 13-acetate (PMA). Pranlukast also significantly inhibited LPS-induced MUC2 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) analysis in NCI-H292 cells. Pranlukast also inhibited LPS-induced MUC2 gene expression in HM3-MUC2 cells. However, pranlukast did not inhibit MUC5AC gene transcription activity induced by lipoteichoic acid (LTA) in NCI-H292 cells. These results suggest that pranlukast may inhibit NF-kappaB activation and MUC2 gene transcription through pathways distinct from cysLT(1) receptor antagonism in cultured human epithelial cells., (Copyright (c) 2005 S. Karger AG, Basel.)

Objective: The formation and growth of nasal polyps requires remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are a family of endopeptidases that can collectively degrade almost all extracellular matrix components. The aim of this study was to investigate the role of MMPs in nasal polyps., Material and Methods: The expression of MMP-2 and -9 was investigated in the nasal polyps of 20 patients undergoing endonasal sinus surgery and compared with that in control nasal mucosal samples obtained from 20 non-allergic hypertrophic rhinitis patients. Tissue samples were either homogenized for reverse transcriptase polymerase chain reaction analysis or frozen for immunohistochemistry., Results: MMP-2 mRNA expression was observed only in the nasal polyp samples and not in the control tissues. MMP-9 mRNA was not expressed in either type of tissue. Similarly, MMP-2 expression was observed in the nasal polyps of chronic sinusitis patients but not in the inferior turbinate mucosa of the control subjects. MMP-2 positivity was present in basal cells in the surface epithelium and in infiltrating cells in subepithelial tissues. MMP-9-positive cells were not observed in either nasal polyps or inferior turbinates. These results suggest that MMP-2 expression is characteristic of nasal polyps., Conclusion: MMP-2 may play a role in the remodeling of nasal polyps.

This article reviews the treatment of chronic sinusitis with macrolides. Chronic sinusitis is often the result of bacterial infections that lead to chronic inflammation with thickening of the sinus mucosa and hypersecretion of mucus. In addition to their anti-infective properties, some macrolides possess immunomodulatory effects. These macrolides have been used successfully to treat diffuse panbronchiolitis, a progressive inflammatory lung disease, and may be useful for treatment of asthma, chronic bronchitis, chronic sinusitis, cystic fibrosis, and bronchiectasis. The clinical benefits of macrolides in patients with chronic sinusitis include decreased nasal secretions and postnasal drip, with improvement in nasal obstruction. In vivo and in vitro studies show that some macrolides affect neutrophil chemotaxis and infiltration, inflammatory cytokine production, mucus production, and the transportability of airway secretions. These findings indicate that macrolides are promising agents for treating chronic inflammation of the airways.

Macrolide antibiotics are believed to inhibit mucus secretion but the mechanism of action is unclear. This study was designed to investigate an effect of roxithromycin on MUC2 gene expression in cultured intestinal epithelial cells (HM3-MUC2 cells). A reporter gene assay was used for analysis. Roxithromycin suppressed MUC2 gene transcriptional activity in a dose-dependent manner in HM3-MUC2 cells. Phorbol 12-myristate 13-acetate (PMA), lipoteichoic acid (LTA), lipopolysaccharide (LPS) and leukotriene D4 (LTD4) significantly increased MUC2 luciferase activities in the following order: PMA > LTA > LTD4 > LPS. Roxithromycin also decreased MUC2 gene transcriptional activity induced by PMA in a dose-dependent manner. NF-kappaB activation, but not AP-1 activation, was significantly suppressed by roxithromycin in HM3-MUC2 cells. A suppression of NF-kappaB activation was also observed in NCI-H292 cells. These results suggest that roxithromycin suppresses MUC2 gene expression in epithelial cells and that this suppression is probably via inhibition of NF-kappaB activation., (Copyright 2004 S. Karger AG, Basel)

We studied the suitability of the Odor Stick Identification Test for the Japanese (OSIT-J) in patients suffering from olfactory disturbance. In 120 patients with olfactory disturbance (age range 12-85 years) there were statistically significant correlations between the odor identification rate on the OSIT-J, the results of the Japanese standardized olfactory test (T&T olfactometry) and subjective symptom scores. In every patient treated for olfactory disturbance, the OSIT-J reflected the grade of recovery from the olfactory disturbance as determined by means of T&T olfactometry. The odor identification rate on the OSIT-J also correlated significantly with the results of the i.v. Alinamin test. Regarding the rate of correct recognition of odors on the OSIT-J, menthol and curry odors were recognized with a high rate and orange and wood odors with a low rate. Although the OSIT-J includes 13 kinds of odorants, the number of odorants used can be reduced to a minimum of 5 as the results obtained with this reduced form of the OSIT-J also correlated with the results of T&T olfactometry and the subjective symptom scores as well as with the results obtained with the 13-odorant OSIT-J. We conclude that the OSIT-J is suitable not only as a screening test for olfactory disturbance but also for practical use in clinical otorhinolaryngology.

