[A MULTICENTER CLINICAL SURVEY ABOUT THE PREVALENCE OF JAPANESE CYPRESS POLLINOSIS AND THE EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH JAPANESE CEDAR POLLEN EXTRACT DURING JAPANESE CYPRESS POLLEN DISPERSAL PERIOD].

BACKGROUND: Little is known whether sublingual immunotherapy using Japanese cedar pollen extract (cedar SLIT) is effective for not only Japanese cedar pollinosis but also Japanese cypress pollinosis. We investigated the prevalence rate of Japanese cypress pollinosis, efficacy of cedar SLIT on cypress pollinosis and patients' wish to receive cypress SLIT. METHODS: We investigated a multi-center (31 institutions), cross-sectional survey using a self-administrated questionnaire with four questions for patients received cedar SLIT aged from 5 to 69 years old. RESULTS: 2523 subjects were enrolled for analysis. 83.4% of them had pollinosis symptoms during cypress season before cedar SLIT. In such patients, 37.4% experienced lessened efficacy of cedar SLIT during cypress season. Both the prevalence of cypress pollinosis and the lessened efficacy of cedar SLIT on cypress pollinosis were significantly seen in western Japan as compared to eastern Japan. 76.1% of the subject having cypress pollinosis before SLIT wished to receive cypress SLIT if it is available. CONCLUSION: A lessened efficacy of cedar SLIT during cypress season was broadly seen in Japan, and further showed a regional difference. Together with the finding of high wish by patients, these results suggest a development of cypress SLIT is desirable.

Phylogeography of Ryukyu insular cicadas: Extensive vicariance by island isolation vs accidental dispersal by super typhoon.

Cicadas tend to be affected by vicariance reflecting poor mobility of nymphs underground and weak flying ability of adults. However, modern collection records of invasive cicada, combined with records of typhoon tracks, and newly obtained phylogeographic data suggest long distance, relatively instantaneous, dispersal of some vicariantly speciated cicadas. We address the importance of this typhoon dispersal mechanism applied to representative species of east Asian endemic cicadas of Cryptotympana, Mogannia, Euterpnosia and Meimuna. We combine BEAST-dated phylogenic and haplotype network analyses, modern collection data of non-native cicadas available in reports of the Japanese insect associations, modern typhoon records by Japan Meteorological Agency, and our own Quaternary geological constriction data. In conclusion, although Ryukyu endemic cicadas were vicariantly speciated, endemic cicadas on some islands were accidentally dispersed long distances to another island possibly by typhoons, particularly those associated with super typhoons generated since 1.55 Ma.

Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/ß-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR.

Integrin ß1 controls VE-cadherin localization and blood vessel stability.

Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin ß1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that ß1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin ß1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin ß1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

Inhibitory action of levocetirizine on the production of eosinophil chemoattractants RANTES and eotaxin in vitro and in vivo.

Eosinophils are well known to play essential roles in the development and maintenance of allergic diseases. However, the influence of histamine H1 receptor antagonists on eosinophil functions, especially chemokine production, are not well-defined. Therefore, in the present study, we examined the influence of histamine H1 receptor antagonist on chemokine production by eosinophils through the use of levocetirizine in vitro and in vivo. Eosinophils prepared from mice were stimulated with specific antigens in the presence of different concentrations of levocetirizine. After 24 h, regulated on activation normal T cell expressed and secreted (RANTES) and eotaxin levels in culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Patients with Japanese cedar pollinosis were treated with 5 mg levocetirizine once a day for four weeks during the pollen season (February 2012 to April 2012). RANTES and eotaxin levels in nasal secretions were also examined by ELISA. The addition of levocetirizine to eosinophil cultures caused a dose-dependent decrease in the ability of cells to produce RANTES and eotaxin in response to antigen stimulation, and the minimum concentration that caused a significant decrease was 0.05 µM. Although cetirizine also exerted suppressive effects on the production of RANTES and eotaxin by eosinophils, the minimum concentration that caused significant suppression was 0.15 µM, which was three-times higher than that of levocetirizine. Oral administration of levocetirizine for four weeks also reduced RANTES and eotaxin levels in nasal secretions from patients with pollinosis, along with attenuation of clinical symptoms. The ability of levocetirizine to reduce RANTES and eotaxin levels may account, at least in part, for the clinical efficacy of the agent for allergic disorders, including allergic rhinitis.

