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STAM-binding protein, STAMBP, is a JAMM-family deubiquitinating enzyme containing the microtubule-interacting/transport domain and STAM-binding domain. Although the biological importance of STAMBP in development has been recognized because the microcephaly-capillary malformation syndrome in human is caused by its somatic mutations, the role of STAMBP in cancer has not yet been determined. In this study, we demonstrate that STAMBP is a key molecule for regulating melanoma migration and invasion, but not survival, by knocking down STAMBP in vitro. STAMBP regulates SLUG expression through a post-transcriptional mechanism to control protein stability and further contributes to the in vivo metastatic potential of melanoma. Collectively, these results indicate the importance of STAMBP in melanoma metastasis by regulating SLUG. It is therefore a potential therapeutic target.

Cancer metastasis is a major cause of mortality in cancer patients. The transcription factor SNAIL plays an important role in cancer metastasis and progression, and its expression is tightly regulated by the ubiquitin-proteasome system through the balance between ubiquitin ligases and deubiquitinating enzymes. While several ubiquitin ligases of SNAIL have been identified, it is not yet clear regarding deubiquitinating enzyme. In this study, we identified COP9 signalosome subunit 5 (COPS5) as a deubiquitinating enzyme of SNAIL by using siRNA library screening. COPS5 downregulation significantly reduced the expression of SNAIL and impaired the metastatic potential of lung cancer cells both in vitro and in vivo. Importantly, we demonstrated that COPS5 binds to SNAIL and stabilizes its expression by deubiquitination. Furthermore, we observed the positive correlation between COPS5 and SNAIL expression in the clinical tissue samples of lung adenocarcinomas by using tissue microarray analysis. These findings provide strong evidence that COPS5 can be a new therapeutic target for cancer metastasis as a deubiquitinating enzyme of SNAIL.

Research on drug metabolism and pharmacokinetics in large animal species including the horse is scarce because of the challenges in conducting in vivo studies. The metabolic reactions catalyzed by cytochrome P450s (CYPs) are central to drug pharmacokinetics. This study elucidated the characteristics of equine CYPs using diazepam (DZP) as a model compound as this drug is widely used as an anesthetic and sedative in horses, and is principally metabolized by CYPs. Diazepam metabolic activities were measured in vitro using horse and rat liver microsomes to clarify the species differences in enzyme kinetic parameters of each metabolite (temazepam [TMZ], nordiazepam [NDZ], p-hydroxydiazepam [p-OH-DZP], and oxazepam [OXZ]). In both species microsomes, TMZ was the major metabolite, but the formation rate of p-OH-DZP was significantly less in the horse. Inhibition assays with a CYP-specific inhibitors and antibody suggested that CYP3A was the main enzyme responsible for DZP metabolism in horse. Four recombinant equine CYP3A isoforms expressed in Cos-7 cells showed that CYP3A96, CYP3A94, and CYP3A89 were important for TMZ formation, whereas CYP3A97 exhibited more limited activity. Phylogenetic analysis suggested diversification of CYP3As in each mammalian order. Further study is needed to elucidate functional characteristics of each equine CYP3A isoform for effective use of diazepam in horses.

To examine the effect of Babesia infection on the level of the drug-metabolizing enzyme hepatic cytochrome P450 (CYP) 2D, we intraperitoneally inoculated Babesia microti into male ICR mice. CYP2D protein and CYP2D9 mRNA were significantly decreased at 12 days after infection with B. microti. The activity of bunitrolol 4-hydroxylase, which is catalyzed by CYP2D, was also significantly decreased. The mRNA levels of transcriptional regulators of CYP2D9, hepatocyte nuclear factor 4α and signal transducer and activator of transcription 5b, were markedly suppressed. These results suggest that Babesia infection represses CYP2D expression in the mouse liver. The decline in CYP2D-dependent drug metabolism might be involved in the incidence of adverse drug reactions in patients with babesiosis.

OBJECTIVE Three-dimensional analysis of video-oculograms can be used to calculate Listing plane for patients and experimental subjects. Listing plane reflects the head's orientation with respect to gravity, which suggests that the plane is derived from otolithic vestibular input, itself, or from a gravity-oriented internal model constructed through integration of visual, vestibular, and proprioceptive sensory inputs. The goal of this study was to determine whether the Listing plane can serve as a parameter for evaluating static (peripheral or central) vestibular function. STUDY DESIGN Prospective study. SETTING Tertiary referral center. PATIENTS Healthy subjects and patients with unilateral vestibular schwannoma without any previous treatment. INTERVENTION Diagnostic. MAIN OUTCOME MEASURES Video-oculograms were recorded from healthy subjects (aged 36.8 ± 6.3 yr) and from patients (aged 60.3 ± 7.5 yr) during voluntary gaze with the head in an upright or each-side-down orientation, and the thicknesses of the calculated Listing planes were then compared. RESULTS Results revealed thickening of the Listing plane in patients only when the head was in an impaired-side-down orientation (1.250 ± 0.795 and 1.074 ± 0.759 degrees in the right- and left-side-down head orientations in healthy subjects versus 2.222 ± 1.237 degrees in the impaired-side-down orientation in patients), and this thickening correlated with caloric weakness. By contrast, neither the sensation of postural instability nor postural disturbance in force platform recordings contributed to the thickness of Listing plane. CONCLUSION The thickness of the Listing plane could be a novel parameter for quantitatively evaluating static vestibular (otolithic) function, although central compensation might exist.

