Long-term changes in serum squamous cell carcinoma antigen levels after surgery in patients with sinonasal inverted papilloma

鼻副鼻腔内反性乳頭腫の術後再発に対する血中 SCC 抗原の長期経過の検討

Nippon Jibiinkoka Tokeibugeka Gakkai Kaiho

日本耳鼻咽喉科頭頸部外科学会会報


A Case of Solitary Plasmacytoma of the Tongue

舌に生じた孤立性形質細胞腫例


Development and validation of equations for predicting appendicular skeletal muscle mass in male patients with head and neck cancer and normal hydration status

Muscle mass is typically assessed by abdominal computed tomography, magnetic resonance imaging, and dual-energy x-ray absorptiometry. However, these tests are not routinely performed in patients with head and neck cancer (HNC), making sarcopenia assessment difficult. The aim of this study was to develop and validate equations for predicting appendicular skeletal muscle mass (ASM) from data obtained in daily medical practice, with bioelectrical impedance analysis (BIA)-measured appendicular skeletal muscle mass (BIA-ASM) as a reference. This cross-sectional study included 103 men with HNC who were randomly placed into development and validation groups. The prediction equations for BIA-ASM were developed by multiple regression analysis and validated by Bland-Altman analyses. The estimated skeletal muscle mass index (eSMI) was also statistically evaluated to discriminate the cutoff value for BIA-measured SMI according to the Asian Working Groups for Sarcopenia. Two practical equations, which included 24-h urinary creatinine excretion volume (24hUCrV), handgrip strength (HGS), body weight (BW), and body height (BHt), were developed: ASM (kg) = -39.46 + (3.557 × 24hUCrV [g]) + (0.08872 × HGS [kg]) + (0.1263 × BW [kg]) + (0.2661 × BHt [cm]) if available for 24hUCrV (adjusted R = 0.8905), and ASM (kg) = -42.60 + (0.1643 × HGS [kg]) + (0.1589 × BW [kg]) + (0.2807 × BHt [cm]) if not (adjusted R = 0.8589). ASM estimated by these two equations showed a significantly strong correlation with BIA-ASM (R > 0.900). Bland-Altman analyses showed a good agreement, and eSMI accuracy was high (>80%) in both equations. These two equations are a valid option for estimating ASM and diagnosing sarcopenia in patients with HNC in all facilities without special equipment.


A Case of Eosinophilic Granulomatosis with Polyangiitis That Developed After the Initial Administration of Dupilumab

デュピルマブ初回投与後に発症した好酸球性多発血管炎性肉芽腫症例


A case of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma of the posterior end of the nasal septum

鼻中隔後端に生じたThyroid-like low-grade nasopharyngeal papillary adenocarcinoma例

JOURNAL OF JAPAN SOCIETY FOR HEAD AND NECK SURGERY


線維化と腫瘍随伴リンパ組織増生を伴う粘表皮癌の1例

線維化と腫瘍随伴リンパ組織増生を伴う粘表皮癌の1例


当科で難聴の遺伝学的検査を施行した症例の検討

当科で難聴の遺伝学的検査を施行した症例の検討


軟骨伝導補聴器が有効であったカルタゲナー症候群例

軟骨伝導補聴器が有効であったカルタゲナー症候群例


The effects of continuous administration of diazepam on the recovery of lesion-induced nystagmus in unilaterally labyrinthectomised rats.

These findings suggested that continuous administration of diazepam accelerates the initial process of VC; however, it does not suppress the nystagmus-driving mechanisms in rats.


A Case of Downbeat Nystagmus Induced by Carbamazepine Intoxication

カルバマゼピン中毒により下眼瞼向き眼振を認めた薬剤性めまい症例


Risk factors of first bite syndrome after surgical resection of parapharyngeal space tumors.

The present findings suggest that concomitant surgical settings of 1) sympathetic denervation of the parotid gland with ligation of the external carotid artery or injury of the sympathetic nerve plexus around the external carotid artery during its mobilization, and 2) residual parotid gland tissue are risk factors for the development of first bite syndrome after surgical resection of parapharyngeal space tumors. J. Med. Invest. 70 : 150-153, February, 2023.

The Journal of Medical Investigation : JMI


Muscle mass, quality, and strength; physical function and activity; and metabolic status in cachectic patients with head and neck cancer.

Cancer cachexia is commonly associated with poor prognosis in patients with head and neck cancer (HNC). However, its pathophysiology and treatment are not well established. The current study aimed to assess the muscle mass/quality/strength, physical function and activity, resting energy expenditure (REE), and respiratory quotient (RQ) in cachectic patients with HNC. This prospective cross-sectional study analyzed 64 patients with HNC. Body composition was measured via direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity on ultrasonography images. Muscle strength was investigated utilizing handgrip strength and isometric knee extension force (IKEF). Physical function was evaluated using the 10-m walking speed test and the five times sit-to-stand (5-STS) test. Physical activity was examined using a wearable triaxial accelerometer. REE and RQ were measured via indirect calorimetry. These parameters were compared between the cachectic and noncachectic groups. In total, 23 (36%) patients were diagnosed with cachexia. The cachectic group had a significantly lower muscle mass than the noncachectic group. Nevertheless, there was no significant difference in terms of fat between the two groups. The cachectic group had a higher quadriceps echo intensity and a lower handgrip strength and IKEF than the noncachectic group. Moreover, they had a significantly slower normal and maximum walking speed and 5-STS speed. The number of steps, total activity time, and time of activity (<3 Mets) did not significantly differ between the two groups. The cachectic group had a shorter time of activity (≥3 Mets) than the noncachectic group. Furthermore, the cachectic group had a significantly higher REE/body weight and REE/fat free mass and a significantly lower RQ than the noncachectic group. The cachectic group had a lower muscle mass/quality/strength and physical function and activity and a higher REE than the noncachectic group. Thus, REE and physical activity should be evaluated to determine energy requirements. The RQ was lower in the cachectic group than that in the noncachectic group, indicating changes in energy substrate. Further studies must be conducted to examine effective nutritional and exercise interventions for patients with cancer cachexia.


耳鼻咽喉科・頭頸部外科領域の4K3D外視鏡手術の現状と展望

耳鼻咽喉科・頭頸部外科領域の4K3D外視鏡手術の現状と展望


Effect of Surgical Training Using a Virtual Reality Sinus Simulator in Medical Education

バーチャルリアリティーを用いた内視鏡下鼻副鼻腔手術シミュレーターによる医学教育実習の効果


Repetitive postoperative extubation failure due to dynamic inspiratory airway collapse concomitant with subglottic stenosis in a patient who previously underwent tracheostomy.

We should be aware of the history of tracheostomy, especially at high tracheostomy sites, even in the absence of respiratory symptoms as risk factors for dynamic inspiratory airway collapse concomitant with subglottic stenosis contributing to repeated respiratory failure after extubation. J. Med. Invest. 70 : 301-305, February, 2023.


Imaging features of a myoepithelial carcinoma of the nasal cavity: A case report and literature review

Myoepithelial carcinoma of the nasal cavity is extremely rare. We report the case of a 66-year-old man with myoepithelial carcinoma of the nasal cavity. Computed tomography (CT) and magnetic resonance imaging revealed a lobulated soft tissue mass with central necrosis and hemorrhage, as well as an invasion of the skull base and left orbit. The patient presented with continuous nasal congestion and heavy head and had no elevated level of squamous cell carcinoma-related antigen. CT, magnetic resonance imaging, or F-fluorodeoxyglucose (FDG) positron emission tomography/CT revealed no evidence of a metastatic lesion. F-FDG accumulation in the tumor was inhomogeneous and moderate. Histopathological examination of the resected specimen confirmed a well-circumscribed solid tumor with septa, a small area of hemorrhage, and necrosis. The subsequent diagnosis was a myoepithelial carcinoma of the left nasal cavity. This case shows that nasal myoepithelial carcinoma might appear as a well-defined lobulated mass with hemorrhagic necrosis and intense contrast enhancement in the solid component. We conjecture that hemorrhagic necrosis and intense enhancement values may be potential markers of nasal myoepithelial carcinoma.


Betuletol, a propolis component, suppresses IL-33 gene expression and effective against eosinophilia

Propolis, a resinous substance produced by honeybees, has been used in folk medicine since ancient times due to its many biological benefits such as antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory effects. Propolis contains flavonoids, terpenoids, aromatic aldehydes, and alcohols, which vary with different climate and environmental conditions. In our study, we examined the antiallergic activity of Brazilian green propolis (BGP) and isolated the active compound that can suppress an allergy-sensitive gene, IL-33, expression and eosinophilia. Ethanolic extract of BGP freeze-dried powder was fractionated with several solvent systems, and the active fractions were collected based on activity measurement. The single active compound was found by thin-layer chromatography. Using column chromatography and NMR, the active compound was isolated and identified as 3,5,7-trihydroxy-6,4'-dimethoxyflavone, also known as betuletol. Further, the antiallergic activity of that has been examined in PMA-induced up-regulation of IL-33 gene expression in Swiss 3T3 cells. Our data showed the IL-33 gene suppression both by BGP and the isolated active compound, betuletol. We also found that betuletol suppressed ERK phosphorylation, suggesting it could be effective in suppressing IL-33 mediated eosinophilic chronic inflammation and will provide new insights to develop potent therapeutics against allergic inflammations.


Development of a Phototherapy Device for Allergic Rhinitis Using LEDs Emitting Narrowband UVB

ナローバンドUVBを発光するLEDを用いたアレルギー性鼻炎の光治療装置の開発


Clinical Outcomes of Treatment for Tongue Cancer at Tokushima University Hospital

当科における舌癌の治療成績 (武田憲昭教授退任記念総説集)


Clinical Outcomes of Treatment for Hypopharyngeal Cancer at Tokushima University Hospital

当科における下咽頭癌の治療成績 (武田憲昭教授退任記念総説集)


Hearing Outcomes After Tympanoplasty for Cholesteatoma at Tokushima University Hospital

当科における真珠腫性中耳炎の手術成績 (武田憲昭教授退任記念総説集)


Clinical Outcomes of Treatment for Laryngeal Cancer at Tokushima University Hospital

当科における喉頭癌の治療成績 (武田憲昭教授退任記念総説集)


New method to evaluate sequelae of static facial asymmetry in patients with facial palsy using three-dimensional scanning analysis.