Suppression of osteopontin functions by levocetirizine, a histamine H1 receptor antagonist, in vitro.

OBJECTIVES: Osteopontin (OPN), a multifunctional glycoprotein secreted from a wide variety of cells after inflammatory stimulation, is well accepted to contribute to the development of allergic diseases. However, the influence of histamine H1 receptor antagonists (antihistamines) on OPN functions is not well understood. The present study was undertaken to examine the influence of antihistamines on OPN functions in vitro. METHODS: Human nasal epithelial cells (5 × 10(5) cells) were stimulated with 250 ng/mL OPN in the presence of either desloratadine (DL), fexofenadine (FEX), or levocetirizine (LCT). The levels of OPN, GM-CSF, Eotaxin, and RANTES in 24 h culture supernatants were examined by ELISA. The influence of LCT on mRNA expression and transcription factor activation in cells were also examined by real-time RT-PCR and ELISA, respectively. KEY FINDINGS: The antihistamines examined significantly suppressed the production of GM-CSF, Eotaxin, and RANTES from cells after OPN stimulation. LCT also exhibited the suppression of mRNA expression for chemokines and transcription factor, NF- κ B and AP-1, activation, which were increased by the stimulation of cells with OPN. CONCLUSIONS: The suppressive activity of LCT on OPN functions on nasal epithelial cells may be responsible for the attenuating effect of the agent on allergic diseases.

Enhancement of clara cell 10-kD protein (CC10) production from nasal epithelial cells by fexofenadine hydrochloride.

BACKGROUND: Clara cell 10-kD protein (CC10) is well known to be an immuno-suppressive protein secreted from airway epithelial cells after inflammatory stimulation and is involved in the development of allergic disorders. Although histamine H1 receptor antagonists are used for the treatment of allergic disorders, the influence of the agents on CC10 production is not well understood. In the present study, we examined the influence of a histamine H1 receptor antagonist, fexofenadine hydrochloride (FEX) on CC10 production in vitro and in vivo. METHODS: Nasal epithelial cells (5 x 10(6) cells/ml) were stimulated with 20 ng/ml TNF-alpha in the presence of various concentrations of FEX for 24 hours. CC10 levels in culture supernatants were examined by ELISA. Patients with Japanese cedar pollinosis were treated orally with FEX twice a day at a single dose of 60 mg for two weeks during Japanese cedar pollen season (February 2011 to April 2011). CC10 levels in nasal secretions were also examined by ELISA. RESULTS: The addition of FEX into cell cultures caused increase in CC10 production induced by TNF-alpha stimulation, and the minimum concentration that caused significant increase was 200 ng/ml. Oral administration of FEX also increased CC10 levels in nasal secretions from pollinosis patients along with attenuation of clinical symptoms. CONCLUSION: The ability of FEX to enhance CC10 production may account, at least in part, for the clinical efficacy of the agent in allergic disorders, including allergic rhinitis.

Proteasome activator PA28γ stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA.

MAFA is a member of the MAF family of basic leucine zipper transcription factors and is a critical regulator of insulin gene expression and islet ß-cell function. To be degraded by the proteasome, MAFA must be phosphorylated by GSK3 and MAP kinases at multiple serine and threonine residues (Ser49, Thr53, Thr57, Ser61, and Ser65) within its amino-terminal domain. In this study, we report that MAFA degradation is stimulated by PA28γ (REGγ and PSME3), a member of a family of proteasome activators that bind and activate the 20S proteasome. To date, only a few PA28γ-proteasome pathway substrates have been identified, including steroid receptor coactivator 3 (SRC3) and the cell cycle inhibitor p21(CIP1). PA28γ binds to MAFA, induces its proteasomal degradation, and thereby attenuates MAFA-driven transcriptional activation of the insulin promoter. Co-expression of GSK3 enhanced the PA28γ-mediated degradation of MAFA, but mutants that contained alanine substitutions at the MAFA phosphorylation sites did not bind PA28γ and were resistant to degradation. We also found that a PA28γ mutant (N151Y) that did not stimulate p21 degradation enhanced MAFA degradation, and another mutant (K188D) that promoted greater p21 degradation did not enhance MAFA degradation.These results suggest that PA28γ stimulates MAFA degradation through a novel molecular mechanism that is distinct from that for the degradation of p21.