We describe a rare case of high-pressure grease injury of the face in a 48-year-old man with severe facial edema, soft palate swelling, and bleeding from the nose and mouth. Preoperative computed tomography (CT) revealed multiple low-density areas in nasal cavity, subcutaneous tissue of the cheek, soft palate, right maxillary sinus, and right infratemporal fossa. The patient complained of a dyspnea feeling, and immediate tracheostomy was performed. The grease was removed by the Caldwell-Luc incision approach but was partially left in the infratemporal fossa. After the operation, the patient still complained cheek and temporal pain. CT and magnetic resonance imaging were useful to diagnose the remaining grease, and the remnant of the grease was completely removed by the Weber-Fergusson incision approach.

Lipoblastoma is a rare benign tumor arising from embryonic white fat. We describe a case of huge lipoblastoma of the neck in a 1-year-old boy. Magnetic resonance imaging (MRI) revealed a 7 x 7 cm neck mass that extruded into the parapharyngeal and paratracheal spaces. At the operation, a well-circumscribed and extensively growing tumor was completely removed. Histopathologic examination showed that the tumor contained lobulated mature adipose tissue and myxoid tissue with lipoblasts and other immature fat cells. The postoperative course was uneventful, and no recurrence of tumor has been noted in more than 2 years follow-up.

We report 2 cases of congenital anosmia, in a 13-year-old girl and the other in a 10-year-old boy. They reported having no concept of "smell". The girl has no complications but the boy has congenital microphthalmia and is completely blind. They showed scale-out results on both T & T olfactometry and intravenous Alinamin test. Brain MRI detected hypoplasia or lack of the olfactory bulbs, tracts, and olfactory sulci in the frontal lobe of the brain in both patients. Neither had endocrinal dysfunction. In the boy, we biopsied the nasal mucosa in the olfactory cleft and found it had no olfactory epithelial cells at all. We found MRI to be the most useful imaging for diagnosing congenital olfactory disturbance.

We have previously reported that stimulation of nasal mucosa inhibits baroreflex vagal bradycardia (BVB) and this inhibition was mediated exclusively by the trigeminal nerve, and occurred principally at pontomedullary level. In this study, to identify the target site of the inhibition, several types of experiments were conducted in chloralose-urethane-anesthetized, beta-adrenergic receptor-blocked rats. Afferent discharges in the ethmoidal nerve (EN5) were increased in response to nasal stimulation by smoke, and electrical stimulation of the EN5 suppressed BVB induced by electrical stimulation of the aortic depressor nerve (ADN). Electrical stimulation of the EN5 inhibited vagal bradycardia evoked by either electrical or chemical stimulation of the nucleus tractus solitarius (NTS), while it rather facilitated bradycardia by stimulation of the nucleus ambiguus (NA) region. Microstimulation of the NTS induced antidromic compound spike potential along the ADN but this was not affected by stimulation of the EN5. ADN-evoked field potentials and unitary responses of neurons in the NTS were suppressed by stimulation of the EN5. These results suggested that barosensitive neurons in the NTS are the major target sites of inhibition of BVB by nasal stimulation in rats.

Background: The topical administration of steroids or antibiotics to the nose and the sinuses is one of the important postsurgical therapies of endoscopic sinus surgery (ESS)., Methods: To investigate the effective deposition of aerosols in the paranasal sinuses after ESS, we restored the human nasosinus model that underwent ESS and studied the particle depositions on the ostiomeatal complex (OMC), maxillary, and ethmoid sinuses quantitatively., Results: A 45 degree nozzle insertion angle significantly increased the particle depositions more than the 30 degree angle (p < 0.05). A computer simulation-assisted analysis shows that the inertial deposition at OMC increased with a nozzle angle of 45 degrees versus 30 degrees. The particles with 5.63 microm in diameter significantly deposit on OMC and maxillary sinus compared with the particles with 16.37 microm (p < 0.05)., Conclusion: The topical administration of drugs to the paranasal sinuses postoperatively must be performed in consideration with aerodynamics of aerosols.