Warfarin, a coumarin rodenticide, is commonly used worldwide for rodent control, and is often reported as the cause for poisoning accidents in nontarget animals, in particular bird species. However, the metabolism of warfarin in birds is still unclear. In a previous study, we found an unknown warfarin metabolite in chicken cytosolic fractions. In the present study, we aimed to clarify the cytosolic warfarin metabolites in chickens compared with those in rats. The cytosol fractions of both chicken and rat livers showed the metabolic activity of 2 diastereomers and 2 enantiomers of warfarin alcohol. In chicken cytosol, we found that the production level of (S)-warfarin-(S)-alcohol was markedly higher (32-fold) than that in rat cytosol. From the results of the inhibition assay, we finally suggest that aldehyde oxidase may mainly contribute to the warfarin alcohol products in chicken cytosol.

Seventeen limonoids (tetranortriterpenoids 1-17) were isolated from the n-hexane extract of Azadirachta indica (neem) seeds. The previously unidentified compound 16 was established by spectroscopy to be 17-defurano-17-oxosalannin. The effects of six compounds, 6 and 11-15, on melanogenesis in B16 melanoma cells was evaluated; 2 compounds, salannin (13) and 3-deacetylsalannin (15), exhibited marked inhibitory effects (70-74% reduction of melanin content at 25 µg/mL) with only minor cytotoxicity (79-85% of cell viability). Eleven compounds, 2, 3, 5, 6, and 9-15, were evaluated for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1.7 nmol/ear) in mice; all exhibited marked anti-inflammatory activity (ID(50) values 0.22-0.57 µmol/ear). In addition, compounds 6 and 11-16 exerted moderate inhibition (IC(50) values of 410-471 mol ratio/32 pmol TPA) of TPA-induced Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells. The triacylglycerol fraction of the n-hexane extract contained oleic acid (50.2%) as the most predominant fatty acid constituent.

A new iridoid glycoside, 9-epi-6alpha-methoxy geniposidic acid (4), three new hemiterpene glycosides, 3-methylbut-3-enyl 2'-O-(beta-D-glucopyranosyl)-beta-D-glucopyranoside (nonioside K) (6), 3-methylbut-3-enyl 6'-O-(beta-D-xylopyranosyl)-beta-D-glucopyranoside (nonioside L) (8), and 3-methylbut-3-enyl 6'-O-(beta-D-xylofuranosyl)-beta-D-glucopyranoside (nonioside M) (9), and two new saccharide fatty acid esters, 6'-O-(beta-D-glucopyranosyl)-1'-O-[(2xi)-2-methylbutanoyl]-beta-D-glucopyranose (nonioside N) (16) and 6'-O-(beta-D-xylopyranosyl)-1'-O-[(2xi)-2-methylbutanoyl]-beta-D-glucopyranose (nonioside O) (17), were isolated from a methanol extract of the fruits of Morinda citrifolia (noni), along with 11 known compounds, namely, three iridoid glycosides (1-3), two hemiterpene glycosides (5 and 7), and five saccharide fatty acid esters (10-15). Upon evaluation of compounds 1-17 on the melanogenesis in the B16 melanoma cells induced with alpha-melanocyte-stimulating hormone (alpha-MSH), 13 compounds (1, 3, 4, 6-14, and 17) exhibited marked inhibitory effects with 34-49% reduction of melanin content at 100 muM with no or almost no toxicity to the cells (91-116% of cell viability at 100 microM).

胃酸による食道外の粘膜上皮障害の機序をより明らかにするため，摘出モルモット気管上皮の初代培養細胞を作成し，上皮膜抵抗を測定することで酸による電気的バリアの変化を検索した。塩酸を頂膜側より投与しpHを徐々に変化させると，pH 3より上皮膜抵抗は低下し，初代培養気管粘膜上皮細胞の電気的バリアのdown regulationが有意に認められた。培養液中にプロトンポンプインヒビターであるランソプラゾールを投与していた群では，pHを変化させても，上皮膜抵抗の有意な変動はみられなかった。この細胞の上皮膜抵抗が，どの因子から構成されているかの手がかりを得るため，代表的なイオンチャネルであるクロライドイオンおよびナトリウムイオンチャネルのブロッカーを頂膜側より順次投与し，上皮膜抵抗を測定した。それぞれ，上皮膜抵抗の有意な上昇効果をきたしたが，これらの効果はランソプラゾール投与群，非投与群との間では，有意な差を認めなかった。また，その後，酸を投与したところ，上皮膜抵抗は減少した。これらの結果から，酸暴露により，気道上皮の電気的バリアの破綻が惹起されることが示され，この反応は一部上皮の頂膜側のイオンチャネルを介していることが示唆された。また，プロトンポンプインヒビター投与は，酸暴露時の電気的バリアの障害を部分的に防止する効果を持つ可能性が証明された。

The first case of oncocytic carcinoma which arose from the inferior turbinate of the nasal cavity with orbital invasion through the nasolacrimal canal and widespread lymph node metastases in the neck and face is reported here. The tumor metastasized rapidly, spread widely to the whole neck and face, and produced tumor emboli in the lymphatics and extranodal extension by rupture of the lymph node capsule in the absence of clinically palpable regional lymph node enlargement. We think the oncocytic carcinoma of the nasal cavity may be a high-grade malignancy tumor.

