Yasuyuki Noyama

Chronic rhinosinusitis patients have decreased lung function

The relationship between upper and lower airway diseases has been reported. However, the pulmonary function of patients with chronic rhinosinusitis (CRS) has not been fully examined.

Neuroendocrine carcinoma of the larynx presenting as a primary unknown carcinoma

OBJECTIVE The case of an 80-year-old man showing a metastatic cervical small cell neuroendocrine carcinoma is presented. RESULTS The primary site could not be found at first; it took 8-10 months to detect the primary lesion in the larynx. CONCLUSION (18)F-deoxyglucose positron emission tomography (FDG-PET) was useful to find the submucosal lesion. Despite surgical treatments and chemotherapy, the patient survived for only 21 months.

Role of macrophage migration inhibitory factor in age-related hearing loss

Hearing loss related to aging is the most common sensory disorder among elderly individuals. Macrophage migration inhibitory factor (MIF) is a multi-functional molecule. The aim of this study was to identify the role of MIF in the inner ear. MIF-deficient mice (MIF(-/-) mice) of BALB/c background and wild-type BALB/c mice were used in this study. Expression of MIF protein in the inner ear was examined by immunohistochemistry in wild-type mice (WT). The hearing function was assessed by the click-evoked auditory brainstem response in both MIF(-/-) mice and WT at 1, 3, 6, 9, 12, and 18months of age. Morphological examination of the cochlea was also performed using scanning electron microscopy and light microscopy. MIF was observed in the spiral ligament, stria vascularis, Reissners membrane, spiral ganglion cells (SGCs), saccular macula, and membranous labyrinth. The MIF(-/-) mice had a significant hearing loss as compared with the WT at 9, 12, and 18months of age. In the MIF(-/-) mice, scanning electron microscopy showed that the outer cochlear hair cells were affected, but that the inner cochlear hair cells were relatively well preserved. The number of SGCs was lower in the MIF(-/-) mice. MIF was strongly expressed in the mouse inner ear. Older MIF(-/-) mice showed accelerated age-related hearing loss and morphological inner ear abnormalities. These findings suggest that MIF plays an important role in the inner ear of mice.

Cellular Responses to Staphylococcus aureus Alpha-Toxin in Chronic Rhinosinusitis with Nasal Polyps

BACKGROUND In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic 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). METHODS Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC). RESULTS Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics CONCLUSIONS S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.

Cervical lymph node extirpation for the diagnosis of malignant lymphoma.

PurposeLymph node enlargement in the neck is a common presentation of malignant lymphoma (ML) and requires tissue sampling for accurate diagnosis. Although delayed diagnosis may be critical for some patients, unnecessary biopsy should be avoided wherever possible. This study examined the process for determining the necessity to perform a biopsy and evaluated the value of an open biopsy as a diagnostic tool to enable definite subclassification of the disease.MethodsThe subjects included 20 patients with suspected ML who underwent cervical lymph node extirpation at Okayama Saiseikai general hospital between 2007 and 2010. The decision to perform a biopsy was made based on the results of sonographic evaluation, fine needle aspiration cytology (FNAC), and serum levels of lactate dehydrase (LDH) and soluble interleukin-2 receptor (sIL-2r).ResultsThe diagnosis was ML in 15 patients (75%), Castleman’s disease in 1 (5%), and benign lymphadenopathy in 4 (20%).ConclusionsA lymph node biopsy remains the gold standard for the diagnostic evaluation of ML. Sonographic evaluation combined with serum levels of LDH and sIL-2r is useful in determining the need for biopsy. Many of the cases of ML where it was difficult to determine whether a biopsy should be performed were relatively low grade and critical conditions could be avoided by close observation of the patient.

Macrophage Migration Inhibitory Factor Deficiency Causes Prolonged Hearing Loss After Acoustic Overstimulation.