To examine the in vivo effects of macrolide antibiotics on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats and by intranasal LPS instillation. Oral administration of clarithromycin (CAM) (5-10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production and neutrophil infiltration, whereas josamycin and ampicillin showed no effect. In vitro effects of macrolide antibiotics on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by ELISA using anti-mucin monoclonal antibodies (anti-MUC5AC and HCS18). CAM and erythromycin significantly inhibited spontaneous and tumor necrosis factor-alpha (20 ng/ml)-induced mucus secretion from NCI-H292 cells at 10-6 to 10-7 M and from human nasal epithelial cells at 10-4 to 10-5 M. MUC5AC messenger RNA expression was also significantly inhibited. These results indicate that the 14-member macrolide antibiotics, CAM and erythromycin, exert direct inhibitory effects on mucus secretion from airway epithelial cells and that they may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

We retrospectively analyzed 72 children suffering from respiratory disturbance during sleep at Mie University Hospital for sleep study or surgical treatment from 1992 to 2001. Their clinical symptoms included snoring (100% of 72 inpatients), sleep apnea (60%), mouth breathing (44%), and nasal obstruction (30%). Forty-seven reported sleep apnea and 28 (60% of total) corresponded to criteria for the sleep apnea syndrome (apnea index: AI > or = 5.0). These symptoms were caused by adenoid vegetation and/or hypertrophy of the palatine tonsils. No significant correlation was seen among size of the adenoid, that of the palatine tonsil, body mass index, AI, and blood oxygen saturation (SpO2) during sleep. Surgical treatment with adenotomy and/or tonsillectomy was performed in 66 patients. After treatment, clinical symptoms diminished within a week, and AI and SpO2 during sleep improved significantly. Recurrence of snoring was observed 19, 23, and 21% of patients 1, 3, and 5 years after treatment. Sleep apnea recurred in only 1 patient 7 years after adenotomy. Seventy-five percent of children who had the clinical symptoms 1 month after treatment have shown the same symptoms continuously for a long time. In conclusion, surgical treatment for children's respiratory disturbance during sleep is effective and involves a low rate of symptom recurrence.

Background: We have produced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of ovalbumin (OVA)-sensitized rats by intranasal challenge with OVA. A variety of allergic mediators and inflammatory cells are capable of stimulating goblet cell degranulation (epithelial mucus secretion); however, little is known about the mechanism by which antigen induces mucus hypersecretion., Objective: Our aim was to explain the mechanism of goblet cell degranulation in allergic inflammation., Methods: Antigen-induced goblet cell degranulation was evaluated by the transient decrease of epithelial mucosubstance 1 to 6 hours after intranasal challenge with OVA in nasal epithelium of OVA-sensitized rats. The effects of the H(1)-antagonist (d -chlorpheniramine malate), H(2)-antagonist (cimetidine), atropine, indomethacin, cysteinyl leukotriene (cysLT) antagonist (ONO1078), and antirat PMN antiserum on OVA-induced goblet cell degranulation were examined., Results: Goblet cell secretion 1 hour after OVA challenge was significantly inhibited by H(1)-antagonist, atropine, and cysLT antagonist, whereas the secretion 6 hours after the challenge was significantly inhibited by cysLT antagonist and antirat PMN antiserum. Circulating PMN cells and mucosal infiltrating eosinophils were completely abolished by antirat PMN antiserum., Conclusions: These results indicate the different mechanisms of goblet cell secretion between early-phase (1 hour after OVA challenge) and late-phase (6 hours after the challenge) reactions. Histamine stimulates early-phase secretion through the H(1)-receptor of cholinergic nerve terminals, and infiltrating inflammatory cells (eosinophils and/or neutrophils) play a role in late-phase secretion. CysLTs (leukotrienes C(4), D(4), and E(4)) are important for both early-phase and late-phase secretion.

To clarify long-term outcome of benign paroxysmal positional vertigo (BPPV), 50 patients were followed up for a mean of 52 months. Overall recurrence rate by Kaplan-Meier estimation was 37% at 60 months. The patients with horizontal canal BPPV (n = 19) had a significantly higher recurrence rate (50%) at 60 months than those with posterior canal BPPV (n = 28; 26%). There was no significant association between recurrence rates and sex or age.

Objective: Histamine is one of the chemical mediators released during the acute phase of allergic rhinitis and is considered to cause the increase in epithelial permeability observed. We tried to examine the effect of histamine on nasal mucosal permeability in vivo., Material and Methods: Histamine at different concentrations was administered to the nostrils of healthy subjects and the nasal transepithelial potential difference (PD) was measured. We also examined nasal mucosal permeability by means of a histochemical technique using horseradish peroxidase (HRP) in guinea pigs., Results: Administration of 10(-1) M histamine significantly reduced the nasal PD in healthy subjects. After administration of 5.4 x 10(-1) M histamine to the noses of guinea pigs, most ofthe intercellular spaces showed positive reactions to HRP and this effect was significantly inhibited by pretreatment with mepyramine and the antihistamine bepotastine besilate., Conclusion: These results indicate that histamine plays an important role in the change in mucosal permeability observed in allergic rhinitis in vivo via the histamine H1 receptor.