When the cochleas of guinea pigs were fixed after decapitation, HRP leakage from the strial capillaries was observed with blood sludge. HRP was transported to the extracapillary space by many pinocytotic vesicles and marginal folds. However, when the cochleas were fixed before decapitation, blood sludge was not observed in the strial capillaries and leakage of HRP from the capillaries was not observed 10 minutes after HRP injection. Thereafter, the level of HRP leakage increased with time. It was noted that capillary permeability to HRP at the basal turn was lower than that of the upper three turns. HRP leakage was not observed in the capillaries of the spiral ligament even beyond one hour after injection.As a result of severe hemorrhagic shock in guinea pigs, blood sludge appeared in strial capillaries and capillary permeability to HRP increased. However, in moderate hemorrhagic shock, both blood sludge and accentuation of capillary permeability did not occur.After the inoculation of endotoxin in the middle ear, a large amount of HRP leaked out of the capillaries through the opened endothelial cell junctions.After vibration administered to auditory ossicle is by a drill, the permeability of the strial capillaries to HRP also increased. High permeability was thought to be caused by damage to the strial endothelial cells. HRP leakage initially took place through the tubules in the endothelial cytoplasm, and HRP leaked in to the extracapillary space when the cell membranes were damaged by vibration. Administration of the steroid inhibited HRP leakage from the strial capillaries.The stria vascularis became markedly edematous after the administration of furosemide, while capillary permeability to HRP was decreased.From the above, the route of HRP leakage is different depending on the type of stimulation, even if it occurs alongside increased capillary permeability.

Objective The effect of tonicity changes in nebulizer solutions and irrigations on nasal mucosa is not well known. The present study aims to determine the basic mechanism of hypertonic solution on airway epithelial barrier. Study design and setting We investigated the electrical potential difference (PD) that is influenced by both active transport and the transepithelial electrical resistance of the epithelial mucosa in the human nose in vivo. The short circuit current (SCC) revealed net ion transport across the epithelium in the guinea pig trachea in vitro. Finally, the size dependency of macromolecules across the tracheal mucosa was determined in vitro using FITC-labeled dextrans of different sizes. Results PD was significantly decreased after topical application of hypertonic solution both in human and in guinea pig nose. SCC was significantly decreased after application of hypertonic solution. The transport of these dextrans from the basolateral to the apical side was not increased significantly after apical application of hypertonic saline. Conclusions Hypertonic saline enhances the electrical permeability of the airway epithelial mucosa but not transport of macromolecule in the short term.

Recently, solitary fibrous tumors (SFTs) have been reported in the head and neck area, such as the nasal cavity, thyroid, salivary gland, etc. We present a rare case of SFT which arose from the sphenoethmoidal recess of the nasal cavity, penetrating into the sphenoid sinus, and which showed different intensities on magnetic resonance imaging (MRI) according to the occupied locations. T2 weighted magnetic resonance (MR) images showed low intensity in the nasal cavity, and iso-intensity in the sphenoid sinus. Enhancement with gadolinium contrast on T1-weighted images was more remarkable in the sphenoid sinus than in the nasal cavity. While the tumor in the nasal cavity showed abundant collagen and high cellularity in microscopic examination, numerous small vessels and dilated vascular spaces were remarkable in the tumor of the sphenoid sinus. MRI findings corresponded to pathological findings. We review SFTs in the head and neck area in the English literature.

(Background) Ramatroban, which is a thromboxane A2 receptor antagonist, has been demonstrated to improve nasal obstruction. Ramatroban was reported to suppress eosinophil aggregation in the nasal mucous membranes. In this study, we investigated whether ramatroban has an effect on the symptoms of allergic rhinitis and action on eosinophil.(Method) In the present study, ramatroban was administered for one month to 20 patients with perennial allergic rhinitis that was otherwise untreated. We assessed RAST scores, ECP in serum and nasal discharge, the total number of eosinophils and the rate of necrosis in nasal discharge, the number of eosinophils in blood, and changes in self-reported symptom scores after treatment with ramatroban.(Result) After one month of treatment, all three of the major symptoms, sneezing, rhinorrhea and nasal obstruction had clearly decreased. Significant difference in RAST scores was observed after treatment with ramatroban. The amount of eosinophils in nasal discharge did not significantly differ after treatment with ramatroban, but the rate of necrosis of eosinophils was decreased.(Conclusion) All nasal symptoms were improved. Nevertheless, the amount of eosinophils in nasal discharge did not significantly differ, although the rate of necrosis of eosinophils was decreased. This study suggests that ramatroban contributed to preventing local necrosis of eosinophils.

Nasal mucus was sampled from nine patients of left nostrils with nasal allergy and lavaged fluid was taken from right nostrils. The mucuses were observed by electron microscope and ECP in lavage fluid was examined. ECP in lavage fluid and destruction index (granule vacuolation score×destruction score of eosinophil cell membrane) showed high correlation (R=0.988, p It was concluded that EOP in nasal mucus was released from lysed eosinophiles with destroyed cell membrane.