The present findings suggest that affected-unaffected side differences in the depth of the nasolabial fold of the measured using three-dimensional scanning analysis can be used as an index of sequelae of static facial asymmetry. It is also suggested that the index can evaluate whether interventions are effective for the treatment of sequelae.


Efficacy of dual sublingual immunotherapy with Japanese cedar pollen and house dust mite allergens in patients with allergic rhinitis sensitized to multiple allergens.


Long-term changes in serum squamous cell carcinoma antigen levels after surgery in patients with sinonasal inverted papilloma.

These findings suggest that SCCA can be a tumor marker of IP. It is also suggested that postoperative elevation of SCCA levels is a clinical marker for monitoring the recurrence of IP during the follow-up period. A SCCA cut-off value of 1.85 ng/ml postoperatively may predict the subsequent recurrence of IP with high sensitivity and specificity.


Development of receptive vocabulary and verbal intelligence in Japanese children with unilateral hearing loss.

These findings suggest that the development of receptive vocabulary and verbal intelligence was delayed in preschool-age children with UHL and that most of them caught up to exhibit normal language ability after school admission.


Effects of sublingual immunotherapy with tablets or drops containing Japanese cedar pollen antigens on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis.

It is suggested that SLIT with JCP tablets improved both nasal symptoms and sleep disturbances at peak pollen period in patients with Japanese cedar pollinosis. SLIT with JCP tablets for one year was more effective than SLIT with JCP drops for two years and prophylactic treatment with antihistamines. J. Med. Invest. 69 : 97-100, February, 2022.

The Journal of Medical Investigation : JMI


Aural stimulation with capsaicin prevented pneumonia in dementia patients

カプサイシン軟膏による外耳道刺激は高齢認知症患者の肺炎を予防する

Nippon Jibiinkoka Tokeibugeka Gakkai Kaiho

日本耳鼻咽喉科頭頸部外科学会会報


Dietary Supplementation with Monosodium Glutamate Suppresses Chemotherapy-Induced Downregulation of the T1R3 Taste Receptor Subunit in Head and Neck Cancer Patients.

(Background) We investigated the effect of dietary supplementation with monosodium glutamate (MSG) on chemotherapy-induced downregulation of the T1R3 taste receptor subunit expression in the tongue of patients with advanced head and neck cancer. (Methods) Patients undergoing two rounds of chemoradiotherapy were randomly allocated to a control or intervention group (dietary supplementation with MSG at 2.7 g/day during the second round of chemotherapy). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative polymerase chain reaction analysis. Dysgeusia was assessed with a visual analog scale and daily energy intake was evaluated. (Results) T1R3 expression levels in the tongue, taste sensitivity, and daily energy intake were significantly reduced after the first round of chemotherapy compared with before treatment. Furthermore, these parameters significantly decreased after the second round of chemotherapy, but the extent of decrease was significantly attenuated in the MSG group compared with the control group. (Conclusions) MSG supplementation suppresses chemotherapy-induced dysgeusia, possibly due to the inhibition of the T1R3-containing taste receptor downregulation in the tongue, thereby increasing energy intake in patients with advanced head and neck cancer.


Effects of vocal nodules on acoustic characteristics of voice in children : an acoustic analysis of voice.

Objective : In the present study, an attempt was made to evaluate the acoustic characteristics of voice in pediatric patients with vocal nodules using acoustic analysis of voice. Methods : Thirty-five pediatric patients with vocal nodules and 32 control children without dysphonia were enrolled in this study. Their voice samples were analyzed using the Multi-Dimensional Voice Program. Acoustic parameters of voice, such as pitch period perturbation quotient (PPQ), amplitude perturbation quotient (APQ), and noise-to-harmonic ratio (NHR), were measured. Results : In phonation at a loudness of over 80 dBA, the PPQ, APQ, and NHR values of the voice significantly increased in children with vocal nodules than in the control children without dysphonia. The sensitivities and specificities of PPQ, APQ, and NHR for prediction of vocal nodules in children were 62.86% and 84.38%, 74.29% and 75.00%, and 31.43% and 93.75%, respectively. Discussion : The present findings suggest that vocal nodules affect vocal fold vibration, resulting in impaired control of pitch and loudness leading to increased noise components. NHR could be used to evaluate the efficacy of treatment, such as voice rehabilitation, in pediatric patients with vocal nodules because of its high specificity for prediction of vocal nodules in children. J. Med. Invest. 68 : 276-279, August, 2021.


Vestibular and cochlear nerve enhancement on MRI and its correlation with vestibulocochlear functional deficits in patients with Ramsay Hunt syndrome.

In patients with RHS, the origin of vertigo may be superior vestibular neuritis, which is affected by reactive varicella-zoster virus from the geniculate ganglion of the facial nerve through the faciovestibular anastomosis. The results also suggested that in some RHS patients, inferior vestibular neuritis contributes to the development of vertigo and that the origin of refractory sensorineural hearing loss is cochlear neuritis.

Among RHS patients, 79%, 53%, 17% and 26% showed CP in the caloric test, abnormal responses to oVEMP and cVEMP, and refractory sensorineural hearing loss, respectively. SIinc rates of the SVN were significantly increased in RHS patients with CP in the caloric test, and with abnormal responses to oVEMP and cVEMP. SIinc rates of the SVN tended to increase in RHS patients with refractory sensorineural hearing loss (p = 0.052). SIinc rates of the IVN were significantly increased in RHS patients with abnormal responses to oVEMP and cVEMP, and refractory sensorineural hearing loss, but not in those with CP in the caloric test. SIinc rates of the CN were significantly increased in RHS patients with CP in the caloric test, abnormal response to oVEMP and refractory sensorineural hearing loss, but not in those with abnormal response to cVEMP.


A Case of Hereditary Angioedema who Underwent Endoscopic Sinus Surgery Under General Anesthesia

全身麻酔下に内視鏡下鼻内副鼻腔手術を行った遺伝性血管性浮腫例

Hereditary angioedema (HAE) is an inherited disease characterized by angioedema, that is caused by a genetic abnormality of C1-inhibitor (C1-INH). Decrease or functional abnormality of the C1-INH protein leads to excessive production of bradykinin, which causes increased vascular permeability. Patients with HAE present with edema of the face, arms and legs, as also of the larynx and gastrointestinal tract. Notably, airway stenosis caused by laryngeal edema can be fatal. Upper airway surgery under general anesthesia in patients with HAE carries the risk of airway stenosis caused by surgical site edema and by laryngeal edema due to tracheal intubation. In one guideline for the management of HAE, administration of C1-INH (Berinert®P) prior to surgery is recommended as prophylaxis against the development of angioedema.

A 68-year-old female patient with HAE (type 1) was referred to our department with the chief complaint of pain in the right maxilla. She had undergone Caldwell-Luc surgery for sinusitis as a 13-year-old. CT showed two cysts in the right maxilla, and she was diagnosed as having maxillary cysts and scheduled for surgery. As she suffered from frequent attacks of HAE, we administered C1-INH to the patient prior to surgery, according to a guideline for the management of HAE, and the patient underwent endoscopic sinus surgery (ESS) under general anesthesia without HAE attacks during the perioperative period.

ESS under general anesthesia in a patient with HAE carries the risk of angioedema developing at the surgical site and laryngeal edema developing as a result of tracheal intubation. We could safely perform ESS without angioedema developing in the perioperative period, by prophylactic administration of C1-INH according to a guideline for the management of HAE.


Effects of Betahistine on the Development of Vestibular Compensation after Unilateral Labyrinthectomy in Rats.

These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats.


A new combined index of SUVmax of lymph node in PET / CT by a weighting coefficient plus its maximum minor axis in CECT to evaluate occult lymph node metastasis in clinical N0 patients with tongue cancer.

To predict occult nodal metastasis in clinical N0 patients with tongue cancer, we developed combined index (CI) : SUVmax of the largest lymph node in PET / CT by weighting coefficient plus its maximum minor axis (< 10 mm) in contrast-enhanced CT (CECT). In this retrospective study, 57 clinical N0 patients with tongue cancer, who underwent elective supraomohyoid neck dissection at cervical levels of I-III were enrolled. The cutoff value of SUVmax of 2.0 obtained using receiver operating characteristic (ROC) analysis predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 54.5% and a specificity of 78.2%. The cutoff value of CI with weighting coefficient of 1.5 obtained using ROC analysis was 9.8 at the maximum area under the curve of 0.750. The cutoff value of 9.8 predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 68.2% and a specificity of 81.5%. These findings suggest that CI of functional PET / CT and morphological CECT components might improve the diagnostic performance of occult nodal metastasis to select clinical N0 patients with tongue cancer preferable for elective neck dissection. J. Med. Invest. 68 : 154-158, February, 2021.


Effects of sublingual immunotherapy on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis.

These findings suggested that SLIT with JC pollen extract suppressed nasal symptoms in patients with JC pollinosis, leading to improvements in AR-related sleep disturbance and daytime troubles with daily life.


Effects of narrow-band UVB on nasal symptom and upregulation of histamine H1 receptor mRNA in allergic rhinitis model rats

Intranasal pre-irradiation with narrow-band UVB dose-dependently inhibited sneezes and upregulation of H1R gene expression of the nasal mucosa in AR model rats, suggesting that the inhibition of nasal upregulation of H1R gene expression suppressed nasal symptom. The suppression after narrow-band UVB irradiation at a dose of 600 mJ/cm


Differential cytokine profiles in pediatric patients with PFAPA syndrome and recurrent tonsillitis.

Objective : An attempt was made to identify characteristic cytokine profiles to distinguish periodic fever with aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPAS) from recurrent tonsillitis, of which clinical manifestations are similar to those of PFAPAS in children. Methods : Serum concentrations of IL-6, IL-4 and IFN-γ were measured during febrile episodes in pediatric patients. Results : The levels of IL-6 during febrile episodes were markedly increased above the upper limit of normal ranges in patients with both PFAPAS and recurrent tonsillitis, but there were no significant differences between groups. The levels of IL-4 during febrile episodes in PFAPAS patients were significantly lower than those in recurrent tonsillitis patients. The levels of IFN-γ during febrile episodes in PFAPAS patients were significantly higher than those in recurrent tonsillitis patients. Conclusion : In pediatric patients with PFAPAS, despite an increase of IL-6, IL-4 was suppressed with a marked increase of IFN-γ during febrile episodes. On the contrary, in febrile pediatric patients with recurrent tonsillitis, both IL-6 and IL-4, but not IFN-γ were increased. The characteristic cytokine profiles of IL-6, IL-4 and IFN-γ can be used for differential diagnosis of PFAPAS from recurrent tonsillitis in children in clinical ear, nose and throat (ENT) settings. J. Med. Invest. 68 : 38-41, February, 2021.

