Role of gastric mucosal blood flow in gastroprotective effect of novel xanthine derivative

The effect of 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119) on 40% ethanol-induced gastric lesions and gastric mucosal blood flow was investigated in rats. Gastric mucosal blood flow was measured by the hydrogen gas clearance technique and the test compounds and vehicle were administered intraduodenally. A90 6119 dose-dependently increased gastric mucosal blood flow and decreased gross and histologic gastric mucosal injury induced by 40% ethanol. Both the gastric mucosal blood flow and protective effects of A90 6119 were completely attenuated by pretreatment with indomethacin. The findings demonstrate that A90 6119 protects against ethanol-induced gastric injury, and this effect involves stimulation of endogenous prostaglandin synthesis and an increase in gastric mucosal blood flow.This work was supported by a grant from Hoechst Japan Ltd., Veterans Administration Research Funds, and the facilities and expertise of the Blood Flow Core of the Center for Ulcer Research and Education.     

Adaptive cytoprotection in cultured rat gastric mucus-producing cells role of mucus and prostaglandin synthesis

In cultured gastric mucosal cells, we investigated whether: (1) adaptive cytoprotection was associated with stimulation of endogenous prostaglandin synthesis; (2) prostaglandins given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage; and (3) a relationship existed between cytoprotection and mucus release. Cytolysis was quantified by measuring⁵¹Cr release from prelabeled cells. Mucus release was determined by measurement of [³H]glucosamine release. Concentrations of ethanol >12% caused cell damage and increased⁵¹Cr release dose dependently. Pretreatment with low concentrations of ethanol (0.5–1.5%) decreased ethanol-induced⁵¹Cr release, but also decreased prostaglandin E₂ synthesis. Prostaglandin E₂ and 16,16-dimethyl prostaglandin E₂ given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage. Treatment with low concentrations of ethanol (1.5%) increased mucus release from cultured gastric mucosal cells. However, prostaglandin E₂ and 16,16-dimethyl prostaglandin E₂ did not affect mucus release. We conclude that in cultured gastric mucus-producing cells: (1) adaptive cytoprotection occurs without stimulation of endogenous prostaglandin synthesis but with increase in mucus release; and (2) exogenous prostaglandins are cytoprotective against ethanol-induced gastric mucosal cell damage without stimulating mucus releasein vitro. We postulate that adaptive cytoprotection in cultured gastric mucus-producing cells is not mediated by prostaglandin, but by mucus released in response to a mild irritant.     

Protective effect of rebamipide on indomethacin-induced intestinal damage in rats

BACKGROUND AND AIM: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats. METHODS: The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin. RESULTS: Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT. CONCLUSION: These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.     

Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P<0.05), an effect that was prevented by VIP antagonist (1 mol/liter/100 g). A substance P antagonist (1 mol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB₄, LTC₄, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P<0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB₄. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P<0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P<0.05). Ketotifen, a mast cell stabilizer (100 g/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC₄ and LTB₄ (P<0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage. The effective mucosal protection by ketotifen suggests a role for mast cells and their mediators in the pathogenesis of acute gastric mucosal damage.     

Effect of acute and chronic alcohol feeding on prostaglandin E2 biosynthesis in rat stomach

The effect of acute and chronic alcohol ingestion on gastric prostaglandin E₂ synthesis and the PGE₂ content in the stomach was studied in rats. Up to 8 hr following a single oral load of 20% alcohol (v/v; 4 g/kg body weight), the PGE₂ synthesis in isolated microsomes from rat stomach remained unchanged as compared with control values. Feeding a liquid alcohol-containing diet (37% of total Joules) for 1,6, or 12 weeks significantly decreased the rate of PGE₂ synthesis (percentage inhibition as compared with control values 39, 27, and 57, respectively). In addition, chronic alcohol feeding led to a drop in the tissue content of PGE₂, the decrease being more pronounced after 6 (–49%) and 12 (–58%) weeks than after 1 week (–24%). The results suggest that the inhibition of endogenous PGE₂ synthesis in the stomach following ingestion of appreciable quantities of alcohol might play a role in the pathogenesis of alcohol-induced injury of the gastric mucosa.     