Proteasome activator PA28{gamma} stimulates degradation of GSK3-phosphorylated insulin transcription activator MAFA.

MAFA is a member of the MAF family of basic leucine zipper transcription factors and is a critical regulator of insulin gene expression and islet ß-cell function. To be degraded by the proteasome, MAFA must be phosphorylated by GSK3 and MAP kinases at multiple serine and threonine residues (Ser49, Thr53, Thr57, Ser61, and Ser65) within its amino-terminal domain. In this study, we report that MAFA degradation is stimulated by PA28γ (REGγ and PSME3), a member of a family of proteasome activators that bind and activate the 20S proteasome. To date, only a few PA28γ-proteasome pathway substrates have been identified, including steroid receptor coactivator 3 (SRC3) and the cell cycle inhibitor p21 (CIP1). PA28γ binds to MAFA, induces its proteasomal degradation, and thereby attenuates MAFA-driven transcriptional activation of the insulin promoter. Co-expression of GSK3 enhanced the PA28γ-mediated degradation of MAFA, but mutants that contained alanine substitutions at the MAFA phosphorylation sites did not bind PA28γ and were resistant to degradation. We also found that a PA28γ mutant (N151Y) that did not stimulate p21 degradation enhanced MAFA degradation, and another mutant (K188D) that promoted greater p21 degradation did not enhance MAFA degradation. These results suggest that PA28γ stimulates MAFA degradation through a novel molecular mechanism that is distinct from that for the degradation of p21.

SUMOylation negatively regulates transcriptional and oncogenic activities of MafA.

Dysregulated expression of Maf proteins (namely c-Maf, MafA and MafB) leads to multiple myeloma in humans and oncogenic transformation of chicken embryonic fibroblasts. Maf proteins are transcriptional activators of tissue-specific gene expression and regulators of cell differentiation. For example, MafA is a critical regulator of crystallin genes and the lens differentiation program in chickens. In mammals, MafA is essential for the development of mature insulin-producing beta-cells of pancreas. It has been shown that MafA protein stability is regulated by phosphorylations at multiple serine and threonine residues. Here, we report that Maf proteins are also post-translationally modified by small ubiquitin-like modifier (SUMO) proteins at a conserved lysine residue in the amino-terminal transactivator domain. A SUMOylation-deficient mutant of MafA (K32R) was more potent than wild-type MafA in transactivating luciferase reporter construct driven by alphaA-crystallin or insulin gene promoter. In ovo electroporation into developing chicken embryo showed that the K32R mutant induced ectopic delta-crystallin gene expression more efficiently than the wild-type MafA. We also demonstrated that the K32R mutant had enhanced ability to induce colony formation of a chicken fibroblast cell line DF-1. Therefore, SUMOylation is a functional post-translational modification of MafA that negatively regulates its transcriptional and transforming activities.

Modelling and observations of electron beam charging of an insulator/metal bilayer and its impact on secondary electron images in defect inspection equipment.

A self-consistent simulation of secondary electron (SE) emission and charging of a SiO(2) layer with the thickness of several tens of nanometres on Si is incorporated into a trajectory simulation of emitted SEs above the surface, the centre area of which is charged by electron beams (EBs) at the energy range from 300 to 2000 eV. In order to study the influence of the charging of an insulating layer on defect inspection, a pseudo-image is reconstructed from net SE yields calculated at each point of the SiO(2) surface locally applied the positive voltage. The image contrast between charged and uncharged areas is compared with the observation of thermally oxidized layer with the thickness of 24-106 nm on a Si wafer. The image contrast is very sensitive to the thickness of the SiO(2) layer, which is verified by both observed and calculated images. The calculated changes of the images with the layer thickness and the primary electron energy reproduce the experimental observations fairly well. This confirms a highly sensitive detection mechanism for tiny defects in insulating patterns on a metal hard mask for an EB defect inspection equipment.

