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Methotrexate-associated lymphoproliferative disorders (MTX-LPD) frequently involve the extranodal organs throughout the body. Among the extranodal occurrences of MTX-LPD, pulmonary involvement is most frequent. In contrast, there are only a few reports of MTX-LPD in the nasal cavity or paranasal sinuses. Moreover, there are no previous reports of MTX-LPD mimicking granulomatosis with polyangiitis (GPA) in imaging examinations. We describe a case of a 53-year-old woman with MTX-LPD mimicking GPA in the nasal cavity and lungs. She complained of left nasal obstruction and discharge, general fatigue, and continual fever for 2 months. The patient had been diagnosed with rheumatoid arthritis and received methotrexate (MTX) for over 10 years. Contrast-enhanced computed tomography revealed unenhanced masses in the nasal cavity and multiple masses with cavitary changes in the bilateral lungs, suggesting GPA. However, histological examination of the nasal lesion and a history of MTX treatment indicated a diffuse large B-cell lymphoma type MTX-LPD. Two weeks after MTX withdrawal, prominent improvements in both lesions were observed. Complete regression of the nasal lesion was observed 3 months after discontinuation of MTX. Thus, MTX-LPD may mimic GPA in imaging examinations.

We describe the case of a 51-year-old woman with immunoglobulin G4-related disease (IgG4-RD) diagnosed using lip biopsy. She reported having bilateral submandibular nodules for a month. Magnetic resonance imaging showed diffuse swelling in the bilateral submandibular glands (SMGs), suggesting inflammatory changes. Laboratory data revealed an elevated level of serum IgG4. Fine needle aspiration cytology of the SMG showed a considerable number of lymphocytes with degeneration but did not demonstrate specific findings for a definitive diagnosis of IgG4-RD. Lip biopsy was performed, and a biopsy specimen from the labial salivary gland showed abundant lymphoplasmacytic infiltration with a large number of IgG4-positive cells. The patient was diagnosed with IgG4-RD based on histological and laboratory findings. Findings of further examinations revealed that the patient had autoimmune pancreatitis, confirming our diagnosis. Four months after prednisolone administration, improvement of the submandibular and pancreatic lesions was observed. One year after the initial presentation, the serum IgG4 level was normalized. In cases of IgG4-RD with salivary gland involvement, lip biopsy might be one of the options for the histological diagnosis of IgG4-RD.

Objectives: Subjective symptoms of dizziness in older adults are affected not only by objective data such as postural balance, but also by complex psychological factors. Published data analyzing how simultaneous evaluations of both objective and subjective assessments of balance can predict fall risk remain lacking. This study examined how fall risk can be predicted based on both objective data for balance and hearing and subjective symptoms of dizziness among older adults visiting otolaryngology clinics.Methods: Medical charts of 76 patients ≥65 years old with dizziness/vertigo who visited the otolaryngology clinic were reviewed. Objective data were evaluated by postural balance (posturographic data with eyes open and closed, and one-leg standing test), spontaneous nystagmus, and mean hearing levels. Subjective handicap associated with dizziness/vertigo was assessed using the Dizziness Handicap Inventory (DHI). Subjective mental status of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Information on history (cardiovascular diseases) and fall accidents within the preceding year was collected using an in-house interview sheet.Results: Objective data on postural balance did not correlate with subjective symptoms on DHI or HADS (P> .05, Pearson’s correlation coefficient). Adjusted logistic regression modeling with the outcome of incident falls revealed that poor postural balance significantly predicted fall risk (P< .05; 4.9 [1.4-16.8] per 10-cm2increment). Nystagmus tended to be associated with fall risk. In contrast, DHI score did not predict fall risk (P= .43; 1.0 [0.9-1.03]). Receiver operating characteristic analysis proposed a cut-off for postural sway with eyes closed >6.1 cm2as optimal to predict falls in patients with nystagmus (AUC, 0.74; 95% confidence interval, 0.48-0.997).Conclusion: Poor postural balance is associated with increased fall risk after adjusting for subjective symptoms in older adults at otolaryngology clinics. Conversely, the self-perceived dizziness handicap of DHI score is an insufficient tool to evaluate their fall risk.

