New measurement of the K+-->pi+ nunu branching ratio.

Three events for the decay K+-->pi+ nunu have been observed in the pion momentum region below the K+-->pi+pi0 peak, 140 < Ppi < 199 MeV/c, with an estimated background of 0.93+/-0.17(stat.) -0.24+0.32(syst.) events. Combining this observation with previously reported results yields a branching ratio of B(K+-->pi+ nunu) = (1.73(-1.05)+1.15) x 10(-10) consistent with the standard model prediction.

Improved measurement of the K+-->pi+nunu; branching ratio.

An additional event near the upper kinematic limit for K+-->pi(+)nunu; has been observed by experiment E949 at Brookhaven National Laboratory. Combining previously reported and new data, the branching ratio is B(K+-->pi(+)nunu;)=(1.47(+1.30)(-0.89))x10(-10) based on three events observed in the pion momentum region 211

Further evidence for the decay K+ -->pi+nu(nu).

Additional evidence for the rare kaon decay K+-->pi+nu(nu) has been found in a new data set with comparable sensitivity to the previously reported result. One new event was observed in the pion momentum region examined, 211pi+nu(nu)) = 1.57(+1.75)(-0.82)x10(-10).

Measurement of direct photon emission in K+-->pi(+)pi(0)gamma decay

We have performed a measurement of the K+-->pi(+)pi(0)gamma decay and have observed 2x10(4) events. The best fit to the decay spectrum gives a branching ratio for direct photon emission of (4.7+/-0.8+/-0. 3)x10(-6) in the pi(+) kinetic energy region of 55 to 90 MeV and requires no component due to interference with inner bremsstrahlung.

Sensitization to grass, ragweed, mugwort pollen allergens in Japanese monkeys (Macaca fuscata): preliminary report.

BACKGROUND: The natural occurrence of Japanese cedar (CJ, Cryptomeria japonica) pollinosis has been reported in Japanese monkeys (Macaca fuscata). Furthermore, most of these monkeys with CJ pollinosis have immunoglobulin (Ig) E sensitization to Japanese cypress (Chamaecyparis obtusa) pollen. However, specific IgE to other pollens has not yet been reported. OBJECTIVES: The present study was designed to investigate IgE sensitization of Japanese monkeys to grass, ragweed, and mugwort pollen. METHODS: Serum samples from 47 monkeys as a general population in one troop were collected at random. We measured specific IgE to grass, ragweed and mugwort pollen. Next, 10 monkeys with CJ pollinosis from the same troop were also examined for their IgE sensitization to grass, ragweed, and mugwort pollen. RESULTS: Of 47 monkeys, 13 (28%) had specific IgE to CJ pollen, 15 (32%) to grass pollen, five (11%) to ragweed pollen, and three (6%) to mugwort pollen. Furthermore, CJ pollinosis monkeys seemed to be sensitized to these pollen allergens with higher frequency; of 10 monkeys, 10 (100%) had specific IgE to CJ pollen, six (60%) to grass pollen, four (40%) to ragweed pollen, and two (20%) to mugwort pollen. CONCLUSION: Japanese monkeys had specific IgE to grass, ragweed, and mugwort pollen in addition to CJ pollen.

The incidence of japanese cedar pollinosis and sensitization to the pollen allergens among Japanese monkeys in a troop.

The natural occurrence of Japanese cedar (Cryptomeria japonica; CJ) pollinosis has been reported in Japanese monkeys (Macaca fuscata), an appropriate animal model for developing antipollinosis therapies. However, there has been no study on the incidence of Japanese cedar pollinosis in monkeys. To evaluate the incidence of CJ pollinosis in Japanese monkeys, we investigated the presence of pollinosis symptoms among monkeys in a troop, and the response to CJ allergens in pollinosis monkeys. We examined the presence of pollinosis symptoms in 272 monkeys in a troop throughout the CJ pollination season (February to April). Of the 272 monkeys, 21 (7.7%) showed pollinosis symptoms during the CJ pollen season. Blood samples were taken from the 21 monkeys that showed pollinosis symptoms and were tested for the presence of immunoglobulin E (IgE) antibody for CJ allergens. All 21 monkeys with CJ pollinosis had anti-CJ IgE. Of the 21 monkeys, peripheral blood mononuclear cells (PBMC) could be taken from 12, all of which showed CJ allergen-specific PBMC proliferation. The incidence of CJ pollinosis in a troop was 7.7%. The monkeys with CJ pollinosis demonstrated specific IgE and PBMC proliferation for CJ allergens.