The Journal of Medical Investigation : JMI


Transnasal Endoscopic Surgery for Juvenile Angiofibroma Involving the Pterygopalatine Fossa

経鼻内視鏡手術にて摘出した翼口蓋窩に進展した若年性血管線維腫例

Juvenile angiofibroma (JA) is an uncommon, locally invasive, highly vascular and benign tumor that occurs in adolescent males. Established external surgical procedures for resection of JA include lateral rhinotomy, midfacial degloving, and transpalatal or infratemporal approaches; however, transnasal endoscopic approaches are increasingly being used because of advances in surgical techniques and endoscopic instrumentation. We report the case of a 14-year-old male who presented with left nasal obstruction and repeated epistaxis. A smooth reddish and hemorrhagic tumor was found in the left posterior nasal cavity. Computed tomography and magnetic resonance imaging showed a markedly enhanced tumor of approximately 40 mm in diameter that had obstructed the left posterior nasal cavity and nasopharynx, with occupancy of the pterygopalatine fossa. The case was diagnosed as Radkowski stage IIB. Preoperative embolization was performed to reduce tumor vascularity and improve visualization for surgical removal. Transnasal endoscopic surgery was used to resect the tumor en bloc after clipping the left maxillary artery. Intraoperative bleeding was 80 mL. To prevent recurrence, careful attention must be paid to tumor invasion into the Vidian canal. The postoperative course of our patient was uneventful, and there has been no evidence of recurrence for over one and a half years since surgery.

若年性血管線維腫は思春期男子に好発し，頻回の鼻出血や鼻閉をきたす比較的稀な良性腫瘍である．治療の第一選択は手術であるが，非常に血流に富む腫瘍のため，従来は経上顎洞法，外側鼻切開法，経口蓋法などが行われてきた．近年は手術手技や機器の発展に伴い内視鏡下摘出術の適応が広がってきている．今回，我々は経鼻内視鏡手術で摘出した翼口蓋窩に進展した若年性血管線維腫例を経験したので報告する．症例は14歳男性で左鼻閉と反復する鼻出血を主訴に近医耳鼻科を受診し，左鼻腔内に腫瘍性病変を指摘され，当科紹介となった．初診時の鼻内所見では左鼻腔後方に表面平滑な赤色腫瘤を認めた．画像所見にて左鼻腔後方から上咽頭，そして翼口蓋窩を占拠する著明な造影効果のある腫瘤を認め，血管造影で栄養血管を確認し若年性血管線維腫のRadkowskiの分類StageIIBと診断した．術中の出血を抑制するために，手術当日に選択的血管塞栓療法を施行した．経鼻内視鏡下に腫瘍を一塊に摘出し，術中の出血を80 mlに抑制できた．若年性血管線維腫の再発部位は翼突管が最多であると報告されており，摘出術では翼突管への腫瘍の残存に注意する必要があると考えられた．


レンコンエキスパウダー摂取による鼻と眼のアレルギー症状軽減効果の検証―プラセボ対照ランダム化二重盲検並行群間比較試験―


Identification and characterization of the anti-allergic compound from lotus root.


Effects of corticosteroid on mRNA levels of histamine H1 receptor in nasal mucosa of healthy participants and HeLa cells.

The purpose of this study is to examine the effect of intranasal corticosteroid (INCS) administration on histamine H1 receptor (H1R) gene expression in the nasal mucosa of healthy participants and the effects of dexamethasone on basal and histamine-induced H1R mRNA expression, and histamine-induced phosphorylation of extracellular signal-regulated kinase (ERK) in HeLa cells. Sixteen healthy participants were given INCS once daily for a week. After pretreatment of dexamethasone, HeLa cells were treated with histamine. Levels of H1R mRNA and phosphorylation of ERK were measured using real time PCR and immunoblot analysis, respectively. Levels of H1R mRNA in the nasal mucosa of healthy participants receiving INCS was significantly decreased. Dexamethasone suppressed basal levels of H1R mRNA, and histamine-induced up-regulation of H1R mRNA and ERK phosphorylation in HeLa cells. These data suggested that corticosteroid inhibited both basal transcription and histamine-induced transcriptional activation of H1R through its suppression of ERK phosphorylation in the signaling pathway involved in H1R gene transcription. It is further suggested that pre-seasonal prophylactic administration of INCS suppresses both basal and pollen-induced upregulation of H1R gene expression in the nasal mucosa of patients with pollinosis, leading to prevention of the exacerbation of nasal symptoms during peak pollen season. J. Med. Invest. 67 : 311-314, August, 2020.


Identification of pyrogallol from Awa-tea as an anti-allergic compound that suppresses nasal symptoms and IL-9 gene expression.

As the expression level of allergic disease sensitive genes are correlated with the severity of allergic symptoms, suppression of these gene expressions could be promising therapeutics. We demonstrated that protein kinase Cδ / heat shock protein 90-mediated H1R gene expression signaling and nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression signaling are responsible for the pathogenesis of pollinosis. Treatment with Awa-tea combined with wild grape hot water extract suppressed these signaling and alleviated nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats. However, the underlying mechanism of its anti-allergic activity is not elucidated yet. Here, we sought to identify an anti-allergic compound from Awa-tea and pyrogallol was identified as an active compound. Pyrogallol strongly suppressed ionomycin-induced up-regulation of IL-9 gene expression in RBL-2H3 cells. Treatment with pyrogallol in combination with epinastine alleviated nasal symptoms and suppressed up-regulation of IL-9 gene expression in TDI-sensitized rats. Pyrogallol itself did not inhibit calcineurin phosphatase activity. However, pyrogallol suppressed ionomycin-induced dephosphorylation and nuclear translocation of NFAT. These data suggest pyrogallol is an anti-allergic compound in Awa-tea and it suppressed NFAT-mediated IL-9 gene expression through the inhibition of dephosphorylation of NFAT. This might be the underlying mechanism of the therapeutic effects of combined therapy of pyrogallol with antihistamine. J. Med. Invest. 67 : 289-297, August, 2020.


A Case of Rosai-Dorfman Disease with Multiple Extranodal Lesion

多発する節外病変を認めたRosai-Dorfman病例

Rosai-Dorfman disease is a rare histiocytic disorder characterized by accumulation of histiocytes in the affected tissue. Herein we report on a case of Rosai-Dorfman disease with multiple lymphadenopathy and multiple extranodal lesions. A 22-year-old woman was referred to our hospital with bilateral submandibular swelling and a localized swelling in the root of the nose. Endoscopic examination revealed mass lesions in both nasal cavities and the subglottic area. A full-body CT revealed multiple nasal masses, cervical lymphadenopathy, and an intrathymic mass. We diagnosed her as having Rosai-Dorfman disease based on the histopathological findings of accumulation of histiocytes and emperipolesis in the nasal lesion and cervical lymph node specimens. Histopathological examination is required for the diagnosis of Rosai-Dorfman disease. After steroid treatment for 3 months, reduction in the size of the lymph nodes in the neck, nasal cavity lesions, and intrathymic mass was noted. However, the size of the subglottic mass remained almost unchanged. In this case, steroid treatment was mostly effective on the lesions. In case of airway obstruction due to increase in the size of the subglottic mass, surgical resection should be indicated.


ヒスタミンH1受容体とIL-33遺伝子発現亢進に対する小青竜湯の抑制効果

ヒスタミンH1受容体とIL-33遺伝子発現亢進に対する小青竜湯の抑制効果


Daily auricular stimulation with capsaicin ointment improved cough reflex sensitivity in elderly patients with dysphagia: a pilot study.

Daily auricular stimulation with capsaicin ointment would be a safe and effective intervention to prevent pneumonia in elderly with a risk of aspiration.


Electroneurography cannot predict when facial synkinesis develops in patients with facial palsy.

The objective of this study is to clarify when facial palsy patients with lower value of Electroneurography (ENoG) should begin the rehabilitation to prevent the development of facial synkinesis. For this purpose, we examined the relationship between the value of ENoG measured 10-14 days after facial palsy onset and the onset day of the development of oral-ocular synkinesis. Sixteen patients with facial palsy including 11 with Bell's palsy and 5 with Ramsay Hunt syndrome (7 men and 9 women ; 15-73 years old ; mean age, 41.6 years) were enrolled in this study. There was no correlation between ENoG value and the onset day of the development of oral-ocular synkinesis (ρ = .09, p = .73). Oral-ocular synkinesis began to develop in 4.0 ± 0.7 months (mean ± SD ; range : 3.1-5.0 months) after facial palsy onset regardless of ENoG value. In conclusion, ENoG value cannot predict when facial synkinesis develops in patients with facial palsy. We recommend that facial palsy patients with a high risk for the development of synkinesis begin the biofeedback rehabilitation with mirror to prevent the development of facial synkinesis 3 months after facial palsy onset. J. Med. Invest. 67 : 87-89, February, 2020.


Aural stimulation with capsaicin prevented pneumonia in dementia patients.

These findings suggest that daily long-term aural stimulation with capsaicin ointment enhanced the cough reflex via Arnold's ear-cough reflex as a glottis protective measure, resulting in the reduction of incidence of pneumonia in elderly dementia patients at high risk of aspiration. The daily aural stimulation with capsaicin ointment may be a safe and promising intervention to prevent aspiration pneumonia in elderly people, especially those who cannot undergo swallowing exercise.


A new immunohistochemical method to evaluate the development of vestibular compensation after unilateral labyrinthectomy in rats.

These findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC.


Effect of Surgical Training Using a Virtual Reality Temporal Bone Simulator in Medical Education

医学教育におけるバーチャルリアリティーを用いた側頭骨手術シミュレーション実習の効果

 To estimate the effects of a virtual reality temporal bone simulator in medical education.

 Two hundred and thirty-five medical students undergoing bedside learning were recruited in this study for two years. The same instructor provided the training during the first year, while several instructors provided the training, based on a guidance manual, during the second year. We examined the students' knowledge of anatomy of the temporal bone and administered a questionnaire to determine their comprehension of surgical procedures involving the temporal bone after the training as compared to the level of understanding before the training.

