Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats.

BACKGROUND AND AIMS: The role of sensory neurones in colitis was studied by chemical denervation of primary sensory neurones as well as antagonism of the vanilloid receptor-1 (VR-1) in rats prior to administration of dextran sulphate sodium (DSS) to induce colitis. METHODS: Neonatal rats were chemically denervated by subcutaneous administration of capsaicin; controls received capsaicin vehicle only. When animals reached maturity, colitis was induced by administration of 5% DSS in drinking water for seven days. Additionally, normal adult rats were treated with a VR-1 antagonist capsazepine (CPZ) or vehicle twice daily via an enema from day 0 to day 6 of the DSS regimen. Control rats were treated with an enema infusion of vehicle and 5% DSS, or without either an enema infusion or DSS in drinking water. For both groups of rats, severity of inflammation was quantitated by disease activity index (DAI), myeloperoxidase (MPO) activity, and histological examination. RESULTS: DSS induced active colitis in all control rats with resultant epithelial ulceration, crypt shortening, and neutrophil infiltration. Both neonatal capsaicinised rats and normal adult rats treated with CPZ enemas exhibited significantly lower levels of DAI, MPO, and histological damage compared with vehicle treated rats (p< 0.05). CONCLUSIONS: Neonatal capsaicinisation and local administration of CPZ prevents intestinal inflammation in a well established model of colitis indicating that primary sensory neurones possessing VR-1 receptors are required in the propagation of colonic inflammation.

Cough receptor sensitivity to capsaicin does not change after allergen bronchoprovocation in allergic asthma.

BACKGROUND: The relationship between cough receptor sensitivity and eosinophilic inflammation of the airway in patients with asthma remains unclear. METHODS: Eighteen patients with asthma sensitised to house dust mite (HDM) were enrolled in a randomised parallel group study. Patients with asthma whose main symptom was cough were not enrolled in the study. Half the patients were randomly assigned to inhale saline and the other half to inhale HDM allergen. Cough receptor sensitivity to capsaicin, airway responsiveness to histamine, and sputum eosinophils analysed with hypertonic saline inhalation were investigated before and 24 hours after saline or HDM allergen bronchoprovocation. RESULTS: Patients inhaling saline showed no significant changes in sputum eosinophils (from 7.87% (95% confidence interval (CI) 5.08 to 12.19) to 8.60% (95% CI 3.03 to 14.18); p=0.97), airway responsiveness to histamine (from 726.68 micro g/ml (95% CI 251.90 to 2096.36) to 773.01 micro g/ml (95% CI 251.36 to 2377.23); p=0.96), or capsaicin sensitivity (from 7.23 micro M (95% CI 2.45 to 21.31) to 7.24 micro M (95% CI 2.46 to 21.31); p=0.96). Early asthmatic response was induced in all patients, and late asthmatic response was observed in six of nine patients inhaling HDM allergen. Although there were significant increases in sputum eosinophils (from 9.83% (95% CI 6.78 to 14.27) to 21.00% (95% CI 13.85 to 28.15); p<0.01) and airway responsiveness to histamine (from 784.16 micro g/ml (95% CI 318.24 to 1932.24) to 377.81 micro g/ml (95% CI 118.43 to 1205.24); p<0.05) 24 hours after HDM allergen inhalation compared with baseline levels, capsaicin sensitivity did not change significantly (from 5.75 micro M (95% CI 1.91 to 17.30) to 6.20 micro M (95% CI 2.21 to 17.38); p=0.77). CONCLUSIONS: These findings suggest that cough receptor sensitivity to capsaicin is not associated with eosinophilic inflammation of the airway in patients with allergic asthma whose main symptoms are wheezing and dyspnoea but not cough.

Change of connectivity on catenane ring: ring expansion by annulation-ring scission sequence.

[reaction: see text]. Ring expansion of a catenane without destruction of the interlocked structure was attained by Diels-Alder reaction followed by ozonolysis. Annulation by Diels-Alder reaction introduced a C4 fragment onto the ring, and the ozonolysis scissored the resulting double bond to expand the catenane ring. The annulation-ring scission sequence provides a general approach for changing the connectivity on a catenane ring without destroying the interlocked structure.

Angiomatoid fibrous histiocytoma in mediastinum.