Background Hyaluronan is one of the major extracellular matrixes in chronic rhinosinusitis (CRS) associated with tissue remodeling. Prostaglandin D2(PGD2) is also associated with the pathogenesis of CRS. However, little is known about whether PGD2regulates hyaluronan production by human airway fibroblasts.Objective We sought to determine the effect of PGD2on the mRNA expression of three isoforms of membrane-bound hyaluronic acid synthase (HAS1, HAS2 and HAS3) in fibroblasts, the major source of hyaluronan production, derived from CRS patients.Methods Nasal polyp-derived fibroblasts (NPDF) and uncinate tissue-derived fibroblasts (UTDF) were established from CRS patients with nasal polyps and those without, respectively. These fibroblasts were stimulated with PGD2or PGD2receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. mRNA levels for HAS1, HAS2 and HAS3 were determined by real-time quantitative PCR.Results PGD2(1 µM) significantly enhanced HAS1 but not HAS2 or HAS3 mRNA expression by NPDF. Enhanced HAS1 mRNA expression was also obtained by stimulation with a DP receptor-selective agonist, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced HAS1 mRNA expression was significantly inhibited by pre-treatment with DP receptor-selective antagonists. Similar induction of PGD2-induced HAS1 mRNA expression was seen in UTDF.Conclusion PGD2selectively stimulates HAS1 mRNA expression in local fibroblasts in CRS via DP, but not CRTH2, receptors.

Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS.

Background A remarkable relationship between upper airway conditions and lung diseases has been reported. At the same time, sinonasal findings in chronic cough patients have not been fully examined.Objective The purpose of this study is to show paranasal sinus findings and lung function in chronic cough patients without asthma and chest X-ray abnormalities.Methods A total of 1412 patients with persistent cough were enrolled in this study. Of these patients, 376 patients were evaluated for further examination, as the patients with asthma and/or chest X-ray abnormality were excluded from the study. Normal control subjects without any chronic respiratory symptoms were also recruited. Pulmonary function was examined by spirometry. A bronchial obstruction reversibility test was applied. The Lund–Mackay computed tomography (CT) score, peripheral blood eosinophil count, and immunoglobulin E concentration in serum samples were examined. The Sino-Nasal Outcome Test was used to determine the severity of clinical symptoms.Results The patients with an abnormal soft tissue shadow in the paranasal sinus had significant obstructive lung function. The percent predicted forced expiratory volume in 1 second (FEV1.0) and the FEV1.0/forced vital capacity ratio negatively correlated with Lund–Mackay CT scores both before and after bronchodilator inhalation. There was a statistically significant correlation between pulmonary function and eosinophil count.Conclusion The patients with chronic cough frequently had paranasal sinus abnormalities. The Lund–Mackay CT score may be useful for assessing the condition of the lower airway in chronic cough patients. Upper airway examinations should play a part in the management of chronic cough.

IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS).

Swallowing syncope is a rare medical condition. Even though it has been known as a neurally mediated syncope, the definitive mechanism of this condition remains unclear. We show in this study an additional case of swallowing syncope and review the 122 reported cases from the literature. A 47‐year‐old Japanese man had been suffering from recurrent syncopal attacks, when he fainted immediately after swallowing. Holter electrocardiogram monitoring demonstrated a sinus pause (maximum R‐R interval of 3.8 seconds) after he swallowed a noodle quickly. A permanent pacemaker was implanted because the frequency of syncope increased.

The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis.

IL-10 is a major anti-inflammatory cytokine that prevents inflammation-mediated tissue damage. We characterized the production of IL-10 by sinonasal tissue cells following exposure to Staphylococcus aureusenterotoxin B (SEB), which elicits cellular responses and is associated with the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS).

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IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP).

Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production. In the present study, we sought to determine whether PGD2regulates VEGF release by nasal polyp fibroblasts.

Minimal persistent inflammation (MPI) contributes to hyperreactivity in allergic rhinitis. However, little is known regarding whether pre-onset activation of eosinophils and mast cells is present or not in Japanese cedar pollinosis (JCP). Furthermore, a prophylactic effect of intranasal corticosteroids on such MPI in JCP has not been investigated.