 The percentage of correct answers in the examination of anatomical knowledge about the temporal bone after the simulation in the first and second year improved from 51.8% to 83.9% and 49.4% to 80.0%, respectively. The percentages of medical students who responded with "well understood" or "I think I understood" to questions in the questionnaire on comprehension of surgical procedures involving the temporal bone in the first and second year were 84.3% and 76.4% for mastoidectomy, 74.8% and 66.4% for tympanotomy and 67.8% and 52.3% for cochleostomy, respectively. The anatomical and surgical comprehension levels, except for the case of cochleostomy, did not differ between students who received instructions from several instructors and those who received from the same instructor in this study. The training using a virtual reality temporal bone simulator was useful to improve the students' anatomical knowledge about the temporal bone and their comprehension of surgical procedures involving the temporal bone, and to unify the training content, regardless of the instructor because of standardization and customization of the surgical procedure. Thus, the training using a virtual reality temporal bone simulator is one of the most effective tools of medical education for both medical students and instructors.


Short-term pre-operative systemic administration with low-dose of steroid does not make a false-negative diagnosis of definite eosinophilic chronic rhinosinusitis after endoscopic sinus surgery.

According to JESREC criteria, definite eosinophilic chronic rhinosinusitis (ECRS) is postoperatively diagnosed based on over 70 eosinophils in high power magnification fields of the resected nasal polyps in patients with probable ECRS. Preoperative systemic administration with steroid is a standard practice, because it reduced intraoperative bleeding during endoscopic sinus surgery (ESS) in patients with ECRS. However, it was recently reported that systemic administration with steroid decreased the number of eosinophils in the nasal polyps, leading to a false negative diagnosis of definite ECRS. To overcome the risk, we have adopted short-term pre-operative systemic administration with low-dose of steroid and examined if our steroid administration makes a false-negative diagnosis. We performed a retrospective chart review of 42 patients with probable ECRS. Eleven patients were administered with 0.5 mg of bethametasone for 7 days before ESS, and other 31 patients were not administered. The average number of eosinophils in nasal polyps in patients who were administered with steroid was 188 ± 167, which was not different from 199 ± 149 in the patients who were not administered. These findings suggest that short-term preoperative administration with low-dose of steroid has few risk of a false-negative diagnosis of definite ECRS. J. Med. Invest. 66 : 233-236, August, 2019.

The Journal of Medical Investigation : JMI


Effects of irradiation with narrowband-ultraviolet B on up-regulation of histamine H1 receptor mRNA and induction of apoptosis in HeLa cells and nasal mucosa of rats.

once a day for three days suppressed TDI-induced sneezes and up-regulation of H1R mRNA in nasal mucosa without induction of apoptosis. These findings suggest that repeated intranasal irradiation with low dose of NB-UVB could be clinically used as phototherapy of AR.

, irradiation with 310 nm NB-UVB induced apoptosis. Western blot analysis showed that the suppressive effect of NB-UVB irradiation on H1R gene expression was through the inhibition of ERK phosphorylation. In TDI-sensitized rat, intranasal irradiation with 310 nm NB-UVB at an estimated dose of 100 mJ/cm


Receptor and Interleukin-9 Gene Expressions Responsible for the Pathogenesis of the Allergic Rhinitis.

phosphorylation of PKCδ in HeLa cells. In RBL-2H3 cells, RJ and BGPP also suppressed NFAT-mediated IL-9 gene expression. These results suggest that RJ and BGPP improve allergic symptoms by suppressing PKCδ and NFAT signaling pathways, two important signal pathways for the AR pathogenesis, and suggest that RJ and BGPP could be good therapeutics against AR.


Effect of wild grape on the signaling of histamine H1 receptor gene expression responsible for the pathogenesis of allergic rhinitis.

receptor (H1R) and IL-9 gene expressions, respectively, are responsible for the pathogenesis of allergic rhinitis. We explore anti-allergic compounds that suppress these signaling pathways and found that wild grape (WG) contains such compounds. Here, we investigated the effect of WG hot water extract (WGE) on the signaling pathways for PKCδ-mediated H1R and NFAT-mediated IL-9 gene expressions. WGE suppressed histamine/PMA-induced H1R gene up-regulation in HeLa cells. Toluene-2,4-diisocyanate (TDI)-induced H1R mRNA elevation in TDI-sensitized rats was also suppressed by WGE treatment. Treatment with WGE in combination with Awa-tea, suppresses NFAT signaling-mediated IL-9 gene, markedly alleviated nasal symptoms. Furthermore, WGE suppressed PMA-induced IL-33 gene up-regulation in Swiss 3T3 cells. Data suggest that combination of WGE, suppresses PKCδ signaling with Awa-tea, suppresses NFAT signaling would have distinct clinical and therapeutic advantages as a substitute for anti-allergic drugs. In addition, as the expression level of IL-33 mRNA was correlated with the blood eosinophils number in patients with pollinosis, WG could alleviate eosinophilic inflammation through the suppression of IL-33 gene expression. J. Med. Invest. 65:242-250, August, 2018.


Effects of repeated snowboard exercise in virtual reality with time lags of visual scene behind body rotation on head stability and subjective slalom run performance in healthy young subjects

After repeated snowboard exercises in the virtual reality (VR) world with increasing time lags in trials 3-8, it is suggested that the adaptation to repeated visual-vestibulosomatosensory conflict in the VR world improved dynamic posture control and motor performance in the real world without the development of motion sickness. The VR technology was used and the effects of repeated snowboard exercise examined in the VR world with time lags between visual scene and body rotation on the head stability and slalom run performance during exercise in healthy subjects. Forty-two healthy young subjects participated in the study. After trials 1 and 2 of snowboard exercise in the VR world without time lag, trials 3-8 were conducted with 0.1, 0.2, 0.3, 0.4, 0.5, and 0.6 s time lags of the visual scene that the computer creates behind board rotation, respectively. Finally, trial 9 was conducted without time lag. Head linear accelerations and subjective slalom run performance were evaluated. The standard deviations of head linear accelerations in inter-aural direction were significantly increased in trial 8, with a time lag of 0.6 s, but significantly decreased in trial 9 without a time lag, compared with those in trial 2 without a time lag. The subjective scores of slalom run performance were significantly decreased in trial 8, with a time lag of 0.6 s, but significantly increased in trial 9 without a time lag, compared with those in trial 2 without a time lag. Motion sickness was not induced in any subjects.


Irradiation with narrowband-ultraviolet B suppresses phorbol ester-induced up-regulation of H1 receptor mRNA in HeLa cells

Conclusion These findings suggest that low dose irradiation with 310 nm NB-UVB specifically suppressed the up-regulation of H1R gene expression without inducing apoptosis and that UVB of shorter or longer wavelength than 310 nm NB-UVB had no such effects. Objective To develop a narrowband-ultraviolet B(NB-UVB) phototherapy for allergic rhinitis, this study investigated the effects of irradiation with NB-UVB at wavelength of 310 nm on phorbol-12-myristate-13-acetate (PMA)-induced up-regulation of histamine H1 receptor (H1R) mRNA in HeLa cells. Methods The mRNA levels of H1R in HeLa cells were measured using real-time RT-PCR. Apoptosis were evaluated with DNA fragmentation assay. Results PMA induced a significant increase in H1R mRNA expression in HeLa cells. Irradiation with 305 nm UVB and 310 nm NB-UVB, but not with 315 nm UVB at doses of 200 and 300 mJ/cm(2) significantly suppressed PMA-induced up-regulation of H1R mRNA. At a dose of 200 mJ/cm(2), irradiation with 305 nm UVB, but not with 310 nm NB-UVB, induced apoptosis, although exposure of the cells to both 305 and 310 nm UVB induced apoptosis at a dose of 300 mJ/cm(2) after PMA treatment in HeLa cells. Conversely, irradiation with 315 nm UVB at doses of 200 and 300 mJ/cm(2) did not induce apoptosis.


Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats.

Antihistamines inhibit histamine signaling by blocking histamine H1 receptor (H1R) or suppressing H1R signaling as inverse agonists. The H1R gene is upregulated in patients with pollinosis, and its expression level is correlated with the severity of nasal symptoms. Here, we show that antihistamine suppressed upregulation of histidine decarboxylase (HDC) mRNA expression in patients with pollinosis, and its expression level was correlated with that of H1R mRNA. Certain antihistamines, including mepyramine and diphenhydramine, suppress toluene-2,4-diisocyanate (TDI)-induced upregulation of HDC gene expression and increase HDC activity in TDI-sensitized rats. However, d-chlorpheniramine did not demonstrate any effect. The potencies of antihistamine suppressive effects on HDC mRNA elevation were different from their H1R receptor binding affinities. In TDI-sensitized rats, the potencies of antihistamine inhibitory effects on sneezing in the early phase were related to H1R binding. In contrast, the potencies of their inhibitory effects on sneezing in the late phase were correlated with those of suppressive effects on HDC mRNA elevation. Data suggest that in addition to the antihistaminic and inverse agonistic activities, certain antihistamines possess additional properties unrelated to receptor binding and alleviate nasal symptoms in the late phase by inhibiting synthesis and release of histamine by suppressing HDC gene transcription.


Suplatast tosilate alleviates nasal symptoms through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene expression in toluene-2,4-diisocyanate-sensitized rats.

Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.


A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C--dependent signaling pathway.

Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti-allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869-6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13-acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4-diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA-induced phosphorylation of PKCδ at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCδ activation.


Effects of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis induced by controlled cedar pollen challenge in an environmental exposure unit.

In the present study, we examined the effects of antihistamine on the up-regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non-responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders.


Effects of chemotherapy on gene expression of lingual taste receptors in patients with head and neck cancer.

