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Background and objective Nasal symptoms of allergic rhinitis can be reduced with allergen‐specific subcutaneous immunotherapy (SCIT). However, the mechanisms underlying the effectiveness of SCIT for Japanese cedar pollinosis are not well understood. We studied changes in the numbers of metachromatic cells, eosinophils and neutrophils in nasal swabs following SCIT for Japanese cedar pollinosis. Methods Subjects were either untreated or given SCIT for 0.5 to 13 years duration. For the 2019 seasons, nasal swabs were taken in the pollinosis preseason (immunotherapy n = 36; untreated control, n = 62) and in the pollinosis season (immunotherapy n = 45; untreated control n = 46) and the numbers of mast cells, eosinophils and neutrophils assessed by microscopy. Results There were significant improvements in symptom severities following SCIT in comparison to untreated subjects (P, The number of metachromatic cells in nasal swabs in untreated subjects (B) and SCIT (C) for Japanese cedar pollinosis in pre‐season and in season.

Background As part of the planning for a future multicenter study, this preliminary clinical trial was performed to explore candidate biomarkers useful for predicting the therapeutic effects of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP) using serum samples from patients. Methods This prospective study included patients undergoing SLIT for JCP at our hospital. All enrolled patients (n = 17) started SLIT between June and November of 2015. With informed consent from the patients, in January, March, and June of 2016, blood samples were obtained, and an inquiry was conducted using the Japan rhino-conjunctivitis quality of life questionnaire (JRQLQ). Based on the JRQLQ results, we allocated 6 patients with the most favorable results into the high response group (HRG), and 5 patients with the most unfavorable results into the poor response group (PRG). Subsequently, we compared the serum data between the two groups to identify useful biomarkers. Results The IL-12p70 and VEGF levels tended to be higher in the HRG than in the PRG in January, March and June (0.10 > p > 0.05). In addition, the IL-17 level was significantly higher (p Conclusions IL-12p70 and VEGF may be useful biomarkers for predicting the effects of SLIT. In addition, although it does not appear to be useful as a biomarker for evaluating treatment response at the start of SLIT, IL-17 may be useful as a biomarker after the beginning period of SLIT.

Background The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Methods Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Results Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p < 0.001), with improvements maintained or increased at week 52 (p < 0.001). There was no significant interaction between ECRS subgroup (non-/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p > 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP.

OBJECTIVES/HYPOTHESIS Dupilumab, which blocks the shared receptor component for interleukin-4 and interleukin-13, reduced polyp size, sinus opacification, and symptom severity, and was well tolerated in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-52 study (NCT02898454). We assessed dupilumab in patients enrolled at Japanese centers. METHODS Patients on a background of mometasone furoate nasal spray, received dupilumab 300 mg every 2 weeks (q2w) for 52 weeks (Arm A); dupilumab 300 mg q2w for 24 weeks, followed by every 4 weeks (q4w) for 28 weeks (Arm B); or placebo (Arm C). Co-primary endpoints were week 24 nasal polyp score (NPS), nasal congestion (NC) score, and sinus Lund-Mackay CT (LMK-CT) scores. Symptoms, sense of smell, health-related quality of life, and safety were assessed during the 52-week treatment period. RESULTS Of 49 patients enrolled in Japan, 45 completed the study. Week 24 least squares (LS) mean improvement versus placebo were as follows: NPS (Arm A: -3.1, P

Background The influence of S-carboxymethylcystein (S-CMC) on the proliferation ability of goblet cells in nasal polyp epithelium in response to inflammatory stimulation was examined. Methods The subjects were patients with chronic paranasal sinusitis. An epithelial cell culture system was established using nasal polyp mucosa excised during endoscopic paranasal sinus surgery. The samples were divided into 4 groups (group a: control group, group b: 10 ng/mL tumor necrosis factor-α (TNF-α) treatment group, group c: 10-7 M S-CMC and 10 ng/mL TNF-α treatment group, group d: 10-5 M S-CMC and 10 ng/mL TNF-α treatment group). The total number of epithelial cells and number of goblet cells were measured under a microscope, and the ratio of goblet cells to the total number of epithelial cells was calculated. Results In group b, 10 ng/mL of TNF-α significantly increased the number of goblet cells compared with group a, suggesting involvement of TNF-α in goblet cell proliferation. In addition, the number of goblet cells significantly decreased in group d compared with that in group b, and it also decreased in group c compared with that in group b, although the difference was not significant, and the decrease was smaller than that in group d, suggesting that S-CMC inhibited goblet cell proliferation in a concentration-dependent manner. Conclusion TNF-α promoted goblet cell proliferation in nasal polyps, suggesting its influence on nasal polyp formation. As S-CMC inhibited inflammatory stimulation-induced goblet cell proliferation in nasal polyp epithelium, it may be useful for the treatment of sinusitis.