Objectives: The purpose of the study is to know if mucin gene expression can be detected in the middle ear effusion and if so, which mucin genes are expressed in the effusions., Methods: Mucin gene expression in the middle ear effusions obtained from five patients with otitis media with effusion were analyzed by reverse transcription-polymerase chain reaction. Ribonucleic acids (RNAs) were extracted from the effusion and the expression of 12 mucin genes was analyzed by reverse transcription-polymerase chain reaction., Results: Mucin gene expression examined by reverse transcription-polymerase chain reaction indicated the expression of MUC1, MUC4, MUC5AC, MUC6, MUC7, MUC8, MUC9, MUC11 and MUC12 mRNA in the effusion. This mucin gene expression was similar to that in BEAS-2B cell, a bronchial epithelial cell line., Conclusion: Middle ear effusion can give us valuable information on mucin gene expression in the middle ear. There is similarity between mucin gene expression in the middle ear effusion and that in the bronchial epithelia.

Aerobic bacterial examination for sinusitis was conducted using specimens from maxillary sinuses collected by antral puncture in 540 patients--284 men and 256 women aged 6-89 years--between May 1999 and April 2000. We obtained 528 strains of bacteria. Our results were as follows: 1. We obtained 303 pathogens from 540 patients. In acute sinusitis, the most frequently found was Streptococcus pneumoniae (30.4%), followed by Hemophilus influenzae (27.7%). In chronic cases, the most frequently found was Streptococcus pneumoniae (16.0%), followed by Hemophilus influenzae (15.1%) and Staphylococcus epidermidis (12.6%). 2. We found an increase in bacteria resistant to multiple drugs, with 11.1% of the Staphylococcus aureus isolates methicillin-resistant in acute sinusitis and 40% methicillin-resistant in chronic sinusitis, and that 30.6% of Streptococcus pneumoniae isolates were penicillin-resistant. 3. Ciclacillin was effective against 64.7% of all pathogens isolated in this study, cefpodoxime proxetil effective against 6.5%, and cefixime effective against 2.4%. 4. In considering pathogens, we therefore choose antibiotics and make a maxillary aspiration puncture.

We studied changes in histamine release from basophil measured by HRT Shionogi kit as laboratory procedure to evaluate immunotherapy of allergic rhinitis. Nine cedar pollinosis patients (ages 12-64 yrs, 3 male and 6 female) that started immunotherapy with standardized cedar pollen extract (Torii Co) in 2001 were evaluated. Histamine release rate was measured before immunotherapy and at 6 months after starting immunotherapy. As a result, the histamine release rate after immunotherapy was suppressed in all cases. The average of histamine release rate was significantly decreased by the stimulation at 3, 30 and 300 ng/ml with cedar pollen antigen (p<0.05). These data suggested that the measurement of histamine release rate was usable for evaluating the efficacy of immunotherapy, and it has a possibility for monitoring in immunotherapy. In addition, a new different mechanism that T lymphocyte or serum does not concern can be considerable, because the procedure by HRT Shionogi kit is measured from basophils at the condition without serum.

Objective: To clarify 1) which mucin gene expression is influenced by glucocorticoid and 2) whether glucocorticoid influences steady-state mucin expression or mucin gene expression induced by lipopolysaccharide., Methods: Dissociated cells obtained from nasal polyps were cultured on a collagen gel substrate in an air-liquid interface. Dexamethasone was added to the culture medium in the steady-state and prior to the stimulation by LPS. RNAs were extracted from culture cells, and semiquantitative reverse transcriptase-polymerase chain reaction was performed for MUC2, MUC5AC, MUC5B, MUC8, and beta-actin., Results: Dexamethasone did not influence steady-state messenger RNA levels of either mucin gene. Dexamethasone suppressed lipopolysaccharide-induced messenger RNA levels of MUC8., Conclusion: Glucocorticoid does not influence steady-state mucin gene expression but suppresses mucin gene expression induced by secretagogues such as lipopolysaccharide.

The influence of epithelial damage on mucociliary transport was studied in relation to the amount of mucus. The mucosal epithelium of mucus-depleted frog palate was dissected and mounted on a plastic plate. Mechanical damages were created on the frog mucosa by pressing a different thickness of boards (2, 3, 5, and 8 mm). Two different amounts of frog mucus (7.9 microL [small amount of mucus (S-mucus]]) and 51.0 microL [large amount of mucus [L-mucus]]) were acpplied on the frog mucosa witih and without mucosal damage. There was no difference in mucociliary transport rate (MTR) on undamaged frog mucosa between S-mucus and L-mucus. However, on the damaged mucosa, MTR of S-miucus was significantly decreased compared with that of L-mucus. Moreover, capability of mucus transportation across the mucosal damage was significantly lower in S-mucus than in L-mnucus. Results indicate that the larger the mucus amount becomes, the more the mucus travels the damaged epithelium. Moreover, MTR of L-mucus was decreased with increasing the degree of epithelial damage. This study indicates that the degree of loss of cilia is an important factor of mucociliarn deceleration.