Typical carcinoid tumor arising in the nose and paranasal sinuses--case report.

Carcinoid tumors arise from neuroendocrine cells, many of which are present in the digestive tract and lungs. There have been few reports of carcinoid tumors occurring in the nose and paranasal sinus area, and they are very rare. We encountered a patient with a carcinoid tumor that arose in the nose and paranasal sinuses, and we report the case with a review of the literature. The patient was a 75-year-old woman who began to experience right-sided nasal obstruction, and when her nose began to bleed on the right-side she was examined in our department. A tumor lesion that easily bled and had filled the right nasal cavity was observed. CT revealed a mass lesion with a marked contrast enhancement in the right nasal cavity, ethmoid sinus, and sphenoid sinus, and MRI showed numerous flow voids in the interior that seemed to be tumor blood vessels. The tumor was excised through a lateral rhinotomy. The histopathological diagnosis was a carcinoid tumor. Tumor recurrence was subsequently detected in the vicinity of the opening of the sphenoid sinus, and because the tumor was tending to grow larger, the tumor was resected. The patient has been followed up in the outpatient clinic, recurrence-free.

Glucocorticoid receptor immunoreactivity of eosinophils in nasal polyps.

CONCLUSION: The higher level of glucocorticoid receptor (GR) expression in cases of chronic sinusitis with bronchial asthma or allergic rhinitis suggests that glucocorticoids may exert a greater influence on eosinophils, thereby making them more effective in the treatment of polyps or chronic sinusitis. OBJECTIVES: The GR immunoreactivity of eosinophils in nasal polyps was investigated to elucidate the mechanism by which glucocorticoids interact with eosinophils. MATERIALS AND METHODS: Nasal polyp specimens were divided into 3 groups: 7 patients with chronic sinusitis alone (CS only group), 12 patients with chronic sinusitis complicated by perennial allergic rhinitis (CS/AR group), and 6 patients with chronic sinusitis complicated by bronchial asthma except for aspirin-induced asthma (CS/asthma group). Immunofluorescent staining with an anti-GR polyclonal antibody and anti-major basic protein (MBP) monoclonal antibody was used. RESULTS: The total number of MBP+ cells, GR+ cells, and MBP+/GR+ cells in the CS/asthma group was significantly higher than that in the other two groups. The total number of these cells in the CS/AR group was also higher than that in the CS only group The ratio of MBP+/GR+ cells to GR+ cells was highest in the CS/asthma group. The ratio of MBP+/GR+ cells to MBP+ cells in the CS only group was lower than those in the other two groups.

Evidence for passing down of postnasal drip into respiratory organs.

UNLABELLED: Postnasal drip is believed to be one of the main sources of serious respiratory diseases, such as sinobronchial syndrome. However, there is little direct evidence showing that postnasal drip flows into the trachea and results in the development of inflammatory responses in the lower airway. In the present study, whether postnasal drip entered the respiratory organs and whether material in the trachea moved toward the lungs and the digestive organs were examined by using an experimental model with mice. MATERIALS AND METHODS: In the first set of experiments, 1.0 microL of 51Cr-labeled pseudo-postnasal drip in a normal saline or a glycerin solution was instilled into the nasal cavity of male ICR mice anesthetized with sodium barbital by intraperitoneal injection. In the second set of experiments, the destination of 51Cr-labeled red blood cells (RBCs) after intratracheal instillation was examined in the anesthetized mice. The lungs, the stomach and the intestines were removed from mice killed under anesthesia at various intervals after instillation, and measured for radioactivity. RESULTS: When glycerin solution containing 51Cr (but not normal saline) was instilled in mice, the presence of much higher levels of 51Cr was observed in the lungs. Although the presence of high levels of 51Cr-labeled RBCs was observed in the lungs one hour after instillation radioactivity in the lungs gradually decreased as time went by. On the other hand, radioactivity in the digestive organs gradually increased and peaked three hours after instillation with 51Cr-labeled RBC. CONCLUSION: These results suggest that thicker viscous postnasal drip can flow into the respiratory organs when the host is asleep. In addition, postnasal drip which flows into the trachea can move gradually to the oral side by mucociliary transportation of the tracheal mucosa and thus be swallowed.