Background It is difficult to identify the onset of allergic rhinitis in infants because making a conclusive diagnosis can be challenging. Objective We used a combination of cell differentials in nasal swabs and immunoglobulin E (sIgE) antibody values to food and inhalant allergens to make the diagnosis and identify relevant allergens for investigation of the onset of allergic rhinitis. Methods We studied 302 children, 2 to 120 months old, who visited our clinic for rhinorrhea. Nasal swabs were taken from all children, and neutrophils (N), eosinophils (Eo), and mast cells (Mc) were identified by nasal cytology and their numbers were estimated. Levels of sIgE antibodies to various food and inhalant allergens were determined in patients with nasal Eo and Mc. Results Percentages of participants with Eo-Mc and Eo-Mc-N at 2–14 (n = 84), 15–24 (n = 57), 25–60 (n = 73), and 61–120 months of age (n = 88) were 20, 23, 58, and 65%, respectively. There were no significant differences between the 2–14 and 15–24, and 25–60 and 61–120 months age groups, but there was a significant difference between the 15–24 and 25–60 months age groups (p = 0.00013). The percentages of participants with sIgE antibodies to food and inhalant allergens as solitary or main allergen were 12%/0% at 2–14 months old, 10.5%/7% at 15–24 months old, 1.3%/42.4% at 25–60 months old, and 0%/56.8% at 61–120 months old, respectively with a significant difference between 15–24 and 25–60 months old groups (p = 0.00025) for inhalant allergens. Conclusion Allergic rhinitis associated with inhalant allergens in infants

Background The concept of local allergic rhinitis (LAR) has been advocated recently. Allergic rhinitis in Japan is characterized by house dust mites (HDMs) and Japanese cedar pollen (JCP). To investigate LAR in Japan, total IgE and antigen-specific IgE (sIgE) were measured in inferior turbinate mucosa and their relationships with skin test (ST) and nasal allergen provocation test (NAPT) and as well as serum IgE levels were examined. Methods Subjects were 50 rhinosinusitis patients for surgery. ST was performed and serum total IgE and sIgE levels were measured preoperatively. Patients with class-0 serum anti-HDM or anti-JCP sIgE levels were subjected to NAPT with HDM or JCP, respectively, or both. In all patients, inferior turbinate mucosa was weighed and mashed, and total IgE and sIgE levels were then measured as local mucosal date per gram and per milligram. Because there is no clinical consensus how to evaluate nasal sIgE yet, both positive NAPT and detectable sIgE in obtained nasal mucosa were adopted as the diagnostic criteria of LAR in order to strictly elucidate the possibility of presence of LAR in Japan. Results JCP LAR was definitely diagnosed in 2 of 14 patients (14.3%) and HDM LAR in 5 of 21 (23.8%) in cases with rhinosinusitis symptoms in the absence of positive ST nor serum sIgE. Conclusion The present results positively support LAR by HDM or JCP being present in Japan.

Background and Objective We reported neutrophil-associated tissue damage in cedar pollinosis subjects with refractory nasal symptoms prior to pollinosis season. Because the leukotriene receptor antagonist, montelukast, can inhibit neutrophil recruitment and activation, we investigated its effects on symptom relief and nasal neutrophilia in pollinosis subjects in the preseason. Methods In the pollinosis preseason, symptomatic (PreSyP, n = 149) and asymptomatic subjects (PreAsP, n = 145) were prophylactically treated, and in season symptomatic subjects (InSyP, n = 134) were treated. Individuals were assigned to 1 of 2 treatment protocols: administration of cetirizine and fluticasone nasal spray (Cet-Flu) or montelukast, fexofenadine, and fluticasone nasal spray (Mo-Fex-Flu). Differences in symptom relief and inflammatory cell infiltration in nasal swabs were investigated. Results In pollen season, 59% of PreSyP subjects given Cet-Flu and 88% of those treated with Mo-Fex-Flu had none or mild symptoms ( P 1+ was seen following both Cet-Flu ( P = .027) and Mo-Fex-Flu ( P = .0014) treatments. Conclusion In PreSyP and PreAsP subjects, treatments with Mo-Fex-Flu were more effective than Cet-Flu to reduce nasal symptom scores. These effects were associated with reduction in the number of neutrophils and mast cells in nasal swabs.