Angiomatoid fibrous histiocytoma (AFH) is a rare tumor of soft tissue with low-grade malignancy that occurs most commonly in the soft tissues of the extremities or trunk. We present a case of AFH of the mediastinum, which is a very unusual site for this tumor. The patient has survived with no recurrence of the disease for 60 months after surgery and adjuvant radiotherapy.

Effects of central and peripheral urocortin on fed and fasted gastroduodenal motor activity in conscious rats.

Since few previous studies have examined the effects of urocortin on physiological fed and fasted gastrointestinal motility, we administered urocortin intracerebroventricularly (icv) or intravenously (iv) in freely moving conscious rats and examined the changes in antral and duodenal motility. Icv and iv injection of urocortin disrupted fasted motor patterns of gastroduodenal motility, which were replaced by fed-like motor patterns. When urocortin was given icv and iv in the fed state, the motor activity remained like the fed patterns but % motor index (%MI) was decreased in the antrum and increased in the duodenum. Increase in the %MI in the duodenum induced by urocortin was shown as a nonpropagated event, since the transit of nonnutrient contents in the duodenum was decreased by icv and iv injection of urocortin. Changes in the gastroduodenal motility induced by icv injection of urocortin were abolished in animals with truncal vagotomy but not altered in animals with mechanical sympathectomy, suggesting that the vagal pathway may mediate the central action of urocortin. Neither urocortin antiserum nor alpha-helical CRF-(9-41) affected fed and fasted gastroduodenal motility, suggesting that endogenous urocortin is not involved in regulation of basal gastroduodenal motility.

Nitric oxide formation in the dog sphincter of Oddi from nitric oxide donors as measured with in vivo micro-dialysis.

BACKGROUND: Nitric oxide (NO) is known to play an important role in neurally mediated relaxation of the sphincter of Oddi. AIM: We investigated whether NO donors, such as nitroglycerin or zwitterionic polyamine/NO, applied into the common bile duct or intravenously, may induce the relaxation of the sphincter of Oddi by producing NO in the anaesthetized dog. METHODS: NO production in the sphincter of Oddi was measured by detecting NO oxidation products (NO2- and NO3-) using micro-dialysis methods. RESULTS: Zwitterionic polyamine/NO and nitroglycerin applied into the common bile duct induced a marked increase in NO2- but not NO3-, in the sphincter of Oddi. Intravenous infusion of zwitterionic polyamine/NO and nitroglycerin induced little or no increase in NO2- formation. Nitroglycerin infused into either the common bile duct or intravenously administered produced relaxation of the sphincter of Oddi, but zwitterionic polyamine/NO had no effect on the sphincter of Oddi in spite of the increase in NO2- levels. CONCLUSIONS: Locally or systemically applied NO donors induce relaxation of the sphincter of Oddi by producing NO, although their mode of action differs in different analogues.

Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in conscious fed rats.

Neuropeptide Y (NPY), a 36-amino acid peptide abundantly expressed in the brain, has been implicated in the regulation of feeding and visceral functions. The present study was designed to investigate whether or not NPY specifically regulates duodenal motility. The manometric method was used to measure duodenal motility in conscious, freely moving rats. The rat duodenum showed phasic contractions mimicking the migrating motor complex in the fasted state that were replaced by irregular contractions after the ingestion of food. NPY powerfully affected the contractile activity after intracerebroventricular (i.c.v.) administration, changing fed (postprandial) patterns into phasic contractions characterized as fasted (interdigestive) patterns. This effect was mediated via receptors with pharmacological profiles similar to rat Y(2) and Y(4) receptors, although neither Y(1) nor Y(5) agonists had any effects on motility despite potent feeding-stimulatory effects. Immunoneutralization with anti-NPY antiserum administered i.c.v. abolished fasted patterns and induced fed-like motor activities. An i.c.v. dose of peptide YY produced a different effect from NPY, with increase in the motor activities of both fed and fasted patterns. These results indicate that fasted and fed motor activities are regulated processes and that NPY induces fasted activity through Y(2), and possibly Y(4), receptors, which may represent an integrated mechanism linked to the onset of feeding behavior.

[Tele-medicine system for high-risk asthmatic patients].