Background: Pendred's syndrome (PS) is an autosomal recessive disorder characterized by goiter and congenital sensorineural hearing loss. Recent advances in molecular biology revealed the gene responsible for PS (PDS) and provided an important aid for the diagnosis of this condition., Methods: A case of PS with huge goiter and congenital hearing impairment was diagnosed by mutational analysis of the PDS gene., Results: Physical examination and computer tomography CT revealed a diffuse swelling of the thyroid gland. Thyroid function tests were normal, and the perchlorate discharge test was negative. Audiologic examination confirmed sensorineural hearing loss, and temporal bone CT revealed bilateral enlarged vestibular aqueducts. The mutational analysis revealed that the patient was homozygous for His 723 Arg (2168A-->G) in exon 19, a missense mutation., Conclusions: The results of thyroid function tests in PS patients are usually normal, and the positive perchlorate discharge test has been used for the diagnosis. However, this is a nonspecific test and is not sensitive enough for PS. In our case, despite a negative perchlorate test, the patient was diagnosed by mutational analysis and received total thyroidectomy to relieve respiratory distress caused by thyroid enlargement. This is the first report of a mutation detected in the thyroid tissue and clearly shows that the mutation caused histopathologic change in that gland., (Copyright 2002 Wiley Periodicals, Inc.)

Airway mucociliary clearance depends on the properties and volume of secreted mucus, ciliary function and mucociliary interactions. In chronic airway diseases, mucus viscoelasticity is higher than the optimal values for mucociliary clearance. The mucous glycoproteins (MGs) are produced by goblet and submucosal gland cells and are the most important determinant of the viscoelasticity of normal respiratory mucus, although with chronic infection and inflammation neutrophil-derived DNA and F-actin assume an important role. The quantities and structures of MGs mainly determine the rheological properties of mucus. Mucolytic agents, such as the thiols with free sulphydryl groups (classic mucolytics) and proteolytic enzymes (peptide mucolytics) change the conformation of mucus and lead to the reduction of viscoelasticity. Mucoregulatory medications such as glucocorticoids and macrolide antibiotics may decrease the hypersecretion of MGs., (Copyright 2002 Elsevier Science Ltd.)

Objective: To elucidate a mechanism of proliferation and differentiation of nasal gland cells, we established a serum-free 3-dimensional culture system for human nasal gland (HNG) cells and examined the effects of epidermal growth factor, keratinocyte growth factor, and retinoic acid on proliferation and differentiation of cultured HNG cells., Materials and Methods: Nasal polyps were obtained from patients undergoing endoscopic endonasal sinus surgery. The HNG cells were cultured under a monolayer culture and transferred to a collagen-embedded culture using RPMI 1640 medium containing transferrin, insulin, hydrocortisone, retinoic acid, epidermal growth factor, and keratinocyte growth factor. Cell growth was measured by bromodeoxyuridine incorporation assays. To measure cell differentiation, the percentage of cells containing secretory granules, which were stained with Alcian blue in cytoplasm, was determined., Results: In the serum-free 3-dimensional culture, the HNG cells showed ductal structures containing secretory products in a lumen. The addition of epidermal growth factor promoted the proliferation of HNG cells in its optimal concentrations, and keratinocyte growth factor also enhanced the proliferation of HNG cells. Conversely, the differentiation of HNG cells was not dependent on epidermal growth factor and keratinocyte growth factor. Retinoic acid suppressed the proliferation, but promoted the differentiation of HNG cells., Conclusion: Our culture system could be useful for studying the effects of various growth factors and cytokines on HNG proliferation and differentiation to better understand the mechanisms of growth and morphogenesis of nasal glands.

Gene products of TAP1 and TAP2 (transporters associated with antigen processing) are involved in antigen presentation. It has been reported that polymorphisms in the TAP1 gene are associated with atopy in Tunisians. We designed a case-control study to investigate the potential association of polymorphisms of the TAP1 gene with allergic rhinitis in a Japanese population. We used the amplification refractory mutation system polymerase chain reaction to characterize TAP1 gene polymorphisms in 60 unrelated Japanese patients with allergic rhinitis and 62 healthy control subjects. There was no significant difference in the distribution of TAP1 alleles between the patient group and the control group. These findings suggest that the TAP1 gene is not primarily involved in susceptibility to allergic rhinitis in the Japanese population.