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Toll-like receptor 3 (TLR3) is expressed in upper airways, however, little is known regarding whether Toll-like receptor 3 (TLR3) signals exert a regulatory effect on the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), especially on eosinophilic inflammation. We sought to investigate the effect of Poly(IC), the ligand for TLR3, on cytokine production by dispersed nasal polyp cells (DNPCs).

Macrophage migration inhibitory factor plays an important role in noise-induced hearing loss.

This review discussed the contribution of eosinophilic upper airway inflammation includes allergic rhinitis (AR) and chronic rhinosinusitis (CRS) to the pathophysiology and course of asthma, the representative counterpart in the lower airway. The presence of concomitant AR can affect the severity of asthma in patients who have both diseases; however, it is still debatable whether the presence of asthma affects the severity of AR. Hypersensitivity, obstruction and/or inflammation in the lower airway can be detected in patients with AR without awareness or diagnosis of asthma, and AR is known as a risk factor for the new onset of wheeze and asthma both in children and adults. Allergen immunotherapy, pharmacotherapy and surgery for AR can contribute to asthma control; however, a clear preventive effect on the new onset of asthma has been demonstrated only for immunotherapy. Pathological similarities such as epithelial shedding are also seen between asthma and CRS, especially eosinophilic CRS. Abnormal sinus findings on computed tomography are seen in the majority of asthmatic patients, and asthmatic patients with CRS show a significant impairment in Quality of Life (QOL) and pulmonary function as compared to those without CRS. Conversely, lower airway inflammation and dysfunction are seen in non-asthmatic patients with CRS. Treatments for CRS that include pharmacotherapy such as anti-leukotrienes, surgery, and aspirin desensitization show a beneficial effect on concomitant asthma. Acting as a gatekeeper of the united airways, the control of inflammation in the nose is crucial for improvement of the QOL of patients with co-existing AR/CRS and asthma.

Objective: Decreasing language delay in hearing-impaired children is a key issue in the maintenance of their quality of life. Language training has been presented mainly by experience-based training; effective intervention programs are crucially important for their future. The aim of this study was to confirm the efficacy of 6-month domain-based language training of school-age, severe-to-profound hearing-impaired children.Methods: We conducted a controlled before–after study involving 728 severe-to-profound prelingual hearing-impaired children, including an intervention group (n = 60), control group (n = 30), and baseline study group (n = 638). Language scores of the participants and questionnaires to the caregivers/therapists were compared before and after the intervention. Average monthly increase in each language score of the control group and baseline study group were compared with those of the intervention group.Results: Language scores and the results of the questionnaire of the intervention group showed a significant improvement (P< .05). The average monthly language growth of the intervention group was twice that of the control group and 3 to 4 times that of the baseline study group (P< .05). The effect size was largest in communication (1.914), followed by syntax (0.931).Conclusion: Domain-based language training improved the language development and daily communication of hearing-impaired children without any adverse effects.

In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of nonsuperantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP).

Statistically significant results of medical intervention trials are not always clinically meaningful. We sought to estimate the minimal clinically important difference (MCID) (the smallest change in a given endpoint that is meaningful to a patient) during seasonal alteration of Japanese cedar/cypress pollinosis (JCCP).

The usefulness of early interventional treatment (EIT) with intranasal corticosteroids (INSs) compared with postonset treatment (POT) has not been clarified.

Mucopolysaccharidosis type IHurler syndrome is an autosomal recessive disease caused by a deficiency of -L-iduronidase activity. Recurrent middle ear infections and hearing loss are common complications in Hurler syndrome. Although sensorineural and conductive components occur, the mechanism of sensorineural hearing loss has not been determined. The purpose of this study is to evaluate the quantitative inner ear histopathology of the temporal bones of patients with Hurler syndrome.

Little is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP).

Posterior semicircular canal dehiscence has been shown to cause ear symptoms.

There are pathologic changes of vessels in the stria vascularis in patients with Ménière's disease.

To identify pathological changes to vessels in the facial nerve canal among patients with diabetes mellitus.