Protective effect of Irsogladine on monochloramineinduced gastric mucosallesions in rats:a comparative study with rebamipide

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Differences in gastroprotective processes in 6- to 8- and 14- to 16-week-old rats

The gastroprotective effect of opioid peptides, prostaglandin E₂ and capsaicin against acidified ethanol-induced gastric mucosal damage in young mature rats of different (6–8 and 14–16 weeks) ages has been investigated. It was found that gastric mucosal damage was more severe in 14–16 weeks old rats. The gastroprotective effect of opioid peptides - [D-Ala², D-Leu⁵]-enkephalin (DADLE), deltorphin II, [D-Ala², Phe⁴, Gly⁵ -ol]-enkephalin (DAGO) and -endorphin - given either intracerebroventricularly (0.6, 3.3., 0.2, and 0.01 nmol/rat, respectively) or subcutaneously (825 and 960 nmol/kg, respectively) was highly reduced in 14–16 weeks old rats. The mucosal protective action of orally administered capsaicin (1600–3200 nmol/kg) and PGE₂ (280–560 nmol/kg) was also diminished in 14–16 weeks old animals. Both ACTH and corticosterone plasma levels were significantly higher in 14–16 weeks old rats. These results suggest that the gastric mucosal susceptibility to ethanol and the gastroprotective effect of opioid peptides, capsaicin and PGE₂ are age-related.     

Effects of prostaglandin E2 on gastric irritant-induced apoptosis

We previously reported that various gastric irritants induced both apoptosis and necrosis in cultured gastric mucosal cells. In a continuation of this work, the present study has examined the effects of prostaglandin E₂ (PGE₂), a cytoprotective factor for gastric mucosa in vivo, on gastric irritant-induced apoptosis and necrosis in vitro. PGE₂ inhibited ethanol-induced apoptosis and increased cell viability in a dose-dependent manner in primary cultures of guinea pig gastric mucosal cells. PGE₂ also inhibited hydrogen peroxide-induced apoptosis. In contrast, PGE₂ showed no cytoprotective effects against ethanol-induced necrosis. Based on these results, we consider that the cytoprotective effects of PGE₂ on gastric mucosa in vivo can be partially explained by its inhibitory effect on gastric irritant-induced apoptosis.     

Role of prostaglandin E2 in cholinergic-mediated glycoprotein synthesis in canine antrum

We studied the mechanism of cholinergic stimulation of mucin synthesis in canine antral explants, including the role of PGE₂ as an intermediate messenger. Isolated antral mucosa was incubated with 10^–5 M carbachol (Cb), 10^–5 M indomethacin (IND), 10^–5 M pirenzepine (PZ), 10^–5 M Cb+10^–5 M PZ, 10^–5 M Cb+10^–5 M IND, and 10^–5 M IND +PGE₂ (10^–8, 10^–7 and 10^–6 M) in the presence or absence of [³H]glucosamine. After 24 hr, total glycoprotein synthesis was quantitated by Sepharose-4B chromatography and by 10% TCA/1%PTA precipitation with lipid extraction. PGE₂ released into the media was measured by radioimmunoassay (RIA). Cb significantly increased total glycoprotein synthesis and produced a significant increase in PGE₂ release. The increase in glycoprotein synthesis and the release of PGE₂ was blocked by the addition of muscarinic antagonist PZ. The addition of IND significantly inhibited glycoprotein synthesis and almost entirely suppressed PGE₂ secretion. IND also inhibited the effect of Cb on glycoprotein synthesis and PGE₂ release. Moreover, PGE₂ (10^–6 and 10^–7 M) significantly increased the glycoprotein synthesis in the canine stomach. This suggests the coordinate participation of PGE₂-releasing cell population in modulation of glycoprotein synthesis in gastric mucosa.Supported in part by the Research Service of the Veterans Administration and grant R01-DK37989 and Michigan Gastrointestinal Peptide Research Center, 5P30-DK34933 awarded by the PHS, DHHS.Presented in part at the annual meeting of American Gastroenterological Association in 1990 (Gastroenterology 98: A153).     