Input/output (I/O) curves of evoked otoacoustic emissions (EOAEs) reveal a saturation at 30 dB or thereabout above their detection threshold. It has been suggested that such I/O relation corresponds to that of the basilar membrane vibration related with an active electro-mechanical process of outer hair cells. EOAEs in response to 1–2 kHz short tone bursts were measured. EOAEs were examined in ears with idiopathic sudden hearing loss (HL), low tone type acute sensorineural HL, Meniere's disease and noise-induced HL. Three types of shift that were downward, horizontal and combined were observed in their I/O curves. The downward shift was seen mainly in the ears with high tone HL and the horizontal shift was in the ears with low tone HL. Three types of shift were observed in the ears of Meniere's disease, in which glycerol administration augmented EOAE amplitude beyond the normal saturation level of its cotralateral side. Measurements of EOAE I/O curves are useful for diagnosis of inner ear impairments related to outer hair cell dysfunction in ears with sensorineural HL.

It is still unknown how eosinophils degranulate in nasal mucus. Currently, cytolysis is being reevaluated as the mode of degranulation of eosinophils in allergic nasal mucosa. To examine whether eosinophils migrating to the nasal mucus degranulate by cytolysis, we sampled nasal mucus from 9 patients with nasal allergy and observed it under electron and light microscopes. Both intact and necrotic eosinophils were observed in the nasal mucus. Although the total eosinophil count in the nasal mucus was not correlated with the frequency of sneezes, there was a significant correlation (p = .0025) between the rate of eosinophil lysis and the frequency of sneezes. Whereas extracellular release of eosinophil peroxidase was not detected from the eosinophils with intact cell membranes, large quantities of eosinophil peroxidase were found outside the eosinophils with injured cell membranes. We concluded that eosinophils migrating to the nasal mucus degranulate mainly by cytolysis, and that granular proteins released from the necrotic eosinophils into the nasal mucus are one of the important factors causing hypersensitivity in the nasal mucosa.

In this study we examined 310 patients with sudden deafness treated in our hospital between 1996 and 2001. Seventy-one patients were treated with steroid only (steroid group), 130 patients were treated with steroid and Lipo-PGE1 combined therapy (steroid-LipoPGE1 group) and 53 patients were treated with Lipo-PGE1 only (LipoPGE1 group).The improvement rate was 39.4, 67.7 and 81.1% in the steroid, steroid-LipoPGE1 and LipoPGE1 groups, respectively. The improvement rate was significantly higher in the steroid-LipoPGE1 and LipoPGE1 groups than in the steroid group (p

A seventy-five-year-old man consulted our clinic, complaining of a rapidly enlarging mass in the left neck arising over the past one month. A hard tumor in the left thyroid lobe and tumor in the left posterior neck were palpated. CT and MRI showed tumor of the left lobe expanding into the thorax and an isolated mass in the left neck. Thyroid function was normal and there were no other general symptom noted.Malignant thyroid tumor and metastatic lymph nodes were preoperatively diagnosed. Therefore, left thyroid lobectomy and neck mass exenteration were performed. Pathological diagnosis with Congo red dye established amyloid goiter without malignant cell. Rectal biopsy postoperatively was also positive for amyloid.This case was thought to be primary amyloid goiter with general extension, and the type of amyloid was AA. The patient's postoperative course has been good without mass recurrence.Pathological diagnosis of thyroid mass has been very varied, but amyloid goiter seems to be underestimated because of its rare incidence. Amyloid goiter tends to rapidly enlarge and becomes hard in some case. Preoperative distinguishing between malignant tumor and amyloid goiter might be clinically very difficult.Many amyloid goiters have a good prognosis without serious symptoms, but goiter may sometimes be fatal due to cardiac failure. Therefore, amyloid goiter should be carefully observed postoperatively.

Computer-aided navigation in otolaryngology has been used mainly for nasal operation and rarely for ear surgery. The reason for its limited use in ear surgery appears to be that microscopic observation may be sufficient in most cases of ear surgery. We report a case of congenital cholesteatoma at the petrous apex operated on using navigation. A 65-year-old man with facial palsy, deafness, and canal paresis in caloric test on the left ear was found in preoperative computed tomograph (CT) showed a large mass at the apex with an expansively eroded skull base and inner ear. Navigation used for the operation was magnetic (Insta Trak). A probe 3.2 mm in diameter was moved in the operative field and 3 axial CTs were simultaneously monitored on a workstation to show the tip location. With this image-guided system, cholesteatoma was thoroughly and safely removed. We concluded that navigation should be used for safe surgery, especially in ear surgery at the petrous apex, because anatomical identification is very easy and damage to vital areas around the inner ear, nerve, brain, and internal carotid artery could be avoided.

We produced drill-induced damage of the auditory ossicles of guinea pigs to study changes over time in the permeability of the blood vessels of the stria vascularis to horseradish peroxidase (HRP). In group A, the stimulus was applied for 10 seconds after intravenous injection of HRP In group B, it was applied for 30 seconds, and in group C, for 60 seconds. The cochlea was fixed with 2% glutaraldehyde perfused through the round window, and the guinea pigs were then decapitated. The stria vascularis of the basal and third turns was examined. The leakage of HRP from the blood vessels of the stria vascularis significantly increased in relation to the duration of the stimulus in both the basal and third turns. The damage to intermediate cells also tended to be in relation to the duration of the stimulus. Extravascular permeation of HRP took place through the tubules in the endothelial cytoplasm. The vibratory stimulation presumably opened channels that are not normally open.