We have developed a tele-medicine system to monitor the airway status at home for patients with poorly controlled asthma, whereby a nurse provides instructions to individuals via the telephone to help them manage exacerbation under the supervision of their physicians. We examined the effectiveness of this system with a randomized control study. Patients with high hospitalization risk were enrolled in the study by screening patients for those with multiple previous emergency room visits and randomly assigned to either the tele-medicine or control group. After six months of participation in the program, the number of emergency room visits decreased significantly and the activities of daily living were improved in the tele-medicine group. Most of the patients in the tele-medicine group were able to continue measuring and transmitting peak expiratory flow (PEF) value successfully, and at six months had noticed an improvement in PEF. We therefore conclude that the system effectively contributes to the management of poorly controlled asthma. In addition, further consideration suggests that the reduction of emergency room visits may lead to reduction in hospitalization since we found a good correlation between number of emergency room visits and hospitalization from the studies published previously.

Effect of theophylline withdrawal on airway inflammation in asthma.

Theophylline has been used as a bronchodilator in acute and chronic asthma management, although there is accumulating evidence that it may have anti-inflammatory effects. We have investigated the effect of theophylline withdrawal for 6 weeks in asthmatic subjects whose peak expiratory flow (PEF) readings were more than 80% of the predicted value and its variability was less than 20% (Green Zone) by treatment with both a moderate dose of inhaled corticosteroids (BDP), 400-800 microg/day) and low dose theophylline (400 mg/day) for more than 3 months. In 38 asthmatic subjects, changes in clinical symptoms, respiratory function and airway inflammation detected with hypertonic saline induced sputum, and airway reactivity to histamine were investigated. One half of the patients were randomly withdrawn from theophylline, while the other half continued to take the same dose of theophylline for a period of 6 weeks. Mean steady state plasma theophylline concentrations when receiving treatment with theophylline were 8.08 microg/mL in the theophylline withdrawal group and 7.64 microg/mL in the control theophylline group, respectively. Although a significant increase in asthma symptoms emerged in the theophylline group, there were no significant changes in the theophylline administration group. In the theophylline withdrawal group, there were small but significant falls in PEF in the morning, FEV1 and V50 at the end of the study period. Analysis of induced sputum showed that there was also a significant increase in the percentage of total and activated (EG2+) eosinophils only in those patients who withdrew from theophylline. These results indicate that chronic treatment with low dose theophylline exerts an anti-inflammatory effect and that the additional use of theophylline with inhaled corticosteroids provides an effective treatment for moderate asthma. Taken together, we conclude that theophylline has long-term beneficial effects on the chronic asthma management.

Design of and metrological results from a bent parabolic mirror.

This article describes the successful design and fabrication of, and metrological results from, an elastically bent parabolic mirror. The mirror is equipped with a bending structure that allows the mirror to be bent meridionally to a parabolic shape. This bent parabolic mirror is the key component of the extremely high-quality monochromators designed for the SPring-8 figure-8 soft X-ray undulator and the 2.0 GeV high-brilliance synchrotron radiation source (VSX).

Thermal and deformation analyses of side-cooled monochromator mirrors for the SPring-8/Figure-8 soft X-ray undulator.

The numerical results for a bent parabolic mirror monochromator designed for the SPring-8/Figure-8 soft X-ray undulator are described. A thermal and structural finite-element analysis is presented for side-cooled premirrors of the bent parabolic mirror monochromator. Using a ray-tracing code, the effect of the final induced figure errors on the performance of the premirror are discussed.

Comparison of monochromators with a bent parabolic mirror and a varied-spacing grating for the 2.0 GeV high-brilliance synchrotron radiation source (VSX).

A design study of monochromators for a 2.0 GeV electron/positron storage ring for high-brilliance synchrotron radiation in the vacuum ultraviolet (VUV) and the soft X-ray regions is described. Two types of VUV/soft X-ray grazing-incidence monochromators, one with a bent parabolic mirror and the other with a varied-spacing grating, are designed. Without any slope error, the expected resolving power of the former is much higher, but the latter is less affected by slope errors of the optical elements.

Neurotropic pyrimidine heterocyclic compounds. II. Effects of novel neurotropic pyrimidine derivatives on astrocytic morphological differentiation.

Astrocytes play an important role in supporting nerve regeneration after brain injuries. In this study, the effects of novel neurotropic synthesized pyrimidine compounds on astrocytic morphological differentiation were examined. Treatment of protoplasmic cultured astrocytes with 2-piperidino-5,6-dihydro-7-methyl-6-oxo(7 H)pyrrolo[2,3-d]pyrimidine maleate (MS-430) and the related compounds caused astrocytic process formation in 60 min. The morphology of MS-430-treated cells was similar to that of dibutyryl cAMP (DBcAMP)-treated cells. The astrocytic process formation by MS-430 was observed within 60 min and the maximum effect was obtained at the drug concentration of 0.5-1.0 mM. Rhodamine-phalloidin staining showed that astrocytic cytoskeletal actin was reorganized by MS-430 and DBcAMP. MS-430 did not increase cAMP accumulation in cultured astrocytes. These results suggest that the neurotropic pyrimidines induced astrocytic morphological differentiation through a cAMP-independent mechanism.