Background Although it is well known that olfactory receptor neurons differentiated from stem cells have an unusual lifelong ability to continue neurogenesis, effective treatment of patients with sensorineural olfactory loss is still lacking. The purpose of this study was to determine whether intranasal prolactin (PRL) is an effective inducer of proliferation in the olfactory epithelium (OE).Methods The OE of mice treated with PRL for 6 consecutive days and of pregnant mice on gestation day (GD) 7 was investigated by immunohistochemical study using antibodies to bromodeoxyuridine.Results The number of bromodeoxyuridine -labeled cells in the OE increased significantly in PRL-treated female mice and GD 7 mice (but not PRL-treated male mice) compared with controls.Conclusion Pregnancy may induce proliferation in the OE, and administration of intranasal PRL may have almost the same effect as pregnancy on the OE of female mice.

We have recently found that exposure to acute restraint stress suppresses antigen-specific antibody production, including IgE, in a murine model of allergic rhinitis. Although age-related alterations in immune responses are known, it remains unclear whether aging modulates the antibody production under stressful conditions. In this study, we set out to determine the effects of aging on antibody production under acute restraint stress in mice.

To disclose the histopathologic findings of the cochlea in young adults with generalized arteriosclerosis.

Objectives: Newborn hearing screening was started in Okayama Prefecture in 2001 as part of a nationwide pilot study in Japan. Nearly 50,000 infants have been screened to date, and an observational study and more than 2 years of follow-up of this population are described in this report.Methods: Between June 2001 and March 2005 (45 months), 47,346 neonates were screened with automated auditory brain stem response systems and followed up for at least 2 years. This total corresponds to 95% of the infants born in the 44 gynecologic institutions in this district.Results: After undergoing the screening process twice, 248 infants (0.52%) received referrals; 108 of them had apparent bilaterally affected hearing, and 140 had apparent unilaterally affected hearing. Among the bilateral cases, hearing impairment was diagnosed in 40 infants, for a total prevalence of hearing impairment of 0.08%. In 3 additional infants who received a bilateral pass result and 1 infant who received a unilateral pass result, hearing impairment that was progressive or of late onset was subsequently diagnosed. The positive and negative predictive values were calculated as 40% and 99.993%, respectively.Conclusions: The screening program was carefully designed to work in the Japanese society and to be well managed in Okayama Prefecture.

To disclose the histopathologic findings in the contralateral temporal bone in unilateral Ménière's disease.

Background Signal transducer and activator of transcription (STAT) 1 signaling pathway mediates biological functions of interferon (IFN) γ, which is a key cytokine-regulating T helper 1 (Th1) differentiation. Although constitutive activation of STAT1 has been reported in the airway epithelium of patients with chronic asthma, its in vivo role in the pathogenesis of allergic rhinitis is not clear. We determined the role of STAT1 in the pathogenesis of allergic rhinitis in vivo using STAT1 gene-deficient (STAT1–/–) mice and a murine model of Schistosoma mansoni egg antigen (SEA)–induced allergic rhinitis.Methods STAT1 –/– BALB/c and wild-type (WT) mice were sensitized by intranasal administration of SEA, and their immunologic responses were examined.Results STAT1 –/– mice showed impaired nasal eosinophilia and markedly reduced histamine-induced nasal hyperresponsiveness after SEA sensitization. Moreover, levels of Th2-associated SEA-specific IgG1 and IgE antibodies were lower in STAT1 –/– mice. Anti-CD3–stimulated nasal lymphocytes from STAT1–/–mice also produced less amounts of Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 compared with WT mice, but both produced comparable levels of IFN-γ.Conclusion These results show that STAT1 is involved in the pathogenesis of SEA-induced allergic rhinitis in BALB/c mice. Furthermore, they reveal a surprising role of STAT1 in induction of nasal eosinophilia, and Th2-type cytokine production from nasal lymphocytes during allergic rhinitis.

Otitis media with effusion is one of the most common and intractable ear diseases. However, the role of Th1, Th2, and immunoregulatory cytokines on the pathogenesis of the disease in adult patients remains to be determined. The aim of this study is to disclose the cytokine expression in middle ear effusions (MEEs) in adults and to compare the profile on the basis of the presence of allergic rhinitis and the type of effusions.