OBJECTIVES Macrolide therapy is an important conservative therapy for chronic rhinosinusitis, especially in Japan. The mechanism underlying this therapy involves anti-inflammatory and not antimicrobial activity. However, the administration of long-term low-dose macrolides (LTLMs) causes an increase in the number of antibiotic-resistant bacteria. EM900 is a derivative of erythromycin (EM), with anti-inflammatory but not antibacterial effects. It does not induce macrolide-resistant bacteria as shown by LTLM. In the present study, we analyzed the inhibitory effects of EM900 in comparison with those of clarithromycin (CAM) on inflammatory cytokine production in human nasal epithelial cells (HNEpCs). METHODS After HNEpCs were cultured for 4 days, CAM or EM900 was added into the culture, followed by stimulation with tumor necrosis factor (TNF)-α. Interleukin (IL)-8 and vascular endothelial growth factor (VEGF) levels were measured using real-time polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS Both the ELISA and RT-PCR showed that EM900 and CAM significantly inhibited IL-8 production in HNEpCs. In contrast, EM900 and CAM did not suppress the increased VEGF production when HNEpCs were stimulated with TNF-α. CONCLUSION EM900 showed an anti-inflammatory effect, such as that of CAM, due to the inhibitory effect on IL-8 production in HNEpCs.

Objective Sublingual immunotherapy (SLIT) appears to offer practical advantages for the treatment of allergic rhinitis (AR). Based on a review of the scientific literature, we present recommendations as guiding principles to administer SLIT safely. Methods Clinical questions concerning SLIT were prepared. Literature published between January 2003 and December 2012 was searched from PubMed, the Cochrane Library, and Japana Centra Revuo Medicina. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. We answered 17 clinical questions and, based on this, presented evidence-based recommendations. Results Sublingual immunotherapy improved symptoms (e.g., quality of life [QOL]) and reduced medication scores in seasonal AR and perennial AR. Most SLIT-induced adverse effects were local oral reactions, although systemic adverse effects such as gastrointestinal symptoms, urticaria, and asthma are occasionally reported. There have been no reports of lethal anaphylactic reactions by SLIT. When SLIT is continued for 3–4 years, its effect persists long after discontinuation. Conclusion A correct diagnosis of AR and sufficient informed consent from patients are required before initiating SLIT. Sublingual immunotherapy should be continued for 3 years or longer. The initial administration of SLIT during the uptitration of an allergen vaccine and the general condition of patients are critical for the safe performance of SLIT.

BACKGROUND Health-related social media data are increasingly used in disease-surveillance studies, which have demonstrated moderately high correlations between the number of social media posts and the number of patients. However, there is a need to understand the causal relationship between the behavior of social media users and the actual number of patients in order to increase the credibility of disease surveillance based on social media data. OBJECTIVE This study aimed to clarify the causal relationships among pollen count, the posting behavior of social media users, and the number of patients with seasonal allergic rhinitis in the real world. METHODS This analysis was conducted using datasets of pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis from Kanagawa Prefecture, Japan. We examined daily pollen counts for Japanese cedar (the major cause of seasonal allergic rhinitis in Japan) and hinoki cypress (which commonly complicates seasonal allergic rhinitis) from February 1 to May 31, 2017. The daily numbers of tweets that included the keyword “kafunshō” (or seasonal allergic rhinitis) were calculated between January 1 and May 31, 2017. Daily numbers of patients with seasonal allergic rhinitis from January 1 to May 31, 2017, were obtained from three healthcare institutes that participated in the study. The Granger causality test was used to examine the causal relationships among pollen count, tweet numbers, and the number of patients with seasonal allergic rhinitis from February to May 2017. To determine if time-variant factors affect these causal relationships, we analyzed the main seasonal allergic rhinitis phase (February to April) when Japanese cedar trees actively produce and release pollen. RESULTS Increases in pollen count were found to increase the number of tweets during the overall study period (P=.04), but not the main seasonal allergic rhinitis phase (P=.05). In contrast, increases in pollen count were found to increase patient numbers in both the study period (P=.04) and the main seasonal allergic rhinitis phase (P=.01). Increases in the number of tweets increased the patient numbers during the main seasonal allergic rhinitis phase (P=.02), but not the overall study period (P=.89). Patient numbers did not affect the number of tweets in both the overall study period (P=.24) and the main seasonal allergic rhinitis phase (P=.47). CONCLUSIONS Understanding the causal relationships among pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis is an important step to increasing the credibility of surveillance systems that use social media data. Further in-depth studies are needed to identify the determinants of social media posts described in this exploratory analysis.