The incidence of Japanese cedar pollinosis and sensitization to the pollen allergens among Japanese monkeys in a troop.

The natural occurrence of Japanese cedar (Cryptomeria japonica; CJ) pollinosis has been reported in Japanese monkeys (Macaca fuscata), an appropriate animal model for developing antipollinosis therapies. However, there has been no study on the incidence of Japanese cedar pollinosis in monkeys. To evaluate the incidence of CJ pollinosis in Japanese monkeys, we investigated the presence of pollinosis symptoms among monkeys in a troop, and the response to CJ allergens in pollinosis monkeys. We examined the presence of pollinosis symptoms in 272 monkeys in a troop throughout the CJ pollination season (February to April). Of the 272 monkeys, 21 (7.7%) showed pollinosis symptoms during the CJ pollen season. Blood samples were taken from the 21 monkeys that showed pollinosis symptoms and were tested for the presence of immunoglobulin E (IgE) antibody for CJ allergens. All 21 monkeys with CJ pollinosis had anti-CJ IgE. Of the 21 monkeys, peripheral blood mononuclear cells (PBMC) could be taken from 12, all of which showed CJ allergen-specific PBMC proliferation. The incidence of CJ pollinosis in a troop was 7.7%. The monkeys with CJ pollinosis demonstrated specific IgE and PBMC proliferation for CJ allergens.

Nitric oxide, superoxide radicals and mast cells in pathogenesis of indomethacin-induced small intestinal lesions in rats.

We investigated the pathogenic mechanism of indomethacin-induced small intestinal lesions, in relation to nitric oxide (NO), superoxide radicals and mast cells. Rats received indomethacin (1-6 mg/kg) s.c. once daily for 3 days, and the small intestine was examined for lesions 24 hr after the final administration of indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, mostly in the jejunum and ileum, in dose- and time-dependent manners, with concomitant increase of mucosal microvascular permeability. This treatment also caused an increase of inducible NO synthase (iNOS) activity with the expression of its mRNA, myeloperoxidase (MPO) activity as well as thiobarbituric acid reactants (TRBAS) in the mucosa, and the changes in iNOS activity preceded those in MPO activity and TRBAS as well as lesion development. These lesions induced by indomethacin were prevented by aminoguanidine (a selective inhibitor of iNOS), dexamethasone (an inhibitor of iNOS mRNA transcription), allopurinol (a xanthine oxidase inhibitor), hydroxyurea (a neutrophil reducing agent) and FR167653 (an inhibitor of interleukin-1/tumor necrosis factor-alpha production) as well as 16,16-dimethyl prostaglandin E2n. Likewise, the severity of these lesions was also reduced by mast cell stabilizers FPL-52694 and disodium cromoglycate and a lipoxygenase inhibitor TMK-688, but not affected by tripelennamine (a histamine H1-receptor antagonist) or methysergide (a serotonin receptor antagonist). These results suggest that: 1) the pathogenic mechanism of indomethacin-induced small intestinal lesions involves superoxide radicals as well as NO produced by iNOS, 2) the deleterious effect of NO may be accounted for by the cytotoxic action of peroxynitrite, produced from NO in the presence of superoxide radicals, and 3) the mast cells may also be involved in the process of small intestinal ulceration, although the mediator responsible remains undefined.

Effects of pantoprazole, a novel H+/K+-ATPase inhibitor, on duodenal ulcerogenic and healing responses in rats: a comparative study with omeprazole and lansoprazole.

BACKGROUND: Pantoprazole, 2-[(2-pyridylmethyl) sulphinyl] benzimidazole, is a new substituted benzimidazole that inhibits the parietal cell H+/K+-ATPase. METHODS: In the present study, the anti-secretory and anti-ulcer activities of pantoprazole were compared with those of omeprazole and lansoprazole in rats. RESULTS: Pantoprazole (0.3-3 mg/kg, p.o.) as well as omeprazole (1-10 mg/kg, p.o.) and lansoprazole (1-10 mg/kg, p.o.) dose-dependently decreased both basal acid secretion in pylorus-ligated rats and the stimulated acid secretion induced by mepirizole in acute fistula rats, and the effects of pantoprazole were more potent than those of omeprazole and lansoprazole, the ED50 values for the stimulated acid secretion being 0.8, 2.0 and 1.2 mg/kg, respectively. Neither of these drugs had any effect on duodenal HCO3- secretion. These pump inhibitors prevented the development of duodenal lesions in response to mepirizole in a dose-related manner, the ED50 values for pantoprazole, omeprazole and lansoprazole being 0.4, 2.0 and 1.3 mg/kg, respectively. Likewise, pantoprazole showed the healing promoting action on chronic duodenal ulcers induced by acetic acid, and this effect was also more potent when compared to omeprazole or lansoprazole. CONCLUSIONS: We conclude that pantoprazole exhibited both anti-ulcer and healing promoting effects on duodenal ulcers in rats, and the effects may be attributable to its potent anti-secretory action. Other pump inhibitors such as omeprazole and lansoprazole were almost equally effective as pantoprazole, yet this drug was most potent on the basis of ED50 values.