Influence of epinastine hydrochloride, an H1-receptor antagonist, on the function of mite allergen-pulsed murine bone marrow-derived dendritic cells in vitro and in vivo.

There is established concept that dendritic cells (DCs) play essential roles in the development of allergic immune responses. However, the influence of H(1) receptor antagonists on DC functions is not well defined. The aim of the present study was to examine the effect of epinastine hydrochloride (EP), the most notable histamine H(1) receptor antagonists in Japan, on Dermatophagoides farinae (Der f)-pulsed mouse bone marrow-derived DCs in vitro and in vivo. EP at more than 25 ng/mL could significantly inhibit the production of IL-6, TNF-alpha and IL-10 from Der f-pulsed DCs, which was increased by Der f challenge in vitro. On the other hand, EP increased the ability of Der f-pulsed DCs to produce IL-12. Intranasal instillation of Der f-pulsed DCs resulted in nasal eosinophilia associated with a significant increase in IL-5 levels in nasal lavage fluids. Der f-pulsed and EP-treated DCs significantly inhibited nasal eosinophila and reduced IL-5. These results indicate that EP inhibits the development of Th2 immune responses through the modulation of DC functions and results in favorable modification of clinical status of allergic diseases.

Suppressive activity of epinastine hydrochloride on eosinophil activation in vitro.

The influence of a histamine H1 receptor antagonist, epinastine hydrochloride (EP), on eosinophil functions was examined in vitro and in vivo. The first set of experiments was undertaken to examine whether EP could suppress eosinophilia and IgE hyperproduction induced by Mesocestoides cortii infection in BALB/c mice. The number of peripheral blood eosinophils and levels of IgE were examined 21 days after infection. Oral administration of EP at a daily dose of 0.3 mg/kg, which is the recommended human therapeutic dose, for 21 days was not able to suppress either peripheral blood eosinophilia or IgE hyperproduction, which was observed in mice infected with M. cortii. The second part of the experiment was designed to examine the influence of EP on eosinophil activation induced by stem cell factor (SCF) stimulation in vitro. Eosinophils were obtained from M. cortii-infected mice and stimulated with SCF in the presence of different concentrations of EP for 24 h. The addition of EP into cell cultures suppressed eosinophil activation induced by SCF stimulation as assessed by measuring the contents of acronym for Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES), macrophage inflammatory protein-1beta (MIP-1beta) and leukotriene C4 (LTC4) levels in culture supernatants. The minimum concentration of EP which caused significant suppression of factor productions was 25 ng/ml, which is similar to the concentration in plasma after oral administration of the therapeutic dose in humans. These results may suggest that EP exerts inhibitory effects on eosinophil activation and results in favorable modification of the clinical status of allergic patients.

Suppressive activity of tiotropium bromide on matrix metalloproteinase production from lung fibroblasts in vitro.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling with an accumulation of inflammatory cells. There is also increasing evidence that metalloproteinases (MMPs) may contribute to the pathogenesis of COPD, but the influence of agents that used for the treatment of COPD is not well understood. OBJECTIVE: We evaluated whether tiotropium bromide hydrate (TBH), a M3 muscarinic receptor antagonist, could inhibit MMP production from lung fibroblasts (LFs) in response to tumor necrosis factor (TNF)-alpha stimulation. METHODS: LFs were established from normal lung tissues taken from patients with lung tumors. LFs (5 x 10(5) cells/ml) were stimulated with TNF-alpha in the presence of various concentrations of TBH. After 24 h, culture supernatants were obtained and assayed for the levels of MMPs and tissue inhibitor of metalloproteinases (TIMPs) by ELISA. The influence of TBH on mRNA expression of MMPs and TIMPs in 4h-cultured cells was also examined by real-time RT-PCR. Furthermore, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in LFs treated with TBH for 4h was examined by ELISA. RESULTS: TBH at more than 15 pg/ml inhibited the production of MMP-2 from LFs after TNF-alpha stimulation, whereas TIMP-1 and TIMP-2 production was scarcely affected by TBH through the suppression of both mRNA expression and transcription factor, NF-kappaB, activation in LFs induced by TNF-alpha stimulation. CONCLUSION: These results suggest that the attenuating effect of TBH on MMP-2 production from LFs induced by inflammatory stimulation may be additional beneficial therapeutic effects not directly relating to its bronchodilatory effects.