The aim of this study was to investigate the efficacy of suplatast tosilate prescribed before the pollen season and during the pollen season. Suplatast tosilate, 300mg/day, was prescribed for 10 patients before the start of the pollen season and for 6 patients during the pollen season. Patients kept a diary of nasal symptoms.Based on the nasal symptom diaries a nasal symptom score was prepared. The rate of improvement was 70% with preseasonal administration and 33% with administration after pollen scattering.Pollen levels showed three peaks (3/5, 3/14, 3/29) during the pollen season in 1998, and in the preseasonal administration, the symptoms were suppressed at these three peakses pecially at third peak in 70% of patients.In the administration during pollen season, the symptom score was high at second and third peaks in the noneffective patient, but the symptoms were suppressed at the second and third peaks in the effective patients.Based on these findings we suggest that suplatast tosilate should be administered more than one month before the first peak in pollen levels.

Azunol® ST contains 5mg water soluble Azunol in one tablet, and in this study Azunol® ST was administered into the nasal cavity of 67 patient (nasal group) and into the labiogingival region of the upper jaw in 47 patients (oral group) with common cold in the early stage and the effects were compared to non-administration in 111 patients (control group). In all patients in the nasal and oral groups, one tablet was given before bed. The following results were obtained:1) The rate of desease of common cold did not significantly differ among the three groups. (x2 test)2) In the nasal and oral groups, the rate of preventing progression was higher than in the control group (P

突発性難聴および低音障害型急性感音難聴における内耳病態を機能的に追究するために, それらの患耳から測定した誘発耳音響放射の入出力曲線を検討した。 検出閾値の上昇と共に飽和レベルが低下した。 2型の低下パターン, すなわち截頭型と平行移動型が認められ, 前者は高・中音域障害の突発性難聴耳に多く, 後者は低音障害耳に多かった。 平行移動型に回復例が多かったが, 飽和パターンは予後の推測因子として十分とはいえなかった。 誘発耳音響放射の入出力曲線の飽和レベルは外有毛細胞に連係した能動的基底板振動を表現しており, 感音難聴耳で入出力曲線の変化の推移を観察することにより蝸牛内障害の細別診断が可能である。

内耳障害に起因すると考えられる急性感音難聴耳の誘発耳音響放射 (EOAE) 記録において, 遅成分と速成分の検出閾値差は予後の推測に役立つことが示唆されてきた。純音聴力レベル4分法平均値55dB以下の低音障害型急性感音難聴と突発性難聴のEOAEを比較検討すると両者の遅成分検出閾値は共に聴力レベルと有意な相関を示した。聴力レベル30dB以下の両疾患非回復群のEOAE検出閾値では遅成分から速成分を差し引いた値が負を呈することは極めて稀であった。EOAE検出閾値の遅成分-速成分の値の正負は予後判断に有用な指標であるといえる。

Escherichia coli-derived endotoxin was inoculated in the middle ear of guinea pigs 24 hours after being injected intraperitoneally. Twenty-four hours after the middle ear inoculation, horseradish peroxidase (HRP) was injected via the femoral vein and the permeability of HRP through the capillaries of the stria vascularis and the destination of the leaked HRP were examined. A large amount of HRP leaked out of the capillary through the opened endothelial cell junctions and penetrated the enlarged intercellular spaces. Leaked HRP entered the pinocytotic vesicles of the intermediate cells. Even slightly degenerated intermediate cells retained this function. The HRP penetrated the spongelike structure of the marginal cells leading to the intercellular space. This structure was not observed without endotoxin. The HRP could not pass to the cochlear duct through the tight junctions between marginal cells. Blood sludging was observed in the strial capillaries. It appeared more frequently in the upper three turns than in the basal turn. The HRP leakage out of the capillaries was observed not only in the upper three turns but also in the basal turn.

Guinea pigs weighing 350 g each were used in this experiment. A small piece of Gelform containing 0.04 mg of E. coli derived endotoxin was set on the round window 24 hours after intraperitoneal injection of 0.02 mg endotoxin. Morphological changes in the cochlea were observed at 24 hours (previous report), 48 hours, 72 hours and 7 days after the introduction of the endotoxin into the middle ear. As the results of the morphological changes of cochlea at 24 hours after the introduction of the endotoxin were reported in previous paper we present only an outline of these. Inflammatory cell infiltration and bleeding were observed in both endolymphatic and perilymphatic spaces. Inflammatory cells also infiltrated the stria vascularis, spiral ligament, spiral prominence and organ of Corti. Almost all of the inflammatory cells were neutrophils. Blood sludge was observed in all of the strial capillaries of the upper three turns. The hair cells were intact in every turn except for having small vacuoles. Intermediate cells and marginal cells of the stria vascularis were shrunken. At 48 hours after the introduction of the endotoxin into the middle ear, the changes in the stria vascularis were almost the same as at 24 hours. However the infiltrated inflammatory cells changed from neutrophils to macrophages. Macrophages had phagocytosed many neutrophils. The hair cells had many large vacuoles. At 72 hours, the enlargement of the intercellular space in the stria vascularis disappeared and damage to the hair cells decreased although many macrophages were still observed. At 7 days, the cochlea was morphologically normal.