Background Prostaglandin D2 (PGD2) is the major prostanoid produced in the acute phase of allergic reactions. However, its pathophysiological role in addition to the pathway of production in allergic rhinitis remains unclear. We sought to determine the expression of synthases and receptors for PGD2 in human nasal mucosa. These expressions were compared between allergic and nonallergic patients.Methods The expression and localization of hematopoietic-type (h)-PGD2 synthase (PGDS) and lipocalin-type (l)-PGDS were detected by immunohistochemistry. The expression of D prostanoid (DP) receptor and chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) was determined by quantitative real-time PCR.Results The h-PGDS but not l-PGDS was clearly expressed in nasal mucosa. The expression of h-PGDS in allergic patients was significantly higher than in control patients without mucosal hypertrophy. A variety of infiltrating cells including mast cells, eosinophils, macrophages, and lymphocytes as well as constitutive cells such as epithelial cells and fibroblasts expressed h-PGDS. The expression of both DP and CRTH2 was confirmed also. Although either the amount of DP or the amount of CRTH2 was not correlated with serum levels of IgE, the amount of CRTH2 but not DP was highly and significantly correlated with the number of eosinophils infiltrating into nasal musosa.Conclusion These results suggest that PGD2 is released via the action of h-PGDS from various cells, and the expression of h-PGDS may be associated with the hypertrophic inflammation in the nose. In addition, ligation of PGD2 to CRTH2 appears to be selectively involved in eosinophil recruitment into the nose regardless of atopic status.

Background Interaction between CD40 and CD40L is thought to regulate immune responses in several allergic diseases. However, little is known about its in vivo role in the pathophysiology of allergic rhinitis. We sought to determine whether the lack of signals through CD40 affects the pathophysiology of allergic rhinitis using a murine model.Methods Wild type (WT) and CD40-deficient BALB/c (CD40-/-) mice were sensitized intranasally to Schistosoma mansoni egg antigen (SEA). After repeated sensitization, histamine responsiveness, serum antibody titer including immunoglobulin E (IgE), nasal eosinophilia, and cytokine production by nasal mononuclear cells were determined in each group.Results Intranasal sensitization with SEA in WT mice elicited a strong Th2 response including SEA-specific IgE production, nasal eosinophilia, and interleukin (IL)-4, and IL-5 production by nasal mononuclear cells after antigen challenge. Production of SEA-specific IgE and IgG1 was abolished in SEA-sensitized CD40-/-mice. These mice showed impaired nasal eosinophilia and displayed markedly reduced histamine-induced nasal hyperresponsiveness as compared with WT mice. Furthermore, reduced production of IL-4 and IL-5 by nasal mononuclear cells was seen in CD40-/-mice.Conclusion These results show that signals through CD40 play a critical role in not only IgE production but also pathophysiology of allergic rhinitis such as nasal hyperresponsiveness and nasal eosinophilia.

Background Little is known about the immunologic aspects and the pathogenesis of the paranasal sinus mucocele.Methods The fluids of paranasal sinus mucoceles were obtained from 12 subjects. The concentration of macrophage migration inhibitory factor (MIF), interleukin 1β, tumor necrosis factor a, and regulated on activation normal T cell expressed and secreted (RANTES) were determined by enzyme-linked immunosorbent assay, and the levels of endotoxin were detected with kinetic Turbidimetric Assay.Results MIF and endotoxin were detected in the fluid of all samples, whereas interleukin-1β and RANTES were detected in 1 and 3 subjects out of 12 samples. Tumor necrosis factor a was not detected in any of the samples. A significant positive correlation between the levels of MIF and the period with symptoms such as pain, swelling of face, and visual disturbance was observed.Conclusion These findings suggest that MIF and endotoxin may play an important role in the pathogenesis of paranasal sinus mucocele. MIF may be an important factor causing the development and exacerbation of the disease.

Cochleosaccular dysplasia is the most common pathologic finding seen in children with profound congenital sensorineural hearing loss. There has been no quantitative study on the peripheral vestibular system in cochleosaccular dysplasia.