Hypothesis Macrophage migration inhibitory factor plays an important role in noise-induced hearing loss. Background Macrophage migration inhibitory factor is an essential factor in axis formation and neural development. Macrophage migration inhibitory factor is expressed in the inner ear, but its function remains to be elucidated. Methods Macrophage migration inhibitory factor-deficient mice (MIF−/− mice) were used in this study. Wild-type and MIF−/− mice received noise exposure composed of octave band noise. Auditory brainstem response thresholds were examined before (control) and at 0, 12, and 24 hours and 2 weeks after the intense noise exposure. Morphological findings of cochlear hair cells were investigated using scanning electron microscopy. Histopathological examination with hematoxylin and eosin staining and TUNEL assay were also performed. Results In both the wild-type and MIF−/− mice, acoustic overstimulation induced significant hearing loss compared with the control level. Two weeks after the intense noise exposure, the MIF−/− mice had an increased hearing threshold compared with the wild-type mice. Scanning electron microscopy demonstrated that the outer hair cells in the MIF−/− mice were affected 2 weeks after noise exposure compared with the wild-type mice. TUNEL-positive cells were identified in the organ of Corti of the MIF−/− mice. Conclusion The MIF−/− mice had prolonged hearing loss and significant loss of cochlear hair cells after intense noise exposure. Macrophage migration inhibitory factor may play an important role in recovery from acoustic trauma. Management of macrophage migration inhibitory factor may be a novel therapeutic option for noise-induced hearing loss.

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression

BACKGROUND 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). METHODS IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. RESULTS IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. CONCLUSIONS These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

Regulatory effect of TLR3 signaling on staphylococcal enterotoxin-induced IL-5, IL-13, IL-17A and IFN-γ production in chronic rhinosinusitis with nasal polyps

BACKGROUND 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). METHODS DNPCs were pretreated with or without Poly(IC), and were then cultured in the presence or absence of staphylococcal enterotoxin B (SEB), following which the levels of IL-5, IL-10, IL-13, IL-17A and interferon (IFN)-γ in the supernatant were measured. To determine the involvement of IL-10 and cyclooxygenase in Poly(IC)-mediated signaling, DNPCs were treated with anti-IL-10 monoclonal antibody and diclofenac, the cyclooxygenase inhibitor, respectively. Poly(IC)-induced prostaglandin E2 (PGE2) production was also determined. RESULTS Exposure to Poly(IC) induced a significant production of IL-10, but not of IL-5, IL-13, IL-17A or IFN-γ by DNPCs. Pretreatment with Poly(IC) dose-dependently inhibited SEB-induced IL-5, IL-13 and IL-17A, but not IFN-γ production. Neutralization of IL-10 significantly abrogated the inhibitory effect of Poly(IC). Treatment with diclofenac also abrogated the inhibitory effect of Poly(IC) on SEB-induced IL-5 and IL-13 production. However, unlike exposure of diclofenac-treated DNPCs to lipopolysaccharide, the ligand for TLR4, exposure of these cells to Poly(IC) did not enhance IL-5 or IL-13 production. Poly(IC) did not significantly increase PGE2 production by DNPCs. CONCLUSIONS These results suggest that TLR3 signaling regulates eosinophilia-associated cytokine production in CRSwNP, at least in part, via IL-10 production.

Pulmonary function in never-smoker patients with chronic rhinosinusitis

A close relationship between upper and lower respiratory tract diseases has been reported. The purpose of this study was to evaluate lung function in patients with chronic rhinosinusitis (CRS) who have never smoked.

Early interventional treatment with intranasal corticosteroids is superior to post-onset treatment in Japanese cedar/cypress pollinosis

Background The usefulness of early interventional treatment (EIT) with intranasal corticosteroids (INS) as compared to post-onset treatment (POT) has not been clarified. We sought to determine the efficacy and safety of EIT with INS compared with POT and placebo in Japanese cedar/cypress pollinosis. Method Results The placebo and POT groups, but not the EIT group, showed a significant exacerbation of TNSS and TOSS soon after the start of pollen counts being high on conse- cutive days. The 12-week average TSS in the EIT group (score, 2.3) was significantly lower than in the placebo (5.0; P<0.01) and POT (3.9; P=0.03) groups. All subjects in the placebo and POT groups were classified as having persistent rhinitis, while 80% of the EIT group met the ARIA classification criteria (P=0.03). QOL score and nasal ECP levels were lower in the EIT and POT groups as compared with the placebo group. Daytime sleepiness, smell disturbance and the average dose of loratadine taken as the rescue medication were similar. Treatment with mometasone was well tolerated. Conclusion