We aimed to test the hypothesis that chemotherapy changes the gene expression of taste receptors in the tongue to induce dysgeusia in patients with head and neck cancer. Prospective observation study. We enrolled 21 patients who received chemoradiotherapy and five patients who underwent radiotherapy for head and neck cancer. The messenger RNA (mRNA) levels of the taste receptor subunits T1R1, T1R2, T1R3, and T2R5 were measured in lingual mucosa scrapings obtained with a small spatula. The perception thresholds of umami, sweet, and bitter tastes were assessed by the whole mouth gustatory test. In four patients with severe stomatitis induced by chemoradiotherapy, the mRNA levels of T1R1, T1R2, T1R3, and T2R5 in the lingual mucosa were significantly decreased. However, in 17 patients with mild/moderate stomatitis, the mRNA levels of T1R3 were significantly and transiently decreased, whereas those of T1R1 and T1R2 remained unchanged and those of T2R5 mRNA were significantly and transiently increased after chemotherapy. There was a significant negative correlation between the perception thresholds of umami or sweet tastes and lingual mRNA levels of T1R3 in patients with mild/moderate stomatitis after chemotherapy. Although the perception threshold of bitter taste remained unchanged, lingual mRNA levels of T2R5 were significantly increased in patients who complained of phantogeusia after chemotherapy. Chemotherapy specifically changed the gene expression of T1R3 and T2R5 in head and neck cancer patients with mild/moderate stomatitis, resulting in both dysgeusia of umami and sweet tastes as well as phantogeusia. 4. Laryngoscope, 126:E103-E109, 2016.


Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (-)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

The histamine H1 receptor (H1R) gene is an allergic disease sensitive gene, and its expression level is strongly correlated with the severity of allergic symptoms. (-)-Maackiain was identified as a Kujin-derived anti-allergic compound that suppresses the up-regulation of the H1R gene. However, the underlying mechanism of H1R gene suppression remains unknown. Here, we sought to identify a target protein of (-)-maackiain and investigate its mechanism of action. A fluorescence quenching assay and immunoblot analysis identified heat shock protein 90 (Hsp90) as a target protein of (-)-maackiain. A pull-down assay revealed that (-)-maackiain disrupted the interaction of Hsp90 with PKCδ, resulting in the suppression of phorbol 12-myristate 13-acetate (PMA)-induced up-regulation of H1R gene expression in HeLa cells. Additional Hsp90 inhibitors, including 17-(allylamino)-17-demethoxygeldanamycin, celastrol, and novobiocin also suppressed PMA-induced H1R gene up-regulation. 17-(Allylamino)-17-demethoxygeldanamycin inhibited PKCδ translocation to the Golgi and phosphorylation of Tyr(311) on PKCδ. These data suggest that (-)-maackiain is a novel Hsp90 pathway inhibitor. The underlying mechanism of the suppression of PMA-induced up-regulation of H1R gene expression by (-)-maackiain and Hsp90 inhibitors is the inhibition of PKCδ activation through the disruption of Hsp90-PKCδ interaction. Involvement of Hsp90 in H1R gene up-regulation suggests that suppression of the Hsp90 pathway could be a novel therapeutic strategy for allergic rhinitis.


Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes.

Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)-4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin-derived antiallergic compound and investigate its mechanism of action. The H1R and IL-4 mRNA levels were determined by real-time quantitative RT-PCR. To investigate the effects of maackiain in vivo, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as a nasal hypersensitivity animal model. We identified (-)-maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL-4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (-)-Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr(311) on PKCδ, which led to the suppression of H1R gene transcription. However, (-)-maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI-induced upregulations of H1R and IL-4 gene expressions in TDI-sensitized rats. These data suggest that (-)-maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI-sensitized allergy model rats through the inhibition of H1R and IL-4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation.


A Case of Adenomatoid Odontogenic Tumor in the Maxillary Canine

上顎犬歯から発生した腺様歯原性腫瘍例

The adenomatoid odontogenic tumor (AOT) is a rare benign odontogenic tumor that is mostly found in jawbone. It is generally found in the incisor region of the maxilla of young females. It rarely extends into the paranasal sinuses. This article describes a case of AOT found in the maxilla and occupying the maxillary sinus and nasal cavity.<br>A 20-year-old woman was referred to our department because of swelling of the left cheek. CT examination showed a cystic lesion in the left maxillary sinus including calcified structures and an impacted tooth. A biopsy specimen of the lesion revealed an adenomatoid odontogenic tumor. We performed tumor extirpation combined with the Caldwell-Luc operation. There is no evidence of recurrence 3 years after the operation.


Endoscopic Approach to Organized Hematoma of Maxillary Sinus Using the Swinging Technique of Nasolacrimal Duct and Inferior Turbinate

鼻涙管下鼻甲介スイング法にて内視鏡下に摘出した上顎洞血瘤腫例

We report a 63-year-old woman with recurrent nasal bleeding diagnosed with organized hematoma in the maxillary sinus. Computed tomography showed an expanding lesion with thinning and defect of the adjacent bone and magnetic resonance imaging showed heterogeneous signal intensity with thickening of the maxillary sinus mucosa and marked patchy enhancement. After selective embolization of the feeding artery, we conducted endoscopic sinus surgery and applied the swinging technique of the nasolacrimal duct and inferior turbinate for resection of the organized hematoma. It provides a wide surgical field for the maxillary sinus, resulting in en bloc resection with a straight endoscope and instruments. The postoperative course was uneventful and no recurrence was observed in the 1.5-year follow-up. The swinging technique allows wide and direct access to the maxillary sinus through anterior space of the nasolacrimal duct without damaging the nasolacrimal duct or inferior turbinate mucosal function. This technique is a safe and effective method to remove benign maxillary sinus diseases endoscopically by good accessibility to and visualization of the maxillary sinus.

鼻涙管下鼻甲介スイング法を用いて内視鏡下に摘出した上顎洞血瘤腫例を経験したので報告する．症例は63歳女性で主訴は右鼻出血．CTでは右上顎洞内に膨張性の発育を示す軟部組織陰影が充満し，上顎洞自然口付近から腫瘤中心部にかけて不均一な造影効果を認めた．MRIではT1強調画像で等信号域，T2強調画像で辺縁が低信号域，内部が低信号域と高信号域が混在した腫瘤を認めた．画像所見から血瘤腫を疑い血管造影で栄養血管を確認し，手術前日に塞栓術を施行した．内視鏡下副鼻腔手術により，腫瘤を一塊に切除する目的で鼻涙管下鼻甲介スイング法を用いて摘出術を行った．まず粘膜下下鼻甲介骨切除術を行った後，下鼻道側壁粘膜を剥離し，鼻涙管と下鼻甲介粘膜を一塊として温存した．次に鼻涙管と下鼻甲介を内側・外側へスウィングさせながら上顎洞内側壁を広く切除し，上顎洞を大きく開放した．鼻涙管と下鼻甲介を内側へスウィングさせることで，鼻涙管の前方を経由して上顎洞へアプローチし，上顎洞内の大部分を直視鏡下に弯曲の少ない手術器具を用いて処理でき，血瘤腫を一塊に上顎洞粘膜から切除した．鼻涙管下鼻甲介スイング法は，鼻涙管や下鼻甲介粘膜機能を温存して上顎洞内の処理を広い術野で直視鏡下に行うことが可能であり，血瘤腫などの上顎洞を主座とする腫瘤性病変に広く有用であると考えられた．


A Case of Sinonasal-type Hemangiopericytoma Resected with Endoscopic Sinus Surgery

We report herein on a 75-year-old woman with sinonasal-type hemangiopericytoma (HPC). She complained of nasal bleeding and a nasal tumor originated from the left nasal septum was found. It was successfully resected using endoscopic sinus surgery without preoperative embolization, because we were uncertain of its feeding artery. Its pathological examination gave a diagnosis of sinonasal-type of HPC. The sinonasal-type HPC is a rare benign sinonasal tumor, but WHO has classified it as a borderline malignancy, because it may have multiple relapses. Our patient remained free of relapse 36 months after the treatment.


難治性中耳炎症状を呈するANCA陽性症例の疫学調査と診断基準の問題点に関する検討


Effects of aural stimulation with capsaicin ointment on swallowing function in elderly patients with non-obstructive dysphagia.

In the present study, an attempt was made to examine the effects of aural stimulation with ointment containing capsaicin on swallowing function in order to develop a novel and safe treatment for non-obstructive dysphagia in elderly patients. A prospective pilot, non-blinded, non-controlled study with case series evaluating a new treatment. Secondary hospitals. The present study included 26 elderly patients with non-obstructive dysphagia. Ointment containing 0.025% capsaicin (0.5 g) was applied to the external auditory canal with a cotton swab under otoscope only once or once a day for 7 days before swallowing of a bolus of colored water (3 mL), which was recorded by transnasal videoendoscopy and evaluated according to the endoscopic swallowing score. After a single application of 0.025% capsaicin ointment to the right external auditory canal, the endoscopic swallowing score was significantly decreased, and this effect lasted for 60 minutes. After repeated applications of the ointment to each external auditory canal alternatively once a day for 7 days, the endoscopic swallowing score decreased significantly in patients with more severe non-obstructive dysphagia. Of the eight tube-fed patients of this group, three began direct swallowing exercises using jelly, which subsequently restored their oral food intake. These findings suggest that stimulation of the external auditory canal with ointment containing capsaicin improves swallowing function in elderly patients with non-obstructive dysphagia. By the same mechanism used by angiotensin-converting enzyme inhibitors to induce cough reflex, which has been shown to prevent aspiration pneumonia, aural stimulation with capsaicin may reduce the incidence of aspiration pneumonia in dysphagia patients via Arnold's ear-cough reflex stimulation.


The Molecular Mechanism of Up-regulation of Histamine H1 Receptor mRNA in the Nasal Mucosa of Patients with Allergic Rhinitis and the Effect of Antihistamine on Histamine H1 Receptor Expression

アレルギー性鼻炎におけるヒスタミンH1受容体遺伝子発現亢進の分子機構とその制御

We are focusing on the histamine H1 receptor (H1R) as an allergic disease-sensitive gene. H1R is a rate-limiting molecule of the H1R signal because the signal is increased with elevated receptor expression levels. We discovered that the direct stimulation of H1R induced the up-regulation of H1R gene expression through PKCδ activation. The mechanism of H1R gene expression was revealed to play a key role in the receptor expression level in studies using cultured HeLa cells and allergic rhinitis model rats. Antihistamines have three effects: the blocking effect on histamine signaling of H1 receptors; the suppressive effect on histamine-induced up-regulation of H1R mRNA that is the transcriptional activation of H1R; and the suppressive effect on H1R mRNA in the absence of histamine that is the basal transcription of H1R. The third effect may be another side of the inverse agonist action of antihistamine. We demonstrated that repeated pretreatment with antihistamines in the allergic rhinitis model rats resulted not only in the improvement of symptoms but also in the suppression of the up-regulation of H1R mRNA in the nasal mucosa. We next investigated the effect of preseasonal prophylactic treatment with antihistamines on nasal symptoms and the expression of H1R mRNA of the nasal mucosa in patients with cedar pollen pollinosis. During the peak pollen period, the expression of H1R mRNA in the nasal mucosa and the scores of sneezing and watery rhinorrhea in patients receiving preseasonal prophylactic treatment with antihistamines were significantly suppressed in comparison with those in the patients without treatment. These results suggest that H1R is an allergic disease-sensitive gene and H1R plays an important role in allergic rhinitis through the regulation of histamine signaling.