Objective: Late phase response (LPR) is difficult to investigate in patients with perennial nasal allergy because of their continuous presentation with nasal symptoms. Contribution of histamine to the LPR is also controversial. In this study, we investigated whether exogenous histamine can induce LPR in asthmatic patients with perennial nasal allergy to house dust., Methods: A total of 40 asthmatic children were divided into clinical, subclinical and non-rhinitis groups based on their daily nasal symptoms. Changes in nasal patency and in inflammatory cells in nasal secretion were quantitatively measured for 6 h by acoustic rhinometry and light microscopy respectively before and after nasal challenge with allergen or histamine., Results: The allergen challenge produced a significant biphasic decrease in nasal patency in the subclinical group and a marginal decrease in the clinical group, with increases in eosinophils 6 h after the challenge. By contrast, histamine challenge induced significant responses in the clinical group and only a slight response in the subclinical group. Eosinophils also accumulated in nasal secretion of the clinical group to significant levels 6 h after histamine challenge. Eosinophil accumulation following histamine challenge was earlier than that after exposure to allergen., Conclusion: We conclude that LPR can be demonstrated in asthmatic children with perennial nasal allergy. Exposure to exogenous histamine also induced LPR, mediated mainly by eosinophil-related mediators.

To examine the differential properties of mucous glycoproteins, we produced hypertrophic and metaplastic changes in goblet cells of rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats, and by intranasal lipopolysaccharide (LPS) instillation. The epithelial mucosubstance was quantitatively examined by alcian blue-periodic acid-Schiff (AB-PAS) and lectin histochemistry. The newly produced mucin after OVA challenge or LPS instillation contained a high amount of sulfomucin and a low amount of neutral glycoprotein: LPS-induced mucin contained more sulfomucin (70.1% of total) and less neutral glycoprotein (8.6%) than OVA-induced mucin (sulfomucin, 33.6%; neutral glycoprotein, 41.8%; p < 0.01). Four of the lectins stained some of the mucosubstance, indicating the presence of galactose-N-acetylgalactosamine, alpha2,3- and alpha2,6-linked sialic acid-galactose, and fucose residues. After LPS instillation, the reactivity was higher for galactose-N-acetylgalactosamine (64.8% of total) and alpha2,3-linked sialic acid-galactose (75.8%) than after saline instillation (3.5 and 19.1%, respectively) or OVA challenge (5.8 and 32.3%; p < 0.05). OVA challenge did not induce the alteration of terminal sugar residues. A 2-fold increase in mucin mRNA (rat Muc5ac) expression was induced after LPS instillation or OVA challenge, compared with animals treated with saline instillation (p < 0.05). These results indicate that mucin mRNA expression (for peptide backbone) increases similarly after LPS instillation or OVA challenge; however, carbohydrate compositions of newly produced mucin are different between the two groups.

Objectives: Sinusitis is characterized by quantitative and qualitative changes in mucus biosynthesis that contribute to sinus disease. In general, patients with acute sinusitis complain of purulent rhinorrhea, whereas those with chronic sinusitis complain of mucoid or mucopurulent rhinorrhea Locally produced mucin largely contributes to the high viscoelasticity of mucus in sinusitis. In this study, the authors attempt to quantify the concentrations of mucin and lectin in the maxillary sinus fluids from these patients., Study Design: To assess the concentrations of mucin and lectin in aspirates of 11 acutely and 11 chronically inflamed maxillary sinuses, the concentration of mucin was measured by enzyme-linked immunosorbent assay (ELISA) and that of lectin by sandwiched enzyme-linked lectin assay (ELLA)., Results: The concentrations of mucin and lectin that were measured using monoclonal antibodies (HCS 4, HCS 14, and HCS 18) and Ulex europaeus agglutinin-1 (UEA-1) in chronic sinusitis were higher than those in acute sinusitis. The concentration of total protein in chronic sinusitis was lower than that in acute sinusitis. Each mucin and lectin versus total protein ratio in chronic sinusitis was higher than that in acute sinusitis., Conclusions: These data suggest that hypersecretion in chronic sinusitis may result from locally increased mucin production. Comprehension of this mechanism may be a strategy to prevent the viscous cycle of paranasal sinus fluids in chronic sinusitis.

Background: Airway epithelial cells produce cytokines and participate in the regulation of mucosal immunity. Although nasal epithelial cells express histamine receptors, it is not exactly known how nasal epithelial cells respond to histamine., Objective: The objective of this study was to examine whether histamine can alter the expression of the 4 genes encoding H1 receptor, IL-8, TNF-alpha, and ZO-1 tight-junction protein in cultured nasal epithelial cells., Methods: We added histamine or vehicle to cultured human nasal epithelial cells and extracted RNA from them 4 hours later. After DNase treatment, mRNAs of beta-actin, H1 receptor, IL-8, TNF-alpha, and ZO-1 tight-junction protein were amplified by using RT-PCR., Results: Histamine significantly upregulated IL-8 mRNA expression and significantly downregulated ZO-1 mRNA expression. The latter effect was blocked by pretreatment with mepyramine, an H1 receptor antagonist., Conclusion: The reduction of ZO-1 mRNA by histamine may cause increased permeability of the mucosa during allergic reactions in the nose.