Background: Health-related social media data are increasingly used in disease-surveillance studies, which have demonstrated moderately high correlations between the number of social media posts and the number of patients. However, there is a need to understand the causal relationship between the behavior of social media users and the actual number of patients in order to increase the credibility of disease surveillance based on social media data. Objective: This study aimed to clarify the causal relationships among pollen count, the posting behavior of social media users, and the number of patients with seasonal allergic rhinitis in the real world. Methods: This analysis was conducted using datasets of pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis from Kanagawa Prefecture, Japan. We examined daily pollen counts for Japanese cedar (the major cause of seasonal allergic rhinitis in Japan) and hinoki cypress (which commonly complicates seasonal allergic rhinitis) from February 1 to May 31, 2017. The daily numbers of tweets that included the keyword “kafunshō” (or seasonal allergic rhinitis) were calculated between January 1 and May 31, 2017. Daily numbers of patients with seasonal allergic rhinitis from January 1 to May 31, 2017, were obtained from three healthcare institutes that participated in the study. The Granger causality test was used to examine the causal relationships among pollen count, tweet numbers, and the number of patients with seasonal allergic rhinitis from February to May 2017. To determine if time-variant factors affect these causal relationships, we analyzed the main seasonal allergic rhinitis phase (February to April) when Japanese cedar trees actively produce and release pollen. Results: Increases in pollen count were found to increase the number of tweets during the overall study period (P=.04), but not the main seasonal allergic rhinitis phase (P=.05). In contrast, increases in pollen count were found to increase patient numbers in both the study period (P=.04) and the main seasonal allergic rhinitis phase (P=.01). Increases in the number of tweets increased the patient numbers during the main seasonal allergic rhinitis phase (P=.02), but not the overall study period (P=.89). Patient numbers did not affect the number of tweets in both the overall study period (P=.24) and the main seasonal allergic rhinitis phase (P=.47). Conclusions: Understanding the causal relationships among pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis is an important step to increasing the credibility of surveillance systems that use social media data. Further in-depth studies are needed to identify the determinants of social media posts described in this exploratory analysis.

Objective Clarification of the association between the swallowing function and respiratory and phonatory functions. Methods The subjects were 30 patients with a chief complaint of swallowing disorder with clear consciousness capable of retaining a sitting position. Patients with organic and functional diseases of the larynx were excluded. Twenty-two and eight patients were male and female, respectively, and the mean age was 77.0 ± 14.6 years old. The chest expansion score was measured as an index of the respiratory function, and the maximum phonation time (MPT) was measured as an index of the phonatory function. The presence or absence of aspiration was judged using videoendoscopic swallowing study (VESS) and videofluoroscopic swallow studies (VFSS). The patients were divided into those with and without aspiration, and the chest expansion score and MPT were compared. In addition, the distance of laryngeal elevation was measured in the lateral view of VFSS, and its correlations with the chest expansion score and MPT were closely analyzed. To evaluate reliability of the test, the distance of laryngeal elevation and videoendoscopic score were compared between the presence and absence of aspiration. Results The distance of laryngeal elevation was significantly shortened and the videoendoscopic score was significantly higher in the group with aspiration, as previously reported. On comparison of the chest expansion score between the groups with and without aspiration, no significant difference was noted at the axillary or xiphoid process level, and shortening was significant only at the 10th rib level in the group with aspiration. On comparison of MPT, it was significantly shortened in the group with aspiration. In addition, a significant positive correlation with the distance of laryngeal elevation was noted in both chest expansion score and MPT. Conclusion It was suggested that declines of the respiratory and phonatory functions are risk factors of aspiration through limiting laryngeal elevation, and the chest expansion score at the 10th rib level and MPT are useful for screening of aspiration.

For the treatment of nasal and nostril stenosis caused by facial burn, it is necessary to perform rhinoplasty and nasal vestibuloplasty using various flaps, perform cicatrectomy of the nostrils with a rhinosurgical procedure, and prevent restenosis of the nostrils and nasal cavity for a certain period by methods such as placement of a nasal retainer or transnasal airway and gauze packing of the nasal cavity. With all methods, postoperative placement of a retainer or nasal treatment is necessary for the prevention of postoperative restenosis, and the patient's cooperation is essential. In a patient who did not cooperate in postoperative treatments due to autism and had recurrences of nasal and nostril stenosis after conventional surgical treatments, adequate patency of the nasal cavity and nostrils could be maintained with minimal postoperative treatment by placing a self-expandable metallic esophageal stent.