Sphingosine-1-phosphate can promote mast cell hyper-reactivity through regulation of contactin-4 expression

Both genes and the environment are determinants in the susceptibility to allergies and may alter the severity of the disease. We explored whether an increase in the levels of the lipid mediator S1P in vivo, a condition found during allergic asthma, could affect the sensitivity or the response of MCs to IgE/Ag and the onset of allergic disease. We found that increasing S1P levels by genetic deletion of S1P lyase, the enzyme catabolizing S1P, led to elevated activity of circulating tryptase. Accordingly, MCs of S1P lyase-deficient mice were mostly degranulated in the tissues and showed enhanced calcium levels, degranulation, and cytokine production in response to IgE/Ag in vitro. Th 1-skewed mice (C57BL/6) had lower levels of S1P in circulation and histamine responses than did Th 2-skewed (129/Sv) mice. However, when S1P levels were increased by pharmacologic inhibition of S1P lyase, the C57BL/6 mice showed increased histamine release into the circulation and anaphylactic responses similar to those in the 129/Sv mice. Culturing of MCs in the presence of S1P enhanced their degranulation responses, and when the S1P-treated MCs were used to reconstitute MC-deficient (Kit(W-sh)) mice, they caused enhanced anaphylaxis. Gene expression arrays in S1P lyase-deficient MCs and MCs treated with S1P continuously revealed increased expression of numerous genes, including the adhesion molecule CNTN4,which contributed to the enhanced responses. Our findings argue that dysregulation in the metabolism of S1P is a contributing factor in modulating MC responsiveness and the allergic response.


An Intractable Case of MPO-ANCA-associated Middle Ear Disease

難治性MPO-ANCA関連中耳疾患例

We report herein on an intractable case of MPO-ANCA-associated middle ear disease with sensorineural hearing loss and facial palsy. A 73-year-old female complained of otitis media-like symptoms, but the treatment for otitis media with effusion was ineffective. She then showed bilateral progressive sensorineural hearing loss and facial palsy. PR3-ANCA was negative, but MPO-ANCA was positive in the serum. CT imaging revealed that the lesion was limited to the middle ear cavity without lesions in the lung and kidney. Non-specific findings were obtained in the histopathological examination of granular tissue of the mastoid cavity. She was diagnosed as having MPO-ANCA-associated middle ear disease with sensorineural hearing loss and facial palsy on the basis of the clinical findings and we administered cyclophosphamide in addition to a steroid. Discontinuance of the immunosuppressive therapy was, however, forced because of bacterial infection. Thereafter, steroid therapy alone failed to improve the left deafness, right moderate sensorineural hearing loss and right facial palsy.


Combination of leukotoriene receptor antagonist with antihistamine has an additive suppressive effect on the up-regulation of H1-receptor mRNA in the nasal mucosa of toluene 2,4-diisocyanate-sensitized rat.

An attempt was made to clarify the additive suppressive effects of pranlukast, a cysteinyl leukotriene-receptor (LTR) antagonist, in combination with chlorpheniramine, an antihistamine, on the up-regulation of histamine H1-receptor (H1R) mRNA in toluene 2,4-diisocyanate (TDI)-sensitized rats. Although pre-treatment with pranlukast partially, but significantly, suppressed TDI-induced up-regulation of H1R mRNA and nasal symptoms, pre-treatment with the combination of pranlukast and chlorpheniramine significantly suppressed them in a manner greater than either drug alone. These findings suggest that the additive therapeutic effect of the combination of LTR antagonist and antihistamine is due to their additive suppression of H1R up-regulation.


Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells.

It has been reported that the histamine H1 receptor (H1R) gene is up-regulated in patients with allergic rhinitis and H1R expression level strongly correlates with the severity of allergy symptoms. Accordingly compounds that suppress the H1R gene expression are promising as useful anti-allergic medications. Recently, we demonstrated that histamine or phorbol-12-myristate-13-acetate (PMA) stimulation induced the up-regulation of H1R gene expression through the protein kinase C (PKC)/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells expressing H1R endogenously. Quercetin is one of the well-characterized flavonoids and it possesses many biological activities including anti-allergic activity. However, effect of quercetin on H1R signaling is remained unknown. In the present study, we examined the effect of quercetin on histamine- and PMA-induced up-regulation of H1R gene expression in HeLa cells. We also investigated its in vivo effects on the toluene-2,4-diisocyanate (TDI)-sensitized allergy model rats. Quercetin suppressed histamine- and PMA-induced up-regulation of H1R gene expression. Quercetin also inhibited histamine- or PMA-induced phosphorylation of Tyr(311) of PKC and translocation of PKC to the Golgi. Pre-treatment with quercetin for 3weeks suppressed TDI-induced nasal allergy-like symptoms and elevation of H1R mRNA in the nasal mucosa of TDI-sensitized rats. These data suggest that quercetin suppresses H1R gene expression by the suppression of PKC activation through the inhibition of its translocation to the Golgi.


PMA-induced dissociation of Ku86 from the promoter causes transcriptional up-regulation of histamine H1 receptor.


A case of suspected perilymphatic oozer with CTP-positive cerebrospinal otorrhea


Effects of Oral Administration of Prostaglandin I2 as a Salvage Treatment in Patients with Sudden Deafness

突発性難聴難治例に対するプロスタグランディンI2製剤を用いた二次治療の検討

We examined the effect of oral administration of beraprost sodium, a derivative of prostaglandin I2 (PGI2) in patients with sudden deafness as a salvage treatment after failure of initial systemic steroid therapy with prostaglandin E1. We then compared them with those of mecobalamin, a derivative of vitamin B12. A significant improvement in the average hearing level was obtained in patients who received beraprost sodium for 12 weeks, but not in patients who received mecobalamin. The hearing levels at 125 Hz, 250 Hz, 500 Hz and 8000 Hz significantly improved after the salvage treatment of beraprost sodium over those of mecobalamin. These findings suggested that oral administration of the PGI2 derivative could be utilized as a salvage treatment for refractory sudden deafness after failure of initial steroid therapy.


Preseasonal prophylactic treatment with antihistamines suppresses IL-5 but not IL-33 mRNA expression in the nasal mucosa of patients with seasonal allergic rhinitis caused by Japanese cedar pollen.

These findings suggest that the down-regulation of interleukin (IL)-5 gene expression in collaboration with the suppression of histamine H(1) receptor (H1R) gene expression in the nasal mucosa provides the basis for better therapeutic effects of preseasonal prophylactic treatment with antihistamines in patients with seasonal allergic rhinitis caused by Japanese cedar pollen. The effects of prophylactic administration of antihistamines on the expression of IL-5 and IL-33 mRNA in the nasal mucosa of the patients with pollinosis were investigated. Eight patients had already visited the hospital before the peak pollen period and started preseasonal prophylactic treatment with antihistamines. Seventeen patients who first visited the hospital during the peak pollen period were designated as the no treatment group. After local anesthesia, nasal mucosa was obtained by scraping the inferior concha with a small spatula during the peak pollen period. During the peak pollen period, the expression of IL-5 mRNA, but not that of IL-33 mRNA, in the nasal mucosa of patients receiving preseasonal prophylactic treatment with antihistamines was significantly lower in comparison with that of patients without treatment. Moreover, there was a significant correlation between the expression of IL-5 mRNA and the nasal symptoms or the expression of H1R mRNA.


Effects of dietary zinc deprivation on zinc concentration and ratio of apo/holo-activities of angiotensin converting enzyme in serum of mice.

These findings suggest that ACE ratio is as sensitive as serum zinc concentration for the evaluation of zinc deficiency and can be used for the biochemical diagnosis of zinc nutritional status in patients with zinc deficiency-induced taste impairment.


Dietary zinc intake and its effects on zinc nutrition in healthy Japanese living in the central area of Japan.

In the present study, we first examined the dietary zinc intake from food groups in 109 healthy Japanese (24-82 years old, 45 male and 64 female) by means of the 72-h recall method. We then used the ratio of apo/holo-activities of angiotensin converting enzyme (ACE ratio) that is a more sensitive index of zinc nutrition than zinc concentration in the serum and examined the correlation between their zinc intake and ACE ratio. Dietary zinc intake in healthy Japanese was maximal from rice and rice products. There were significant inverse correlations between the ACE ratio and dietary zinc intake from rice and rice products and shellfish, and a significant positive correlation between ACE ratio and dietary zinc intake from other beans and bean processed foods. On the other hand, there were no significant correlations between serum zinc concentrations and dietary zinc intake from any food group except processed fish. These findings suggested that rice is a major source of dietary zinc intake in healthy Japanese. It is also suggested that shellfish also has a major impact on zinc nutrition, although dietary zinc intake from this source is minimal. Since beans contain phytic acid, which inhibits the absorption of dietary zinc, it is suggested that intake of beans causes impairment of zinc nutrition.

The Journal of Medical Investigation : JMI


Involvement of protein kinase Cdelta/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 (PARP-1) signaling pathway in histamine-induced up-regulation of histamine H1 receptor gene expression in HeLa cells.

The histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis. However, the mechanism and reason underlying this up-regulation are still unknown. Recently, we reported that the H1R expression level is strongly correlated with the severity of allergic symptoms. Therefore, understanding the mechanism of this up-regulation will help to develop new anti-allergic drugs targeted for H1R gene expression. Here we studied the molecular mechanism of H1R up-regulation in HeLa cells that express H1R endogenously in response to histamine and phorbol 12-myristate 13-acetate (PMA). In HeLa cells, histamine stimulation caused up-regulation of H1R gene expression. Rottlerin, a PKC-selective inhibitor, inhibited up-regulation of H1R gene expression, but Go6976, an inhibitor of Ca(2+)-dependent PKCs, did not. Histamine or PMA stimulation resulted in PKC phosphorylation at Tyr(311) and Thr(505). Activation of PKC by H(2)O(2) resulted in H1R mRNA up-regulation. Overexpression of PKC enhanced up-regulation of H1R gene expression, and knockdown of the PKC gene suppressed this up-regulation. Histamine or PMA caused translocation PKC from the cytosol to the Golgi. U0126, an MEK inhibitor, and DPQ, a poly(ADP-ribose) polymerase-1 inhibitor, suppressed PMA-induced up-regulation of H1R gene expression. These results were confirmed by a luciferase assay using the H1R promoter. Phosphorylation of ERK and Raf-1 in response to PMA was also observed. However, real-time PCR analysis showed no inhibition of H1R mRNA up-regulation by a Raf-1 inhibitor. These results suggest the involvement of the PKC/ERK/poly(ADP-ribose) polymerase-1 signaling pathway in histamine- or PMA-induced up-regulation of H1R gene expression in HeLa cells.


感音難聴と顔面神経麻痺を示すMPO-ANCA関連中耳疾患の1例 診断基準案の提案


ヒスタミンH1受容体遺伝子発現機構のアレルギー疾患における病理学的意義

ヒスタミンH1受容体遺伝子発現機構のアレルギー疾患における病理学的意義

Therapeutics targeting disease-sensitive genes are required for the therapy of multifactorial diseases. There is no clinical report on therapeutics for allergic disease-sensitive genes. We are focusing on the histamine H1 receptor (H1R) as a sensitive gene. H1R mediates allergy histamine signals. H1R is a rate-limiting molecule of the H1R signal because the signal is increased with elevated receptor expression level. We discovered that the stimulation of H1R induced H1R gene expression through PKCδ activation, resulting in receptor upregulation. The mechanism of H1R gene expression was revealed to play a key role in the receptor expression level in studies using cultured HeLa cells and allergic rhinitis model rats. Preseasonal prophylactic treatment with antihistamines is recommended for the therapy of pollinosis. However, the mechanism of the therapy remains to be elucidated. We demonstrated that repeated pretreatment treatment with antihistamines in the allergic rhinitis model rats resulted not only in improvement of symptoms but also in suppressed elevation of H1R mRNA levels in the nasal mucosa. A clinical trial was then initiated. When symptoms and H1R mRNA levels in the nasal mucosa of pollinosis patients with or without preseasonal prophylactic treatment with antihistamines were examined, both symptoms and high levels of H1R mRNA were significantly improved in treated compared with untreated patients. These results strongly suggest that H1R is an allergic disease-sensitive gene.

Journal of the Pharmaceutical Society of Japan


徳島県における過去26年間のヒノキ科花粉の飛散状況

徳島県における過去26年間のヒノキ科花粉の飛散状況

徳島県におけるヒノキ科花粉の飛散状況を1981年から2007年までの26年間測定した．1)ヒノキ科花粉の総飛散数はスギ花粉の総飛散数の3割以下であった．両者の花粉の飛散総数の変化はほぼ一致したが，両者の比率は年によって異なっており，ヒノキ科花粉の独自の飛散予報も必要と考えられた．2)スギ花粉の飛散総数は前年7月の最高気温，平均気温，日照時間との間に有意な正の相関がみられ，湿度との間に有意な負の相関が認められたが，降水量との間に相関は確認されなかった．一方，ヒノキ科花粉の飛散総数は前年7月の最高気温，平均気温との間にのみ相関が認められた．3)ヒノキ科花粉の飛散総数に影響する，スギ花粉とは異なる気象因子の解明が必要であると考えられた．すなわちヒノキ科花粉の飛散期間は3月下旬から4月下旬でスギ花粉飛散期間よりも約1ヵ月遅かった．尚，両花粉は共通抗原性を持つため，ヒノキ科花粉がスギ花粉症患者の症状遷延化や増悪の一因となっていると考えられた．


Preseasonal prophylactic treatment with antihistamines suppresses nasal symptoms and expression of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis.

Administration of antihistamines 2-4 weeks before the pollen season showed a greater inhibitory effect on nasal allergy symptoms in patients with seasonal allergic rhinitis. However, the mechanism of slow-onset effects of preseasonal treatment with antihistamines remains unclear. Here, we investigated the effect of preseasonal prophylactic treatment with antihistamines on nasal symptoms and the expression of histamine H₁ receptor (H1R) mRNA of the nasal mucosa in patients with cedar pollen pollinosis. During the peak pollen period, the expression of H1R mRNA in the nasal mucosa and the scores of sneezing and watery rhinorrhea in patients receiving preseasonal prophylactic treatment with antihistamines were significantly suppressed in comparison with those in the patients without treatment. Moreover, there was a significant correlation between the nasal symptoms and the expression of H1R mRNA in both patients with or without preseasonal prophylactic treatment. These findings suggest that preseasonal prophylactic treatment with antihistamines is more effective than on-seasonal administration to patients with pollinosis in reducing nasal symptoms during the peak pollen period by suppressing H1R gene expression in the nasal mucosa.

Methods and Findings in Experimental and Clinical Pharmacology


スギ花粉症における初期療法の作用機序の検討

スギ花粉症における初期療法の作用機序の検討


Effects of zinc supplementation on serum zinc concentration and ratio of apo/holo-activities of angiotensin converting enzyme in patients with taste impairment.

OBJECTIVE: The aim of the present study was to evaluate the effects of zinc supplementation on hypogeusia, serum zinc concentration and the ratio of apo/holo-activities of angiotensin converting enzyme (ACE ratio) in patients with taste impairment. ACE ratio was used as an index of zinc nutritional status. METHODS: Forty patients complaining of taste impairment were divided into two groups: zinc deficiency taste impairment (n=12) and idiopathic taste impairment (n=28). Patients with zincemia values of less than 63 microg/dl with no history of other disorder or medication known to cause dysgeusia were diagnosed as zinc deficiency group, while those with the same condition and values more than 64 microg/dl were considered to belong to the idiopathic group. Patients orally received 150 mg of polaprezinc containing 33 mg of zinc every day. Subjective symptom was scored according to visual analogue scale (VAS). RESULTS: Zinc supplementation improved hypogeusia in both idiopathic and zinc deficiency groups. The mean improvements of VAS were 3.02+/-3.03 in the idiopathic group and 3.13+/-2.53 in the zinc deficiency group. Thus, there were no significant differences in idiopathic and zinc deficiency groups. Significant correlations were found between the improvement of VAS score and the ACE ratio after zinc supplementation in both idiopathic and zinc deficiency groups. On the contrary, significant correlations were not found between the improvement of VAS score and the zinc concentration in the serum after zinc supplementation in both groups. CONCLUSION: The results of the present study indicated that zinc deficiency is a predominant factor underlying taste impairment and ACE ratio may be a predictor of the prognosis for taste impairment after zinc supplementation, in addition to a more sensitive indicator of zinc nutrition than zinc concentration in the serum.


Sho-seiryu-to suppresses histamine signaling at the transcriptional level in TDI-sensitized nasal allergy model rats.

BACKGROUND: The therapeutic use of Kampo medicine, Sho-seiryu-to (SST) in allergic disorders is well known. As histamine plays a central role in allergic diseases, it is possible that SST affects the allergy-related histamine signaling. In this study, we investigated the effect of SST on allergy-related histamine signaling in the nasal mucosa of toluene 2, 4-diisocyanate (TDI)-sensitized nasal allergy model rats. METHODS: Six-week-old male, Brown Norway rats were sensitized for 2 weeks with 10 microl of 10% TDI, and after a 1 week interval, provocation was initiated with the same amount of TDI. SST (0.6g/rat) was given orally 1 hour before TDI treatment began for a period of 3 weeks. Nasal symptoms were scored for 10 minutes immediately after TDI-provocation. The genes expression in nasal mucosa was determined using real-time quantitative RT-PCR. RESULTS: SST significantly suppressed TDI-induced nasal allergy-like symptoms. TDI provocation showed a significant up-regulation of histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) gene expressions. Prolonged pre-treatment of SST significantly suppressed the mRNA levels of H1R and HDC that was up-regulated by TDI. SST also suppressed TDI-induced interleukin (IL)-4 and IL-5 mRNA elevation. However, SST showed no significant effect for TDI-induced mRNA elevation of IL-13. CONCLUSIONS: These results demonstrate that SST alleviates nasal symptoms by the inhibition of histamine signaling through suppression of TDI-induced H1R and HDC gene up-regulation. SST also suppresses cytokine signaling through suppression of IL-4 and IL-5 gene expression. Suppression of histamine signaling may be a novel mechanism of SST in preventing allergic diseases.


Suplatast tosilate inhibits histamine signaling by direct and indirect down-regulation of histamine H1 receptor gene expression through suppression of histidine decarboxylase and IL-4 gene transcriptions.

Allergic rhinitis (AR) is an inflammatory disorder typified by symptoms such as sneezing, congestion, and rhinorrhea. Histamine plays important roles in eliciting AR symptoms. Up-regulation of the histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) mRNAs was observed in AR patients. Th2 cytokines are also involved in the pathogenesis of AR. We examined the effect of suplatast tosilate on nasal symptoms, and H1R, HDC, and IL-4 gene expression using toluene-2,4-diisocyanate (TDI)-sensitized rats and HeLa cells expressing endogenous H1R. Provocation with TDI increased nasal symptoms, HDC activity, the histamine content of nasal lavage fluid, and the expression of H1R, HDC, and IL-4 mRNAs in TDI-sensitized rats. Pretreatment with suplatast for 2 wk significantly suppressed TDI-induced nasal symptoms and elevation of H1R, HDC, and IL-4 mRNAs. Suplatast also suppressed HDC activity in the nasal mucosa and the histamine content of the nasal lavage fluid. Bilateral injection of IL-4 into the nasal cavity of normal rats up-regulated H1R mRNA, while intranasal application of histamine up-regulated IL-4 mRNA. Suplatast suppressed IL-4-induced up-regulation of H1R mRNA in HeLa cells. However, it did not inhibit histamine-induced H1R mRNA elevation. These results suggest that suplatast alleviates nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through the suppression of histamine- and IL-4-induced H1R gene expression by the inhibitions of HDC and IL-4 gene transcriptions, respectively.