Objective: The purpose of this study is to find out the effects of hearing impairment on the QOL of nursing home residents., Methods: We constructed the self-assessment questionnaire designed for evaluating the QOL for the elderly in nursing homes. The questionnaire is constructed of physical, social, communicational and psychological states. It was administered to 60 subjects >65 years of age (mean age: 79 years) living in nursing homes, with hearing threshold levels in the better ear ranging from normal to severe and their response were analyzed., Results: Chronbach's alpha-values of the questionnaire obtained ranged from 0.66 to 0.91 and was 0.84 overall. The reliability and validity of the questionnaire as well as its brevity, simplicity, ease of administration and interpretation, all satisfied its use in assessing the QOL of the elderly in nursing homes. It tended to decrease the points of communication scale, sociability scale and psychological scale (PGC Morale Scale) accordingly to elevate the threshold. As for subscales of communication, hearing disability was correlated statistically to the sociability and psychological., Conclusion: Our questionnaire is regarded as a useful tool for evaluating the QOL of the elderly. Hearing loss affects the communication, sociability and psychological aspect of the QOL for the elderly in the nursing homes.

In the present study, hypertrophic and metaplastic changes of goblet cells were induced in rat nasal epithelium by intranasal instillation of endotoxin or elastase. A significant increase in the amount of intraepithelial mucosubstance was observed after 24 hours during 3 days of instillation. The elastase-induced mucus production was not inhibited in neutrophil-depleted rats, but the endotoxin-induced change was significantly inhibited. Intranasal instillation of the neutrophil elastase inhibitor ONO-5046 partially inhibited the endotoxin-induced mucus production. Epithelial mucus secretion was evaluated by the temporary decrease in the amount of intraepithelial mucosubstance. The endotoxin-induced mucus secretion peaked 3 to 6 hours after intranasal instillation, coinciding with the peak of the intraepithelial neutrophil infiltration. The elastase-induced mucus secretion peaked 1 to 3 hours after intranasal instillation; intraepithelial neutrophil infiltration was not induced by elastase. These results indicate that neutrophil elastase is an important mediator of the intraepithelial mucus synthesis and secretion induced by endotoxin.

Objectives: It is likely that genetic factors play a role in the etiology of chronic sinusitis, and airway inflammation is an important pathological feature in chronic sinusitis. We hypothesized that individuals with greater inflammatory responses may be more likely to acquire the disease. Polymorphisms of the tumor necrosis factor (TNF) genes have been described, and certain inflammatory diseases are reportedly associated with certain alleles of TNF genes. The purpose of this study is to examine whether there is an association between some alleles of TNF genes and chronic sinusitis., Study Design: Thirty-eight Japanese patients with intractable chronic sinusitis were selected on the basis of the following criteria: 1) persistent mucous or mucopurulent nasal discharge and/or postnasal dripping for longer than 3 years and 2) opacification in bilateral maxillary sinuses and ethmoid cells on plain radiographic films., Methods: Both tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor-beta (TNF-beta) gene polymorphisms were analyzed by polymerase chain reaction (PCR) with restriction fragment length polymorphisms in these patients and 35 healthy control subjects., Results: A significantly higher frequency (P < .05) of TNFB*2 allele of TNF-beta gene polymorphism was observed in patients with chronic sinusitis (74%) compared with control subjects (56%). There was no association between alleles of TNF-alpha and chronic sinusitis., Conclusion: We concluded that TNF-beta gene polymorphism may form a component of the genetic predisposition to chronic sinusitis in Japanese patients.

Endoscopic sinus surgery is commonly used to treat chronic sinusitis. Subjects were 79 chronic sinusitis patients--50 men and 29 women aged 17 to 79 years (average: 50.6 years) undergoing endoscopic sinus surgery in our department from January 1993 to December 1997. Mean follow-up was 17.5 months. We evaluated preoperative staging of chronic sinusitis based on Kennedy staging. Most were stage 3. This type of staging was not effective in predicting nasal polyp relapse. We found that cases with diffuse polyposis and associated disease such as bronchial asthma or aspirin-induced asthma tended to experience a polyp relapse. Our results suggest that postoperative treatment is important in maintaining patency of the ostiomeatal complex, nasal polyp or edematous mucosa relapse must be treated early in on in occurrence.

We produced ovalbumin (OVA)-sensitized rats as an animal model of nasal allergy. Intranasal instillation of OVA induced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of OVA- sensitized rats. Intraepithelial mucosubstance in nasal mucosa increased significantly at 24 h after 3 or 7 d of OVA instillation, accompanied by mucosal infiltration of eosinophils. The effects of H1-antagonist (d-chlorpheniramine malate), H2-antagonist (cimetidine), dexamethasone, indomethacin, cysteinyl leukotrienes (cysLTs)-antagonist (ONO1078), and antirat neutrophil antiserum on OVA-induced changes were examined. Mucus production was significantly inhibited by dexamethasone, and ONO1078, whereas eosinophil infiltration was significantly inhibited by H1-antagonist, dexamethasone, and anti-rat neutrophil antiserum. These results indicate that cysLTs (LTs C4, D4, and E4) may play an important role in antigen-induced mucus production, and that eosinophil infiltration does not relate to mucus production. Intranasal instillation of lipopolysaccharide (LPS) also induced intraepithelial mucus production, and it was significantly inhibited by dexamethasone, indomethacin, and antirat neutrophil antiserum; however, cysLTs antagonist had no effect on LPS-induced change. These results indicate that neutrophil and cyclooxygenase products are important in LPS-induced mucus production, and there are different mechanisms of mucus production between allergic inflammation and LPS stimulation.