Escherichia coli-derived endotoxin was introduced into the middle ears of 10 guinea pigs 24 hr after intraperitoneal injection of the same endotoxin. The cochleae were removed 24 hr after the introduction of the endotoxin into the middle ears and observed by light and electron microscopy. Inflammatory cell infitration and bleeding were observed in both endolymphatic and perilymphatic spaces. Inflammatory cells also infiltrated the stria vascularis, spiral ligament, spiral prominence and the organ of Corti. Blood sludge was observed in almost all of the strial capillaries of the upper three turns, but in few of the basal turns. The hair cells were intact in every turn except for a small number of degenerated mitochondria. Intermediate cells of the stria vascularis were shrunken, and some of them showed degenerative changes. Marginal cells had also shrunken, but they were less shrunken than the intermediate cells. The shrinking of both cells caused the enlargement of the intercellular space of the stria vascularis.

This study concerned the way in which eosinophils adhere to their surroundings. Many fibrils were seen to adhere to the cell membrane of eosinophils migrating into the submucosa. Those eosinophils migrating into the epithelial layer adhered to the epithelial cells in 2 different ways: through the thin filaments bridging 2 cells and at the top of the cell projections. Eosinophils were found to move chemotactically through this eosinophil adhesion to the surrounding filaments or epithelial cells. It is possible that eosinophil granular protein directly affected the epithelial cells as a regulatory agent of the expression of adhesion molecules on individual epithelial cells, because eosinophil peroxidase was detected in the filaments bridging 2 cells. Accordingly, the expression sites of adhesion molecules must momentarily change under the direct cross-talk between 2 cells. Adherence between the eosinophils as well as large particles stretching between 2 eosinophils were also visualized.

Objectives: Bacteria and viruses are rarely isolated from the middle ear fluid in cases of otitis media with effusion (OME). However, since endotoxins are often detected in such effusions, it is suspected that patients with OME have a previous history of gram-negative infection. Recently, fungi have drawn attention as microorganisms that cause chronic sinusitis. We investigated the involvement of fungi in the formation of middle ear effusions of patients with OME and eosinophilic otitis media, in which patients have viscous middle ear effusions and a history of adult bronchial asthma indicating definite involvement of eosinophils. Methods: Middle ear effusions and nasal secretions were collected from patients with eosinophilic otitis media (7 patients) or OME (12 patients), and smears were prepared for methenamine silver staining. The remaining specimens were embedded in Epon and stained with toluidine blue for observation under a light microscope, and ultrathin sections were prepared for examination under an electron microscope. Results: Fungal hyphae were detected in the middle ear fluid in all of the patients with eosinophilic otitis media or OME. Charcot-Leyden crystals (CLCs) were observed in 6 of the 7 patients with eosinophilic otitis media. In regard to the findings in the nasal secretions, fungal hyphae were also detected in the nasal secretions of all patients, whereas CLCs were detected in only 1 patient with eosinophilic otitis media. Conclusions: It was clarified by use of the methenamine silver staining method that fungi were present in the middle ear fluid in 100% of the studied cases of eosinophilic otitis media or OME. Whether fungi are also present in the middle ear cavity of normal persons is unknown, but the possibility that they may contribute as a cause of both diseases cannot be excluded. Particularly in eosinophilic otitis media, the observation of numerous CLCs in the middle ear fluid suggests that many eosinophils have degenerated. The eosinophil granule proteins released from the degenerated eosinophils can cause epithelial injury of the middle ear. The possibility that fungi induce the eosinophils in the middle ear also cannot be excluded.

A new iridoid glycoside, 10-O-(4"-O-methylsuccinoyl)geniposide (7), and two new pyronane glycosides, jasminosides Q and R (13 and 14, resp.), along with nine known iridoid glycosides, 1-6 and 8-10, and two known pyronane glycosides, 11 and 12, were isolated from a MeOH extract of Gardeniae Fructus, the dried ripe fruit of Gardenia jasminoides (Rubiaceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of compounds 1-14 on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, i.e., 6-O-p-coumaroylgeniposide (3), 7, and 6'-O-sinapoyljasminoside (12), exhibited inhibitory effects with 21.6-41.0 and 37.5-47.7% reduction of melanin content at 30 and 50 μM, respectively, with almost no toxicity to the cells (83.7-106.1% of cell viability at 50 μM).

Eight glycosidic compounds, 1-8, including two new compounds, (4ξ)-α-terpineol 8-O-[α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside] (5) and myrtenol 10-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside] (7), were isolated from the BuOH-soluble fraction of a MeOH extract of Momordica charantia leaves. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of compounds 1-8 on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), these compounds were found to exhibit inhibitory activities with 7.1-27.0% and 23.6-46.4% reduction of melanin content at 30 μM and 100 μM, respectively, with no or almost no toxicity to the cells (80.0-103.5% of cell viability at 100 μM). Western blot analysis showed that compound 7 reduced the protein levels of MITF, tyrosinase, TRP-1, and TRP-2 mostly in a concentration-dependent manner, suggesting that this compound inhibits melanogenesis on the α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2.