Effects of hypergravity on histamine H1 receptor mRNA expression in hypothalamus and brainstem of rats: implications for development of motion sickness

The study findings suggest that histamine was released from the axon terminals in the hypothalamus and brainstem and the released histamine activated post-synaptic H1 receptors there, resulting in the development of motion sickness. We first examined which subtype of post-synaptic histaminergic receptor was responsible for the development of motion sickness. We then examined whether H1 receptors were up-regulated in various areas of the rat brain after 2 G hypergravity load, because the stimulation of H1 receptor was reported to up-regulate the level of H1 receptor protein expression through augmentation of H1 receptor mRNA expression. For this purpose, we used an animal model of motion sickness, using pica (eating non-nutritive substances such as kaolin), as a behavioral index in rats. After 2 G hypergravity load, rats ate a significant amount of kaolin, indicating that they suffered from motion sickness. The hypergravity-induced kaolin intake was suppressed by mepyramine, but not by terfinadine or zolantizine. This finding indicates that cerebral post-synaptic H1 but not H2 or peripheral H1 receptors play an important role in the development of motion sickness. The expression of H1 receptor mRNA was up-regulated in the hypothalamus and brainstem, but not in the cerebral cortex after 2 G hypergravity load in rats.


We report a case of Bow hunters stroke with the complaint of cervical vertigo. A 48-year-old man complained of cervical vertigo following head rotation to the left. He showed positional nystagmus when his head was rotated to the left in the supine position and, if the head rotation was maintained, he felt a gradual drop into unconsciousness. The positional nystagmus and fainting were not, however, induced in the patient in the left lateral decubitus position without head rotation. Three-dimensional analysis of his positional nystagmus showed its inconsistent rotational axis, which is different from the single rotational axis in patients with peripheral positional nystagmus. These findings suggested the central cervical positional vertigo/nystagmus in the patients. MRI showed an old infarction of the left cerebellum and MRA showed severe hypoplasia of the left vertebral artery. Vertebral angiography showed severe stenosis of the left vertebral artery and the mechanical occlusion of the right vertebral artery by the atlas-axis joint at C1-C2 when the patients head was rotated to the left. Therefore, it is demonstrated that his positional vertigo/nystagmus with fainting caused by head rotation to the left was induced by the vertebrobasilar insufficiency due to mechanical occlusion of the vertebral artery associated with head rotation, resulting in the diagnosis of Bow hunters stroke in this patient.


鼻過敏症モデルおけるヒスタミンH1受容体発現上昇機構とその制御について

鼻過敏症モデルおけるヒスタミンH1受容体発現上昇機構とその制御について


Two cases of invasive aspergillus sinusitis and mastoiditis successfully treated with voriconazole

ボリコナゾールが著効した副鼻腔と中耳の侵襲性アスペルギルス症例

We report two cases of invasive aspergillosis of the head and neck regions. One patient was a 56-year-old male with invasive aspergillus sinusitis. The other patient was a 14-year-old boy with aspergillus mastoiditis after bone-marrow transplantation. Both cases were inoperable because of vascular invasion by aspergillus, and treatment with antifungal agents was discontinued due to severe side effects. A novel triazole voriconazole (VRCZ) was then used for salvage therapy and successfully treated invasive aspergillosis in both cases. VRCZ is an effective and well tolerated agent to treat invasive aspergillosis of the head and neck regions.


Stimulation of histamine H1 receptor up-regulates histamine H1 receptor itself through activation of receptor gene transcription.

Histamine is a major mediator in allergy acting mainly through the histamine H(1) receptor (H1R). Although H1R up-regulation has been suggested as an important step for induction of allergic symptoms, little is known about the regulation of H1R level. Here we report that the activation of H1R up-regulates H1R through augmentation of H1R mRNA expression in HeLa cells. Histamine stimulation significantly increased both H1R promoter activity and mRNA level without alteration in mRNA stability. H1R protein was also up-regulated by histamine. An H1R antagonist but not histamine H(2) receptor antagonist blocked histamine-induced up-regulation of both promoter activity and mRNA expression. A protein kinase C (PKC) activator, phorbol-12-myristate-13-acetate, increased H1R mRNA expression, whereas an activator of PKA or PKG (8-Br-cAMP or 8-Br-cGMP, respectively) did not. Furthermore, histamine-induced up-regulation of both promoter activity and mRNA level were completely suppressed by the PKC inhibitor Ro-31-8220. H1R antagonists have long been thought to block H1R and inhibit immediate allergy symptoms. In addition to this short-term effect, our data propose their long-term inhibitory effect against allergic diseases by suppressing PKC-mediated H1R gene transcription. This finding provides new insights into the therapeutic target of H1R antagonist in allergic diseases.


The Usefulness of FDG-PET in Diagnosing Head and Neck Cancer : Report of Four Cases

頭頸部癌の診断にFDG-PETが有用であった4例

FDG-PET (2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography) is clinically useful in detecting head and neck cancer providing accurate estimate of primary cancer and metastasis lymph node especially in cancers that are equivocal on conventional imaging. FDG-PET scan shows unknown primary cancer and metastatic lymph nodes that appear normal CT scan/or MRI. Furthmore, whole body FDG-PET makes it possible to simultaneously detect distant metastasis.We reported 4 cases of head and neck cancer and showed the efficacy of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the diagnosis of head and neck cancer. FDG-PET is highly useful for detecting previously unrecognized primary cancer with lymph node metastasis to the neck. FDG-PET also has a high potential for detecting neck lymph node metastasis, staging head and neck cancer and assessing its response to irradiation and chemotherapy. Finally, FDG-PET is useful for diagnosing recurrent or residual head and neck cancer and its distant metastasis.


Dexamethasone suppresses histamine synthesis by repressing both transcription and activity of HDC in allergic rats.

BACKGROUND: Histamine synthesized by histidine decarboxylase (HDC) from L-histidine is a major chemical mediator in the development of nasal allergy which is characterized by nasal hypersensitivity. However the regulatory mechanism of histamine synthesis by HDC remains to be elucidated. The objectives of the present study were to examine the changes of histamine content, HDC activity and HDC mRNA expression in the nasal mucosa of allergy model rats sensitized by the exposure to toluene diisocyanate (TDI) and to investigate the effect of dexamethasone on the above mentioned allergic parameters. METHODS: Rats were sensitized and provocated by TDI and the nasal allergy-like behaviors were scored during a 10 minute period after provocation. Histamine content and HDC activity in the nasal mucosa were determined using fluorometric high performance liquid chromatography. The expression of HDC mRNA in nasal mucosa was determined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In TDI-sensitized rats, nasal allergy-like behaviors such as sneezing and watery rhinorrhea were induced. Histamine content, HDC activity and HDC mRNA expression in nasal mucosa were also significantly increased after TDI provocation. Pretreatment with dexamethasone significantly suppressed nasal allergy-like behaviors, up-regulation of histamine content, HDC activity and HDC mRNA induced by TDI in TDI-sensitized rats. CONCLUSIONS: These findings indicate that increased synthesis of histamine through up-regulation of HDC gene expression and HDC activity in nasal mucosa plays an important role in the development of nasal hypersensitivity. Repression of HDC gene expression and HDC activity by dexamethasone may underlie its therapeutic effect in the treatment of allergy.


Zinc nutrition in healthy subjects and patients with taste impairment from the view point of zinc ingestion, serum zinc concentration and angiotensin converting enzyme activity.

To estimate the zinc nutrition in healthy subjects and patients with taste impairment. Dietary zinc intake, zinc concentration in the serum and the ratio of apo/holo-activities of angiotensin converting enzyme (ACE), a zinc dependent enzyme in the serum (ACE ratio) were used as indices. Healthy paramedical volunteers from a local hospital and patients with taste impairment seen in the Department of Otolaryngology, Tokushima University Hospital. Dietary zinc intake was estimated with the food frequency questionnaire (FFQ). Zinc concentration in the serum was measured by means of atomic absorption spectrometry. The ACE activity in the serum was measured spectrophotometrically as the activity of holo-ACE, which contains zinc and shows full ACE activity. The activity of apo-ACE, which dose not contain zinc, was determined as the increase of its activity over that of the initial holo-ACE activity after the addition of zinc to the serum in vitro. ACE ratio was used as a more sensitive indicator of zinc nutrition than measuring zinc concentration in the serum. There were no differences in dietary intake of zinc after adjusting for energy and zinc concentration in the serum between patients and age-adjusted healthy subjects. The ACE ratio in patients with taste impairment was significantly higher than that in age-adjusted healthy subjects (P<0.05). Our date demonstrate that zinc deficiency is a predominant factor underlying taste impairment and we hypothesize that patients with taste impairment may have malabsorption of dietary zinc.


Effect of glucocorticoid on upregulation of histamine H1 receptor mRNA in nasal mucosa of rats sensitized by exposure to toluene diisocyanate.

OBJECTIVE: Histamine is a major chemical mediator in the development of nasal allergy, which is characterized by nasal hypersensitivity. In this study, we used rats sensitized by exposure to toluene diisocyanate (TDI) as an animal model of nasal hypersensitivity and examined changes in expression of histamine H1 receptor (H1R) in the nasal mucosa. The effect of glucocorticoid on upregulation of H1R in nasal mucosa induced by TDI was also examined. MATERIAL AND METHODS: In rats sensitized by exposure to TDI, nasal allergy-like behavior was scored during a 10-min period after TDI provocation. The expression of H1R in the nasal mucosa was determined by means of a real-time quantitative reverse transcriptase polymerase chain reaction and a [3H]mepyramine binding assay. RESULTS: In TDI-sensitized rats, nasal allergy-like behavior, such as sneezing and watery rhinorrhea, was induced after intranasal application of TDI and nasal hypersensitivity to histamine was significantly increased. The level of H1R mRNA expression and the specific binding of [3H]mepyramine in the nasal mucosa were significantly increased after intranasal application of TDI in TDI-sensitized rats. Pretreatment with dexamethasone significantly reduced both nasal allergy-like behavior and the upregulation of H1R induced by TDI in the rats. CONCLUSION: As shown in TDI-sensitized rats, our findings suggest that the upregulation of H1R in the nasal mucosa is one of the mechanisms responsible for nasal hypersensitivity behavior and nasal hypersensitivity to histamine and that the therapeutic effects of dexamethasone are, in part, due to its inhibitory action on the upregulation of H1R.


Up-regulation of histamine H1 receptors in an allergic rat nasal mucosa model


Increase in the level of histidine decarboxylase mRNA expression in nasal mucosa of rats sensitized by toluene diisocyanate