We have developed an air-liquid interface culture system for human nasal epithelial cells that differentiate into mucociliary phenotypes in a defined serum-free medium. Dissociated cells obtained from nasal polyps were cultured on a collagen gel substrate. At confluence, the cells lost characteristics of differentiated cells, and secretory cell and ciliated cell differentiation appeared after 7 days in an air-liquid interface. After 21 days, about half of the epithelial cells were stained with Alcian blue-periodic acid-Schiff stain or monoclonal antibody HCS18, which was directed against human nasal mucin specific for epithelial secretory (goblet) cells. The quantitative examination using the antibody HCS18 revealed that the antibody-reactive nasal mucin was secreted only on the apical side of the cultures, and interleukin-1beta and tumor necrosis factor alpha stimulated these mucus secretions. The culture system with an antimucin monoclonal antibody developed in this study should be useful for studying polarized mucus secretion from human nasal epithelial cells.

Objective: Chronic sinusitis is a common disease characterized by persistent inflammation of the nasal and paranasal sinus mucosa. Accumulating evidence supports the importance of proinflammatory cytokines and endothelial cell adhesion molecule (CAM) expression as an initiating process in tissue inflammation. This study was conducted to investigate the localization of major cytokines and CAMs in the maxillary sinus mucosa from patients with chronic sinusitis and from normal subjects., Methods: Maxillary sinus mucosal specimens from patients with chronic sinusitis (n = 10) and from normal subjects (n = 6) were immunostained with specific antibodies directed against the cytokines (IL-1alpha, IL-1beta, IL-6, IL-8 and TNF-alpha) and the CAMs (intercellular adhesion molecule-1, ICAM-1 and vascular CAM-1, VCAM-1)., Results: The number of immunoreactive cells for IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha was increased significantly in patients with chronic sinusitis compared with normal controls. Immunoreactivity for ICAM-1 was also increased significantly in patients with chronic sinusitis compared with normal controls, whereas VCAM-1 is only minimally expressed or is absent in both groups., Conclusion: These findings indicate that bacterial and/or viral infection may induce functional and morphologic changes in the maxillary sinus mucosa in chronic sinusitis through enhanced generation of specific cytokines in conjunction with CAMs.

Low-dose, long-term macrolide treatment has recently been reported to be very effective in patients with chronic airway diseases. We examined the in vivo and in vitro effects of 14-membered macrolide antibiotics erythromycin (EM) and clarithromycin (CAM) on interleukin (IL)-8 secretion from human nasal epithelial cells. Fifteen patients with chronic sinusitis received macrolide treatment (CAM 400 mg/day) for 1 to 3 months. The number of infiltrated neutrophils and IL-8 concentrations in the nasal discharges of these patients decreased significantly at 1 to 2 months after the treatment. In vitro effects of EM and CAM on IL-8 secretion were examined in nasal epithelial cells cultured at the air-liquid interface. After 14-day culture in the air-liquid interface, macrolide antibiotics were added in medium for 24 h. EM and CAM at concentrations of 10(-4) M did not affect spontaneous secretions or IL-1 beta-induced secretions of IL-8 either apically or basolaterally. When cells were preincubated with 10(-4) M CAM for 7 days, the IL-1 beta-induced secretion of IL-8 decreased significantly. However, no difference was observed between the effects of 10(-4) M CAM and 10(-4) M josamycin, a 16-membered macrolide. These results suggest that macrolide treatment inhibits neutrophil infiltration and IL-8 secretion in nasal epithelium in vivo and that these clinical effects depend on a mechanism other than the direct action of macrolide on nasal epithelial cells.

Primary ciliary dyskinesia (PCD) is a congenital disorder of cilia mostly associated with ultrastructural defects and resulting in immotility or abnormal motility, with or without a situs inversus. The defects of cilia in PCD cause chronic or recurrent upper and lower respiratory diseases, such as chronic bronchitis, bronchiectasis, chronic sinusitis and otitis media with effusion. Transmission electron microscopy of sperm or respiratory ciliated mucosa allows specific anatomic diagnosis of PCD. Treatment is symptomatic and directed against complications in the respiratory tract. Early physiotherapy is recommended.