Objective Pseudo-images of three-dimensional eye movements captured on an infrared video oculogram can be translated onto a rotational expression around axial vector. This provides a subject's Listing's plane, which moves according to the head's orientation relative to gravity. Optokinetically induced changes in the cognitive gravitational reference frame will affect the context of Listing's plane. The purpose of this study was to estimate the effect of OKS on Listing's plane. Methods In this study, we presented vertical optokinetic visual stimulation with fixation targets, which are thought to induce pseudo-inclination of the head, and evaluated changes in the subjects’ Listing's plane. Results We observed no stimulus-induced movement of Listing's plane that corresponded to the assumed pseudo-recognition of a change in verticality. On the other hand, we did observe vergence movement of Listing's plane (in the yaw plane), which corresponded to exposure to diminished and increased gravitational circumstance. In addition, the thickness of Listing's plane significantly increased with the load of each stimulation. Conclusion Vertical OKS leads to a rotation of Listing's plane mainly around a vertical axis. This may represent false exhibition of central compensatory re-weighting with respect to inherent otoconial mass asymmetry resulting from the OKS-mediated loss of the gravity reference. In addition, a OKS-mediated thickening of Listing's plane suggests to us that confusing visual input can reduce the stability of the internal model, which would likely manifest itself as a thickening of Listing's plane. In other words, fluctuation between the build-up and drop-out of vection induced by optokinetic stimulation will cause a thickening of Listing's plane. The thickness of Listing's plane could be a novel clinical parameter for quantitatively evaluating static vestibular function and accuracy of the internal model.

When conservative therapies are not effective in treating sinus infections, alternate steps can be taken to improve paranasal cavity ventilation. These measures may include surgical procedures such as intranasal endoscopic or maxillary sinus fenestration, and other procedures such as placement of a maxillary sinus tube or a YAMIK sinus catheter. We conducted a prospective study of 25 patients to investigate the effects on the nasal mucosa of improved ventilation between the nasal and paranasal cavities. We accomplished this by comparing (1) the results of simultaneously measured nasal cavity and intramaxillary sinus pressures before and after widening of ventilation openings, (2) changes in mucociliary transport function as measured by the saccharin test, and (3) changes in nasal airway resistance. Just as multiple transit routes between the nasal cavity and maxillary sinus give rise to greater fluctuations in intramaxillary sinus pressure, and just as rapid breathing gives rise to even greater pressure fluctuations than does quiet breathing, we believe that both intranasal cavity airflow velocity and the number of ventilation openings present have an effect on the state of ventilation between the nasal cavity and maxillary sinus. We also suggest that the establishment of maxillary sinus ventilation openings improves mucociliary clearance.

Listing's plane is a construction derived from eye position and reflects gravitational orientation. The cerebellum plays a key role in orienting and integrating sensory input concerning gravity from visual, vestibular and proprioceptive apparatuses. This suggests that the thickness of Listing's plane could serve as a novel parameter for evaluating the accuracy of the constructed gravity-oriented internal model. We report a case with acute cerebellitis along with data on Listing's plane, calculated from consecutive infrared video-oculogram recordings. We found thickening of Listing's plane at the early stage of the disease, and a gradual reduction of the thickness into normal range in parallel with the recovery of the patient's posture and gate. Notably, clinical improvement of the patient's posture was delayed relative to the normalization of the thickness of Listing's plane. The thickness of Listing's plane reflects the stability of the cerebellar-mediated cognitive gravitational reference frame. This thickness value could serve as a parameter to quantitatively evaluate the function of the constructed internal model. Recovery from cerebellar ataxia (manifested as normalization of the thickness of Listing's plane) was followed by recovery of muscular strength lost during the period the patient was by his disease forced to assume a lying position.

Rapid head movement was combined with continuous caloric irrigation of the external ear to evaluate the time courses of the on-step (null-to-supine repositioning) and off-step (supine-to-null repositioning) vestibulo-ocular reflexes (VOR) responses in eight healthy subjects. During continuous air-caloric irrigation, each subject's head was positioned with his/her lateral semicircular canal alternately placed in the null (horizontal) and activating (vertical) planes, and the time course of the slow phase eye velocity was evaluated. The resulting responses were characterized by estimates of activation and adaptation components, and their amplitudes and time constants were calculated. Comparisons of the on-step and off-step responses revealed the activation and adaptation components of the VOR to have similar amplitudes. On the other hand, the time constant for the activation component was prolonged for the off-step response, while that for the adaptation component was shortened. Null-to-supine and reciprocal vestibular stimulation during continuous caloric irrigation of the external ear canal elicited asymmetric VOR responses that exhibited differing time courses.

The objectives of this study were 1) to determine the effects of adding a CIDR to the Ovsynch protocol on plasma concentrations of estradiol-17β and progesterone and conception in dairy cows with cystic ovarian diseases and 2) to examine associations among the estradiol-17β and progesterone concentrations and conception. Cows were diagnosed as having cystic ovarian diseases if they were found to have a cystic follicle (diameter ≥25 mm) without a corpus luteum by two palpations per rectum with an interval for 7 to 14 days. They were treated with either the Ovsynch (GnRH on Day 0, PGF(2α) on Day 7 and GnRH on Day 9, with AI on Day 10; n=15) or Ovsynch+CIDR protocol (Ovsynch protocol plus a CIDR from Day 0 to Day 7; n=23). Plasma estradiol-17β concentrations were determined on Days 0, 7 and 9, and plasma progesterone concentrations were determined on Days 0, 7, 9 and 17. The plasma estradiol-17β and progesterone concentrations at all of the days examined and conception rates did not differ significantly between the two timed AI protocols. The progesterone concentrations on Day 17 and conception rates were lower (P