Backgroud: It has already been reported that the prophylactic treatment by leukotoriene receptor antagonists is more effective on reducing symptoms of Japanese cedar pollinosis than the authentic treatment after the pollen dispersal. However, the treatment above has never evaluated in children cases around school age in ENT out-patient clinic. This study about the prophylactic treatment was planned to focus on the effect in the generation of pre- and post-elementary school entrance.Children of pre- and post-elementary school entrance were enrolled for this study. This study was achieved in seasons of Japanese cedar pollinosis both in 2013 and 2014, and was designed as the comparison of clinical symptoms and quality of life in between two such groups as one group with the prophylactic treatment and another with the authentic treatment.Efficacy of prophylactic treatment by leukotoriene receptor antagonists was elucidated as follows; quality of sleep was significantly better both in 2013 and 2014, and more kinds of clinical symptoms or quality of life impairments were significantly more suppressed than in the group with the authentic treatment in 2014 when less pollen was dispersed.Even in the children of pre- and post-elementary school entrance, the prophylactic treatment by leukotoriene receptor antagonists is more effective on reducing symptoms of Japanese cedar pollinosis than the authentic treatment.

Vascular endothelial growth factor (VEGF) was identified in 1980s as a protein that increases vascular permeability and induces endothelial cell-specific mitosis. VEGF plays an important role in angiogenesis during the embryonic stage and in angiogenesis and in increasing vascular permeability during postnatal life, both physiologically and pathologically. Great progress has been made in studies of VEGF, mainly in the field of oncology, and VEGF-targeted therapy has been successfully used to treat patients with cancer. In research related to chronic inflammation, several reports concerning rheumatoid arthritis or retinopathy and VEGF have been published. In the lower respiratory tract, increased levels of VEGF have been detected in biological samples from patients with asthma. However, VEGF has not been studied in detail in upper-airway diseases, such as rhinosinusitis. This review article focuses on VEGF and allergic rhinitis to advance studies of VEGF in chronic inflammation of the upper respiratory tract. VEGF levels in nasal secretions and nasal lavage fluid were higher in perennial allergic rhinitis than in nonallergic rhinosinusitis, after, rather than before, the antigen provocation test. The major VEGF isoforms were confirmed to be VEGF₁₂₁ and VEGF₁₆₅ in allergic rhinitis. Expression of VEGF mRNA was higher in serous versus mucous acini. In allergic rhinitis, serous acini produced significant quantities of VEGF, which was hypersecreted after antigen provocation. VEGF seems to play an important role in the pathophysiology of allergic rhinitis. Modulation of VEGF function seems to contribute to the successful treatment of conditions with airway inflammation such as allergic rhinitis.

Objectives/Hypothesis: One of the major functions of vascular endothelial growth factor (VEGF) is increasing vascular permeability. We previously reported that VEGF is present in nasal secretions in rhinosinusitis, particularly in allergic rhinitis, and is hyperproduced immediately after antigen provocation. However, its function in nasal mucosa has not yet been investigated. This study was designed to estimate the increased vascular permeability by VEGF in nasal mucosa and to discuss its possible role in allergic rhinitis. Study Design: Prospective animal experiment. Methods: Hartley guinea pigs were used. Ethyl carbamate was injected into the abdomen for anesthesia, followed by intravenous injection of Evans blue into the femoral vein. Phosphate buffered saline, histamine, or VEGF was then applied to nasal cavities. Nasal mucosa was harvested after saline reflux from heart with phlebotomy by amputating the abdominal aorta. Tissue samples were soaked in formamide for 12 hours at 63°C to extract dye exudates from nasal mucosa. To analyze vascular permeability, dye was quantified by colorimetry. Results: VEGF increased vascular permeability in nasal mucosa, and was more than 1 x 10 6 times more potent than histamine on the basis of molar units. Although increased vascular permeability by VEGF was not inhibited by histamine 1 receptor antagonist, it was markedly inhibited by anti-VEGF receptor antibodies. Conclusions: VEGF increased vascular permeability to a greater degree than histamine in nasal mucosa via a different pathway. Regulating VEGF may be a new therapeutic option for persistent nasal symptoms in allergic rhinitis.

A 3-year-old girl presented with a transethmoidal meningoencephalocele manifesting as recurrent rhinorrhea. Initially, she developed meningitis, but after treatment she experienced rhinorrhea. Two months later, she again presented with rhinorrhea. Neuroimaging studies revealed a small protrusion (15 mm x 10 mm) at the roof of the ethmoidal sinus. Nasal endoscopy confirmed the diagnosis of meningoencephalocele. The operative findings revealed a small hole in the left olfactory bulb, which had descended into an enlarged foramen along with the arachnoid membrane. The left olfactory bulb was removed, and the enlarged foramina of the lamina cribrosa were covered with a frontal pericranial flap. The defect in the bone was very small, but contributed to the development of meningitis and leakage of the cerebrospinal fluid. Basal cephalocele should be considered in a patient with recurrent rhinorrhea and intracranial infections, even in the absence of any apparent anomaly.