[Results of a survey of Japanese cedar pollinosis in Hachijyojima].

We performed a questionnaire survey of Japanese cedar pollinosis among 7,946 residents of the Sakashita region (Mitsune, Ogago) and Sakaue region (Kashidate, Sueyoshi, Nakanogo) of Hachijyojima who were at least 15 years of age. The response rate was 21.3%. The percentage of respondents who reported three or more nasal symptoms concurrentry with two ocular symptoms in early spring (from the end of February to the end of March) was 1.8% in the Sakashita region and 0.3% in the Sakaue region. About 1.5% of Hachijyojima residents were suspected to have Japanese cedar pollinosis. On scratch tests of symptomatic subjects, 9.2% showed positive reactions for Japanese cedar antigen, and 12.1% had an IgE RAST score of 2 or more. The peak Japanese cedar pollen concentration between February 11 and March 31, 1992 was 74/cm2 on March 6 in the Sakashita region and 127/cm2 on the same day in the Sakaue region. This survey confirmed the presence of a low incidence of Japanese cedar pollinosis in Hachijyojima, an isolated island 290 km from Tokyo.

[The prevalence of orthostatic dysregulation complicated with bronchial asthma].

Orthostatic dysregulation (OD) has been reported to be complicated with childhood bronchial asthma. 42 patients (28 females and 14 males) with adult-onset bronchial asthma were selected randomly to investigate the prevalence of OD. OD was diagnosed by both questionnaire for subjective symptoms and tilting test (Schellong test and upright ECG). Our results revealed that 64.3% (both 64.3% in females and males) of the patients were complicated with OD. There was no significant difference in the duration of asthma, FEV0.1, %FEV1.0, serum IgE level, and severity of asthma between patients with OD and without OD. Furthermore, no significant difference in the results of tilting test were observed. In serum level of theophylline we couldn't detect any subjective difference between the two groups, however there was significant difference between positive patients and negative patients in tilting test. In conclusion, OD is frequently complicated with adult-onset asthma and we should be careful of the subjective symptoms concerned with OD.

Eosinophil apoptosis caused by theophylline, glucocorticoids, and macrolides after stimulation with IL-5.

BACKGROUND: Glucocorticoids have long been used as the most potent drugs in the treatment of bronchial asthma. Data reported recently have led to the proposal that theophylline and macrolides have antiinflammatory effects. OBJECTIVE: We examined the abilities of theophylline, glucocorticoids, and macrolides to counteract the prolongation of eosinophil survival caused by IL-5. METHODS: Purified guinea pig eosinophils were cultured in the presence or absence of human IL-5 and with or without the aforementioned drugs at various concentrations. The percentage of cells alive after 3 days in culture was determined. RESULTS: Aminophylline (AM), methylprednisolone (MP), erythromycin (EM), and clarithromycin (CAM) suppressed the IL-5 induced prolongation of eosinophil survival in a dose-dependent manner. The effects of these drugs on eosinophil survival were significantly greater at low concentrations of IL-5 than at high concentrations of IL-5. When eosinophils were cultured in the presence of IL-5 (1 ng/ml) with physiologic concentrations of MP (10(-6) mol/L), AM (10(-4) mol/L), and either EM or CAM (both 10 micrograms/ml), the effect of IL-5 was almost completely abolished, and the morphologic changes in eosinophils observed by electron microscopy were consistent with apoptosis. DNA extracted from eosinophils cultured with IL-5 and each of the drugs was definitely fragmented. CONCLUSIONS: One mechanism of the effectiveness of these drugs is induction of eosinophil apoptosis. Some combination of these drugs may be useful in the treatment of bronchial asthma.

Detection of transforming growth factor-beta in sputum from patients with bronchial asthma by eosinophil survival assay and enzyme-linked immunosorbent assay.