When combined with vestibular dysfunction, visual flow can exacerbate reductions in postural stability. This effect may be one of the mechanisms underlying visual vertigo, which can be evaluated using frequency analysis of body sway elicited by optokinetic stimulation (OKS).To clarify the interaction between the postural responses to visual flow and to input from the vestibular apparatus as a mediator of visual vertigo.Horizontal and vertical OKS with a stable fixation target were presented to 14 healthy subjects and 38 peripheral vestibular patients standing in a Romberg's posture, and the center of standing pressure was monitored using a force platform. The direction and amplitude of induced body sway were analyzed, along with the power spectra of the body mass fluctuations.Each directional optokinetic stimulus induced body sway that would compensate for the virtual inclination of the subject's gravitational reference frame. However, the amplitude of this body sway was not increased by vestibular dysfunction. Healthy subjects showed increased stability in response to downward OKS and decreased stability in response to upward OKS, whereas no specific changes were seen in response to horizontal OKS. This stability was greatly diminished in patients with vestibular dysfunction subjected to the same directional OKS.

Ocular flutter is a relatively rare eye movement disorder characterized by intermittent bursts of conjugate horizontal saccades without an intersaccadic interval. Its anatomical and neurophysiological basis remains controversial. Here we present a case of ocular flutter in which the flutter declined as the clinical stage of the associated ailment declined, until it eventually disappeared. Radiological examination revealed a tiny lesion in the right upper pontine tegmentum that included areas of the reticular formation, superior cerebellar peduncle and locus ceruleus. Because the lesion occupied the upper part of the paramedian pontine reticular formation, it did not contain omnipause neurons, which would seem to contradict a previously hypothesized explanation for ocular flutter: loss of pause cell control over saccadic burst neurons. On the other hand, we found no lesion in the area of the deep cerebellar nuclei; instead, the lesion was in the path of the projection from the fastigial nucleus to the brainstem saccadic generator. This is consistent with the idea that, in this case, there is impaired control by the cerebellar fastigial nucleus, especially of the horizontal saccadic system.

A case of parotid carcinoma extending along the facial nerve up to the internal auditory canal is presented. Total parotid resection with neck dissection was performed, as well as resection of the ear canal, eardrum, ossicles, and transmastoid and translabyrinthine facial nerve, and obliteration using the fascia lata and fatty tissue. This was followed by adjuvant radiotherapy. The facial nerve showed continuous swelling along its length with lump formation at the site of the geniculate ganglion and the internal acoustic canal. Pathological examination revealed the salivary duct carcinoma subtype of carcinoma ex pleomorphic adenoma. Within the facial nerve, the epineurium, perineurium and endoneurium were affected throughout its length. Preoperative MRI with a contrast medium revealed the site of lump formation on the facial nerve, though it did not reveal the consecutive spread of the tumor along the nerve trunk. CT of the temporal bone is strongly recommended for detection of swelling of the temporal bone segment of the nerve trunk, which could provide confirming evidence of invasion by a parotid carcinoma.

Endogenous peroxidase activity was observed in the cisternae of the rough-surfaced endoplasmic reticulum (r-ER), including the nuclear envelope, Golgi complex, and secretory granules of the cat's nasal glands. A single injection of propranolol resulted in a decrease of peroxidase-positive secretory granules, an increase of electron-lucent granules, and no change in the level of peroxidase activity in the r-ER and Golgi complex at either 5 or 9 hours after the injection. Continuous administration of propranolol over 7 hours led to the disappearance of peroxidase activity from the r-ER and secretory granules. These data would indicate that propranolol inhibits only the synthesis of peroxidase. Twenty minutes after a single injection of isoproterenol, the rate at which the granule content containing the peroxidase reaction product was discharged into the acinar lumen increased sharply. However, 60 minutes after the injection, the secretion rate of peroxidase-positive granules decreased. The same experiment then was repeated, but this time before the isoproterenol was injected, propranolol was administered to the cats. This time no change in peroxidase activity appeared in the acinar cells. It was concluded, therefore, that the stimulation of β-receptors enhances the synthesis of peroxidase.

We compared synchronization and pregnancy rates, and the increase in blood progesterone concentrations during luteal development, between (1) Ovsynch plus an intravaginal controlled internal drug release (CIDR) device protocol followed by timed embryo transfer (timed ET), and (2) a conventional estrus synchronization method using PGF(2 alpha) and ET in suckled postpartum Japanese Black beef cows. Cows in the PGF group (n=18) received a PGF(2 alpha) analogue when a CL was first palpated per rectum at 10-d intervals after 1 to 2 month postpartum. Cows (n=11), which showed estrus (Day 0) within 5 d of the PGF(2 alpha), and had a CL on Day 7, received ET. Cows in the Ovsynch+CIDR group (n=19) underwent the Ovsynch protocol plus a CIDR for 7 d (GnRH analogue and CIDR on Day-9, PGF(2alpha) analogue with CIDR removal on Day-2, and GnRH analogue on Day 0), with ET on Day 7. The ovulation synchronization (100%) and embryo transfer (100%) rates in the Ovsynch+CIDR group were greater (P