Modulation of eosinophil survival by epinastine hydrochloride, an H1 receptor antagonist, in vitro.

The influence of epinastine hydrochloride (EP) on eosinophil survival was examined by an in vitro cell culture technique. Nasal epithelial cells (NECs) were stimulated with 25 ng/ml TNF-alpha in the presence of EP (10 to 30 ng/ml). After 24 h, the culture supernatants were obtained and used as conditioned media of NECs (CM). Eosinophils (1 x 10(3) cells/ml) prepared from healthy human peripheral blood were incubated with 25% CM and eosinophil survival was assessed by trypan blue dye exclusion test 48 h later. CM prepared from NEC cultures pre-treated with TNF-alpha and EP caused a decrease in eosinophil survival as compared with that from NEC cells pre-treated with TNF-alpha alone. The minimum concentration of EP that caused a significant decrease in eosinophil survival was 25 ng/ml. The addition of EP into eosinophil cultures did not cause inhibition of eosinophil survival, which was prolonged by stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), even when 40 ng/ml EP was added to cell cultures. We then examined the levels of GM-CSF in CM by ELISA. Treatment of NECs with EP at more than 25 ng/ml, reduced the ability of NECs to produce GM-CSF in response to TNF-alpha stimulation. These results may suggest that EP suppresses eosinophil survival through the suppression of GM-CSF production from NECs induced by inflammatory stimulation and that this suppressive effect contributes, in part, to the therapeutic mode of action of EP on allergic diseases.

Suppressive activity of fexofenadine hydrochloride on nitric oxide production in-vitro and in-vivo.

The aim of this study was to examine the effect of fexofenadine hydrochloride (FEX), a histamine H1-receptor antagonist, on nitric oxide (NO) production in-vitro and in-vivo. Nasal fibroblasts (5 x 10(5) cells per mL) were stimulated with 25 ng mL(-1) tumour necrosis factor-alpha in the presence of various concentrations of FEX. NO levels in 24-h-culture supernatants were measured by the Griess method and levels of inducible nitric oxide synthase (iNOS) mRNA levels in 12-h-cultured cells were measured by ELISA. FEX at more than 0.5 microg mL(-1) suppressed NO production from fibroblasts by inhibiting expression of iNOS mRNA. We also examined whether FEX could suppress NO production induced by lipopolysaccharide (LPS) stimulation in-vivo. BALB/c mice were treated with 5.0 mg kg(-1) LPS i.p. after daily oral doses of FEX, 1.0 mg kg(-1), for 1-3 weeks. Plasma was obtained 6 h later and NO levels measured by the Griess method. Expression of iNOS mRNA in lung tissues was measured by ELISA 6 h after LPS injection. Oral administration of FEX for 2 and 3 weeks, but not 1 week, significantly suppressed NO levels in plasma through the inhibition of iNOS mRNA expression, which were enhanced by LPS stimulation. These results suggest that the attenuating effect of FEX on NO production may be of therapeutic benefit in allergic diseases.

The effect of exogenous spatial attention on auditory information processing.

This study investigated the effect of exogenous spatial attention on auditory information processing. In Experiments 1, 2 and 3, temporal order judgment tasks were performed to examine the effect. In Experiment 1 and 2, a cue tone was presented to either the left or right ear, followed by sequential presentation of two target tones. The subjects judged the order of presentation of the target tones. The results showed that subjects heard both tones simultaneously when the target tone, which was presented on the same side as the cue tone, was presented after the target tone on the opposite side. This indicates that spatial exogenous attention was aroused by the cue tone, and facilitated subsequent auditory information processing. Experiment 3 examined whether both cue position and frequency influence the resulting information processing. The same effect of spatial attention was observed, but the effect of attention to a certain frequency was only partially observed. In Experiment 4, a tone fusion judgment task was performed to examine whether the effect of spatial attention occurred in the initial stages of hearing. The result suggests that the effect occurred in the later stages of hearing.