Background Vascular endothelial growth factor (VEGF), a pleiotropic polypeptide that mediates endothelial cell-specific responses such as induction of angiogenesis and vascular leakage, is hyperproduced in a variety of inflammatory disorders. In asthma, VEGF hyperproduction promotes mucosal edema by enhancing vascular leakage. However, in allergic rhinitis, details of the pathophysiological importance remain unclear. This study was designed to investigate and discuss the pathophysiological significance of VEGF in nasal secretions from perennial allergic rhinitis sufferers. Methods Seven allergic rhinitis patients sensitized with house-dust mites and 12 chronic rhinosinusitis patients were enrolled. Nasal secretion VEGF was quantified and compared between groups. In allergic rhinitis cases, nasal lavage VEGF was estimated before and after the antigen provocation. Nasal gland VEGF was immunohistochemically investigated. VEGF messenger RNA (mRNA) levels in serous and mucous acini were analyzed by laser microdissection and light cycler-polymerase chain reaction. Results VEGF levels in nasal secretions and nasal lavage from allergic rhinitis were higher than in nonallergic rhinosinusitis, after rather than before antigen provocation. VEGF mRNA expression was higher in serous versus mucous acini. These results are consistent with the immunohistochemistry results. Conclusion In allergic rhinitis, there was significant VEGF production in serous acini, which was hypersecreted after antigen provocation. VEGF may play an important role in pathophysiology of allergic rhinitis.

Summary Eosinophils, as well as mast cells, play an important role in inducing the clinical symptoms of allergic rhinitis (AR), especially in the late-phase response. Adhesion molecules, type 2 helper T (Th2) cell cytokines, CC chemokines, and eicosanoids from mast cells are key players of the pathophysiological mechanism of eosinophil transendothelial migration and accumulation in nasal mucosa. While tethering and adhesion of eosinophils to nasal microvascular endothelial cells are the critical steps, and adhesion molecules and their ligands expressed on eosinophils and endothelial cells have been well studied, regulation of these adhesion molecules and ligands by Th2 cytokines and CC chemokines is thought to be a very important mechanism of eosinophil migration. Eicosanoids such as cysteinyl leucotrienes (CysLTs) and thromboxanes (TXs) from mast cells are also considered to be major factors effective in the expression of adhesion molecules and their ligands, and eicosanoid receptors are thought to be distributed on nasal mucosal endothelial cells. For transendothelial migration, increasing vascular permeability is an indispensable step after trapping eosinophils in nasal microvasculature. While histamine is one of the best known vasodilators in AR, especially in the acute-phase reaction, CysLTs and vascular endothelial growth factor (VEGF) are also effective vasodilators. Much of the evidence to date has been obtained using commercial cell lines of human umbilical vein endothelial cells (HUVEC), which may have cellular characteristics different from human nasal mucosal endothelial cells. Further studies of human nasal mucosa seem necessary to investigate the mechanisms of eosinophil recruitment in nasal mucosa of AR.

Objective Lung and synovial fibroblasts produce VCAM-1 in response to TNF-α. However, the massive infiltration of eosinophils, the effects of the increased amount of TNF-α and the production of VCAM-1 in human nasal polyp fibroblasts are not yet fully understood. The present study examines the role of VCAM-1 and the molecular mechanism of its expression in nasal fibroblasts. Methods Nasal fibroblasts were isolated from human nasal polyps and after four passages, the cells were stimulated with TNF-α and VCAM-1 expression was examined by ELISA, flow cytometry, and RT-PCR. The activation of NF-κB induced by TNF-α was determined by electrophoretic mobility shift assays and the influence on the expression of VCAM-1 was investigated. Results VCAM-1 protein and mRNA were expressed in unstimulated controls and remarkably increased by TNF-α stimulation. NF-κB activity was enhanced by TNF-α stimulation and remarkably suppressed by NF-κB proteasome inhibitor. Conclusions The present study discovered that nasal fibroblasts produce VCAM-1 protein and mRNA and that production is increased by TNF-α stimulation. Furthermore, VCAM-1 expression in nasal fibroblasts is induced through an NF-κB-dependent pathway. These findings might provide a rationale for using NF-κB inhibitors as a treatment for nasal inflammatory diseases such as polyps.