Luminal calcium in regulation of nitric oxide release and acid secretion in rat stomachs after damage.

We investigated the role of luminal Ca2+ in the regulation of nitric oxide (NO) release and acid secretion in the rat stomach following damage by sodium taurocholate (TC). Under urethane anesthesia, a rat stomach was mounted in an ex vivo chamber, perfused with saline, and transmucosal potential difference (PD), luminal pH, acid secretion, and luminal contents of Ca2+ and NO were measured before and after exposure to 20 mM TC for 30 min, with or without coapplication of EGTA (5 mM) and/or CaCl2 (10 mM). Mucosal exposure to TC caused a reduction in PD and a decrease of acid secretion, with a concomitant increase of NO as well as Ca2+ content in the gastric lumen. The increase of NO release as well as the reduced acid response were attenuated by pretreatment with L-NAME or coapplication of EGTA, and the latter inhibited the luminal increase of Ca2+. The changes caused by L-NAME were antagonized by coadministration of L-arginine, while those induced by EGTA were partially antagonized by coinstillation of CaCl2. Neither treatment tested had any effect on gastric PD responses to TC. These results suggest that: (1) damage in the stomach increases the release of Ca2+ as well as NO in the lumen; (2) acid secretion decreases in response to damage by both an NO- and Ca2+-dependent mechanism; and (3) the increase of luminal Ca2+ is an adaptive response of the stomach to damage and may play an important role in increasing NO production and hence in regulating acid secretion.

Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats.

Roles of enterobacteria, nitric oxide (NO) and neutrophil in indomethacin-induced small intestinal lesions were examined in rats. Indomethacin (10 mg kg-1), administered s.c. as a single injection, caused haemorrhagic lesions in the small intestine, mostly in the jejunum and ileum. The lesions were first observed 6 h after administration of indomethacin, the severity increasing progressively with time up to 24 h later. Following indomethacin, the enterobacterial numbers, inducible NO synthase (iNOS) activity and NO production in the intestinal mucosa were also increased with time, and changes in the former preceded those in the latter two as well as the occurrence of intestinal damage. Treatment of the animals with both NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine prevented intestinal lesions induced by indomethacin, with suppression of NO production. Both dexamethasone and FR167653 (an inhibitor of interleukin-1 beta/tumour necrosis factor-alpha production) also reduced the severity of intestinal lesions as well as the increase in iNOS activity following administration of indomethacin. Likewise, the occurrence of intestinal lesions was attenuated by pretreatment of the animals with anti-neutrophil serum (ANS). None of these treatments, however, affect the translocation of enterobacteria in the mucosa. By contrast, ampicillin (an anti-bacterial agent) suppressed the increase in mucosal iNOS activity as well as the enterobacterial numbers invaded in the mucosa and inhibited the occurrence of intestinal lesions after administration of indomethacin. These results strongly suggest that enterobacterial translocation in the mucosa is the first step required for activation of various factors such as iNOS/NO and neutrophils, all involved in the pathogenesis of indomethacin-induced intestinal lesions.

Gastric mucosal damage induced by compound 48/80: roles of serotonin and nitric oxide.

The roles of nitric oxide (NO) and serotonin (5-HT) in the development of gastric mucosal lesions induced by compound 48/80 (48/80) were investigated in rats. Repeated i.p. administration of 48/80 (1 mg/kg) produced damage in the stomach with severe oedema in the submucosa. The lesions induced by 48/80 were prevented by FPL-52694 (a mast cell stabilizer) and methysergide but not tripelennamine. The lesions were also inhibited by simultaneous administration of N(G)-monomethyl-L-arginine (L-NMMA), and this effect was mimicked by inducible NO synthase (iNOS) inhibitors, such as aminoguanidine or dexamethasone and significantly antagonized by coadministration of L-arginine. The mucosal myeloperoxidase activity, thiobarbituric acid reactants and vascular permeability in the stomach were all increased after 48/80 treatment and the changes were also attenuated by cotreatment with L-NMMA. Repeated s.c. treatment with 5-HT (20 mg/kg) provoked similar gastric lesions, which were also prevented by methysergide and iNOS inhibitors, as well as antioxidative drugs, such as allopurinol (a xanthine oxidase inhibitor) and hydroxyurea (a neutrophil-reducing agent). The Ca2 -independent NO synthase (NOS) activity was increased in the gastric mucosa after administration of 48/80 or 5-HT and this change was inhibited by dexamethasone. These results suggest that: (i) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach, mediated by endogenous 5-HT; (ii) NO/iNOS is involved in the pathogenic mechanism of 48/80-induced gastric lesions, in addition to oxyradical formation; and (iii) the deleterious role of NO in this lesion model can be accounted for by a cytotoxic action of peroxynitrite that is formed in the presence of superoxide radicals.

Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin.

The effects of a nitric oxide (NO)-releasing derivative of aspirin, NCX-4016, on gastric functional and ulcerogenic responses in rat stomachs were examined in comparison with those of aspirin. Topical application of aspirin (80 mM) to the stomach markedly decreased transmucosal potential difference and slightly increased luminal pH (acid back-diffusion) with minimal effect on mucosal blood flow, whereas NCX-4016 caused a marked increase in mucosal blood flow with no effect on potential difference and pH. Aspirin itself was ulcerogenic, causing damage in the mucosa when administered p.o., and it markedly potentiated gastric ulcerogenic response to hypothermic stress (28 degrees C-30 degrees C) with no effect on acid secretion when given s.c. NCX-4016, however, was not ulcerogenic by itself, did not modify the ulcerogenic response to stress and even showed a dose-dependent protection against HCl/ethanol-induced gastric lesions. When NCX-4016 was given intragastrically to pylorus-ligated rats, a large amount of NO was detected in both gastric contents and serum. NCX-4016 administered either p.o. or s.c. produced an equipotent inhibition of mucosal PGE2 generation in the stomach, as compared with aspirin. In addition, both aspirin and NCX-4016 suppressed carrageenan-induced rat paw edema. These results suggest that, unlike aspirin, the NO-releasing derivative of aspirin NCX-4016 neither had a topical irritating action on the stomach nor exerted a worsening effect on gastric ulcerogenic response to stress, but rather provided gastric protection against ethanol, despite inhibiting cyclo-oxygenase activity and showing anti-inflammatory action much as aspirin does. NCX-4016, probably by releasing NO, exerted protective effects that counteracted the potential damaging effects of cyclo-oxygenase inhibition.

Mucosal ulcerogenic action of monochloramine in rat stomachs: effects of polaprezinc and sucralfate.

Effects of a novel zinc compound polaprezinc [N-(3-aminopropionyl)-L-histidinatozinc] and sucralfate on the mucosal ulcerogenic responses induced by monochloramine (NH2Cl) were examined in rat stomachs. Oral administration of NH2Cl (>60 mM) produced severe lesions in unanesthetized rat stomachs, with concomitant increase of lipid peroxidation. These lesions were aggravated by sensory deafferentation but not affected by pretreatment with indomethacin or L-NAME. The mucosal ulcerogenic response to NH2Cl was significantly inhibited by oral pretreatment with either dmPGE2 (10 microg/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastric lesions induced by NH2Cl were also inhibited by prior oral administration of polaprezinc (3-30 mg/kg) as well as sucralfate (30 and 100 mg/kg). The protective effect of polaprezinc was not affected by any pretreatments such as indomethacin, L-NAME, or sensory deafferentation, while that of sucralfate was significantly mitigated in the presence of either indomethacin or L-NAME. On the other hand, mucosal exposure to NH4OH (60 mM) caused a marked PD reduction in ex vivo stomachs made ischemic by bleeding from the carotid artery, followed by severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischemia were also attenuated by prior application of polaprezinc, while dmPGE2 and sucralfate prevented such lesions without affecting the reduced PD response. These results suggest that: (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa, (2) both polaprezinc and sucralfate protect the stomach against injury caused by NH2Cl, and (3) the mechanisms underlying the protective action of sucralfate may be partly mediated by both endogenous PGs and NO but may be different from those of polaprezinc.

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound 48/80 in rats.

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48/80 (48/80) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48/80 (1 mg/kg, i.p.) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhibitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48/80 treatment. The repeated administration of 48/80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48/80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48/80-induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48/80 treatment, but was significantly augmented by the combined administration of L-NAME with 48/80. The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48/80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca(2+)-independent NOS activity in the mucosa was increased four times during 48/80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48/80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.