BACKGROUND: We have shown that interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are present in sputum from patients experiencing acute asthma attacks, by eosinophil survival assay. The viability of guinea-pig eosinophils was significantly increased in the presence of such sputum extracts after 3 days' culture, and it was inhibited by the addition of anti-IL-5 and anti-GM-CSF antibodies. However, the contribution of IL-5 to the increase in eosinophil viability was less than expected from the values of IL-5 measured by enzyme-linked immunosorbent assay (ELISA). Therefore, we speculated that something in sputum inhibited the function of IL-5. OBJECTIVE: Transforming growth factor-beta (TGF-beta) was the only cytokine we tested that inhibited the prolongation of survival of guinea-pig eosinophils induced by IL-5. The objective of this study is to detect TGF-beta in the same sputum. METHODS: Guinea-pig eosinophils were cultured with or without anti-TGF-beta antibody in the presence of sputum extracts, and the eosinophil viability was counted after 3 days. Measurement of TGF-beta 1 in sputum was performed by ELISA. RESULTS: Eosinophil viabilities with and without anti-TGF-beta antibody were 79.7 +/- 2.9% and 69.0 +/- 2.7%, respectively, and the difference between them was statistically significant (P < 0.05, n = 9). The concentration of TGF-beta 1 in the sputum was 21.7 +/- 3.3 ng/mL (n = 9). CONCLUSION: These observations suggest that TGF-beta is present in sputum from patients with bronchial asthma.

[Measurement of serum and sputum eosinophil cationic protein concentrations in asthma].

Concentrations of eosinophil cationic protein (ECP) were measured in serum from patients with asthma, patients with chronic obstructive pulmonary disease (COPD), and healthy subjects. The relationships between serum ECP concentration and percent of predicted FEV1 (%FEV1), and between serum and sputum ECP concentrations were also examined in patients with asthma. Serum ECP concentration in asthma was significantly higher than those in COPD patients and healthy subjects. There was a significant inverse correlation between serum ECP concentration and %FEV1 when analysis was restricted to data from asthma patients less than 60 years old. ECP concentration in serum and in sputum were significantly correlated. These results suggest that in asthma patients, eosinophils are activated in serum, and that the degree of eosinophil activation in the airway can be estimated by measuring serum ECP to some extent. Because it does not require bronchial biopsy or bronchoalveolar lavage, measurement of serum ECP may be useful as a minimally invasive monitoring of asthma.

[Investigation of Cryptomeria japonica pollinosis in Izu-Oshima].

We surveyed by questionnaire 4,673 residents of Izu-Oshima who were 15 or more years of age with regard to Cryptomeria japonica pollinosis. The response rate was 22.3%. In the early spring, nasal symptoms were reported by 8.9% of the respondents, ocular symptoms by 5.7%, and dermal symptoms by 8.1%. On scratch tests of symptomatic subjects, 13.8% were positive for Cryptomeria japonica antigen, and 33.3% had an IgE RAST score of 2 or more. The peak Cryptomeria japonica pollen concentrations between February and April 1990 were 118/cm2 on March 7 at the Northern Clinic and 271/cm2 at the Southern Clinic. A second questionnaire survey (response rate: 53.1%), designed to estimate the number of persons with Cryptomeria japonica pollinosis among all residents, revealed that 4.7% concurrently had three or more nasal symptoms and two ocular symptoms. By combining these results with those of a telephone survey of 100 randomly selected nonrespondents, 5.64% of all inhabitants were estimated to have suspected Cryptomeria japonica pollinosis.

Mechanism of optical isomerization of (S)-N-[1-(2-fluorophenyl)-3,4,6,7- tetrahydro-4-oxopyrrolo[3,2,1-jk] [1,4]-benzodiazepine-3-yl]-1H- indole-2-carboxamide (FK480) in soft capsules containing polyethylene glycol 400 and glycerol.

FK480 is a new synthetic non-peptide antagonist of cholecystokinin (CCK)-A receptors. The dosage form of FK480 is a soft capsule containing a solution of FK480 in a mixture of polyethylene glycol 400 (PEG 400) and glycerol to improve its bioavailability. Studies on the stability of this FK480 dosage form revealed that the main degradation occurred by optical isomerization at the asymmetric C-3 position of the pyrrolobenzodiazepine ring. The degradation reaction was accelerated by formic acid formed in a mixture of PEG 400 and glycerol. Addition of amino acids to the capsule solution retarded the isomerization by reacting with formic acid. Therefore, formic acid appears to accelerate optical isomerization of FK480.