Patients with allergic rhinitis are frequently complicated with some abnormal findings in the paranasal sinuses by X-ray examination. Recently this disease is being diagnosed as allergic rhinosinusitis. In many allergic rhinosinusitis cases, antiallergic drugs such as antihistamines and topical steroids comprise effective medication, but additional macrolide therapy for sinusitis has been reported to be in effective and unnecessary. In this study, the relationship between the type of X-ray shadow of sinuses and the efficacy of macrolide with antiallergic therapy in allergic rhinosinusitis cases was studied as a retrospective therapy. Subjects were 44 allergic rhinosinusitis patients aged from 4 to 60 years old enrolled in the outpatient clinic of the Kagoshima University Hospital ENT clinic. All the allergic rhinosinusitis cases were classified into 3 groups based on the type of X-ray shadow in the sinuses; mucosal thickness, polypous, and diffuse patterns. The X-ray findings were compared between before and after antiallergic therapy with/without macrolide in children and adult cases. X-ray examination revealed that the diffuse type was found in 18 of 42 (42%) children and in 26 of 136 (19%) adults cases. In child cases the diffuse type X-ray shadow was seen more often and macrolide therapy was thought to be more effective in combination with antiallergic medication than in adult cases. This study suggests the efficacy of macrolide therapy in the field of pediatric allergic rhinosinusitis.

Objective: In order to study a new mechanism of efficacy of 14-membered ring macrolides in treating chronic rhinosinusitis, inhibitory effects of macrolides on vascular endothelial growth factor production were examined in vitro. Methods: Vascular endothelisal growth factor production in cultured fibloblasts from human nasal polyps obtained from surgery for chronic paranasal sinusitis stimulated by hypoxia or tumor necrosis factor-α was assessed under the administration of Clarithromycin or Roxisthromycin by enzyme linked immunosorbent assay and reverse transcriptase polymerase chain-reaction. Results: Dose-dependent inhibitory effects on vascular endothelisal growth factor production stimulated by hypoxia or tumor necrosis factor-α were noted in the groups treated with Clarithromycin and Roxisthromycin, including inhibition of vascular endothelisal growth factor mRNA levels. Conclusion: While, to date, several evidences have indicated that the mechanisms by which 14-membered ring macrolides reduce inflammation are not simply bactericidal, these results suggest another new mechanism of efficacy of macrolides in treating chronic rhinosinusitis.

Arytenoid dislocation is sometimes caused by endotracheal intubation or external cervical injury. Al-though the efficacy of closed surgery for this disease has been reported, the procedure is sometimes unsuccessful and various open procedures are necessary to improve the symptoms such as hoarseness. On the other hand, some patients with this disease were reported to be cured spontaneously. In the present study, we reported two patients with arytenoid dislocation caused by endotracheal intubation which were cured spontaneously. The first case was a 17-year-old man who complained of hoarseness after the surgery for hypospadias under general anesthesia. Endoscopic examination revealed the dislocation of the right arytenoid toward an anterior-medial position and dyskinesia of the right vocal cord. The hoarseness was spontaneously cured and completely disappeared on the 29th postoperative day. The examination with laryngeal fiberscope showed that the right arytenoid had returned to normal position. The second case was 46-year-old man who complained of hoarseness after laparoscopic surgery under general anesthesia. Laryngeal fiberscopy showed that his right arytenoid was dislocated toward an anterior-medial position. Hoarseness spontaneously disappeared 48 days after surgery. Several investigators have reported that spontaneous cure is frequently observed in anterior arytenoid dislocation, but not in posterior arytenoid dislocation, as shown in the present study. Those findings suggest that spontaneous reduction might be expected in many patients with anterior arytenoid dislocation.

頭頸部癌における進行癌症例に対して，転移リンパ節の臨床所見から内頸静脈を合併切除する根治的頸部郭清術を必要とすることも少なくない。しかし，術前に内頸静脈に浸潤があると判断されても，術後の病理組織学的検査では明らかな浸潤が認められないこともある。また，遊離皮弁による局所再建のために吻合血管を残す目的で内頸静脈の温存が必要となってくる場合，その是非が問題となる。さらに予後の面から，病理学的に腫瘍組織が内頸静脈内に露出していたりすると遠隔転移が多くなることが予想される。今回，我々は，内頸静脈を合併切除し根治的頸部郭清術を施行した症例について，病理学的に検査し，その後の経過も検討した。その結果，根治的頸部郭清術を施行する必要がある症例では，病理学的に内頸静脈に腫瘍の浸潤がなくても頸部再発率は高かった。遠隔転移については，病理学的に内頸静脈に直接浸潤があった症例が起こしやすい傾向にあった。術前の画像診断で内頸静脈への浸潤を判定するのは困難であったが，癒着がある症例では，内頸静脈静脈周囲に節外性に腫瘍細胞が存在するものとして治療する必要があると考えられた。

A 66-year-old man visited our clinic suffering from swelling of right pharyngeal space. He was not aware of other symptoms. The contrast CT showed patchy enhancement with calcification. The enhanced MRI revealed a non-homogeneous signal pattern and patchy central enhancement. During surgery, egg-shaped hard elastic tumor was observed in parapharyngeal space without any sign indicating an invasion into surrounding nerves or feeding vessels. Then the tumor was removed without significant hemorrhage or damage to the cranial nerve. Histological examination of the tumor revealed a nodular lesion with blood clot and hematoma encapsulated with fibrous tissue having vascular spaces of irregular shape and size. From those findings, the tumor was diagnosed as papillary endothelial hyperplasia (PEH). However, since the location of the tumor differed from that of PEH commonly observed in the intravascular space, the tumor was classified as extravascular PEH.

Summary The number of patients with allergic rhinitis (AR) is increasing. Furthermore, patients with otitis media with effusion (OME) and chronic sinusitis (CS) are frequently complicated with AR. These findings suggest that AR has an impact on the pathogenesis of both OME and CS. The direct and indirect influence of AR on OME and CS was investigated by clinical and experimental studies to clarify the mechanism by which type I allergic reaction is associated with OME and CS. Clinical findings of patients with OME or CS complicated with AR were analysed and compared with those of nonallergic subjects. Samples such as sinus effusions and middle ear effusions (MEE) were collected from the patients and infiltration of inflammatory cells and concentrations of inflammatory cytokines determined. In addition, previous reports discussing the relationship between AR and OME or CS are reviewed. Eosinophil infiltration and oedema were remarkable in paranasal sinus mucosa of patients with CS complicated with AR, suggesting the presence of type I allergic reaction in sinus mucosa. However, there was little evidence of eosinophils in sinus effusions. Endotoxin was frequently detected in sinus effusions of patients with CS having AR as well as suppurative CS. Hypoxia was also considered an important factor inducing sinus pathology. Eosinophils and IgE antibodies in MEE were not increased in OME patients with AR. Anti-allergic medicine was effective in OME patients complicated with AR and improvement of nasal symptoms significantly correlated with that of ear symptoms. AR might be directly and indirectly associated with the pathogenesis of OME and CS.

A case of suspected laryngeal tuberculosis accompanied by lung tuberculosis was reported in this paper. The patient was a 72 year-old male. He had developed hoarseness, sore throat and pain on swallowing, and consulted our clinic. Laryngoscopic examination showed swelling of the left arytenoid as well as laryngeal palsy. Pulmonary tuberculosis was diagnosed by microbiological identification of tubercle bacillus in the sputum. Although there was no evidence indicating laryngeal tuberculosis, local areas in the larynx were markedly improved after treating the patient with anti-tuberculosis chemotherapy. Consequently the patient was diagnosed as having laryngeal tuberculosis. Laryngeal tuberculosis is now rare in Japan, but it was suggested that careful attention should still be paid to the differential diagnosis of laryngeal inflammatory diseases.

Objectives/hypothesis The production of cytokines by adenoids is known to be associated with inflammation of nasopharynx and the pathogenesis of otitis media with effusion. However, the role of adenoids in producing inflammatory cytokines such as interleukin-8 (IL-8) is not yet clear. In the present study, expression of IL-8 in adenoidal fibroblasts was investigated at the level of transcription factors. Further, the effects of clarithromycin, a 14-member ring macrolide, on IL-8 gene expression and nuclear factor-kappa B (NF-kappa B) activation in adenoidal fibroblasts were evaluated. Study design In vitro study for the production of inflammatory cytokine from human adenoidal fibroblasts. Methods Adenoidal fibroblasts were incubated with nontypeable Haemophilus influenzae endotoxin or interleukin-1 beta. Then the expression of IL-8 and the influence of NF-kappa B inhibitor and clarithromycin were evaluated. Interleukin-8 protein production was assessed by ELISA, and IL-8 messenger RNA production was measured by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Activation of NF-kappa B and inhibition of its activation were determined by electrophoretic mobility shift assay. Results The expression of both IL-8 protein and messenger RNA in adenoidal fibroblasts was enhanced by Haemophilus influenzae endotoxin and interleukin-1 beta and was positively correlated with increases in NF-kappa B activity. Treatment of cells with the NF-kappa B inhibitor N-tosyl-(L)-phenylalanine chloromethyl ketone, as well as with clarithromycin, reduced expression of IL-8 and NF-kappa B activity in a dose-dependent manner. Conclusions Results suggest that adenoidal fibroblasts produce IL-8 in response to endotoxin through NF-kappa B activation. The inhibitory effects of clarithromycin on NF-kappa B activation and IL-8 production in adenoidal fibroblasts might explain, in part, the mechanism of this drug in improving otitis media with effusion.