Effect of leukotriene C4D4 antagonist on colonic damage induced by intracolonic administration of trinitrobenzene sulfonic acid in rats

We examined the effects of eicosanoid antagonists on colonic damage induced by trinitrobenzene sulfonic acid (TNB) in a rat inflammatory bowel model. TNB (30 mg) dissolved in 0.25 ml of 50% ethanol, was given intrarectally. The appropriate doses of ONO-1078 (a leukotriene C₄D₄ antagonist), ONO-4057 (a leukotriene B₄ antagonist), and OKY-046 (a thromboxane A₂ synthetase inhibitor) were given to obtain the same blood level, either 4 h before (pre-treatment model) or 24 h after (the post-treatment model) the administration of TNB (n=8 in all groups). Drugs were given once daily for 6 days through a gastric feeding tube. Autopsy was performed on the 7th day. Colonie damage was assessed in terms of colonie damage scores, and myeloperoxidase (MPO) activity and eicosanoid concentrations in colonie tissues were measured. Compared with the group given TNB alone, the colonie damage score was reduced to 10% in the pre-treatment model with ONO-1078, but the score was not reduced in other groups, MPO activity was not changed in any group. The concentration of leukotriene C₄ was reduced with ONO-1078 treatment, in both pre- and post-treatment models. These results demonstrated that a leukotriene C₄D₄ antagonist reduced colonie inflammation; however, its anti-inflammatory effect was limited in this colitis model.     

Nonessential role of leukotrienes as mediators of acute gastric mucosal injury induced by aspirin in rats

The present study was designed to determine the role of leukotrienes in aspirin-induced acute gastric mucosal injury in rats. We examined the effects of aspirin, indomethacin, and sodium salicylate on gastric mucosal injury, and on eicosanoid synthesis and content. Aspirin, indomethacin, and acidified salicylate caused significant mucosal injury, while salicylate at pH 7 did not induce significant injury. Aspirin and indomethacin significantly reduced mucosal prostaglandin synthesis and content. No significant changes in mucosal leukotriene C₄ synthesis and content were observed. There were no correlations between changes in mucosal leukotriene B₄ synthesis and the extent of mucosal injury. We also evaluated the effects of MK-571 (a leukotriene D₄ receptor antagonist) and MK-886 (a leukotriene biosynthesis inhibitor) on aspirin-induced gastric mucosal injury. Neither MK-571 nor MK-886 could reduce the mucosal lesions induced by aspirin. These findings suggest that leukotrienes are not involved in aspirin-induced acute gastric mucosal injury in rats.This work was supported in part by grants from the Research Service of the Department of Veterans Affairs and the National Institutes of Health (DK 16816).     

Effect of synthetic prostaglandin E1 analog (ornoprostil) on gastric emptying and pancreatic polypeptide release after solid-meal ingestion in man

The effect of orally administered ornoprostil, 17S,20-dimethyl-6-oxoprostaglandin E₁ methyl ester, on gastric emptying and on pancreatic polypeptide (PP) release after solid meal ingestion, was investigated in man. A radionuclide technique was used to measure gastric emptying of eight healthy volunteers. In addition, four parameters [SI (starting index): the lag time in the start of emptying;K value: the emptying rate;T1/2: the half emptying time; 120 min RR: the percent retention at 120 min] were determined for evaluation. Also, the PP response was analyzed according to two parameters: IPPR_SI, the integrated PP response for periods up to SI, and IPPR₁₂₀, the integrated PP response for 120 min. The results demonstrated that 5 g of orally administered ornoprostil significantly reduced the gastric emptying rate of solid meal (T1/2 and 120 min RR,P<0.05). However, ornoprostil affected neither the basal PP concentrations nor the cephalic phase of PP secretion which was determined as IPPR_SI. This thus suggests that ornoprostil affects the gastric motor function without interfering with the vagal-cholinergic pathway to the stomach.     

Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats

The potential effect of recombinant human interleukin-11 (rhIL-11) on trinitrobenzene sulfonic acid (TNB) -induced colitis was investigated in rats. Intrarectal TNB (40 mg in 0.25 ml 40% ethanol) produced significant ulcerative colitis. The lesions were most severe at three days after TNB instillation, and then declined, but lesions were still observed after two weeks. TNB administration also significantly enhanced the colonic mucosal myeloperoxidase (MPO) levels, which paralleled the severity of colitis. The rhIL-11 at subcutaneous doses of 300 or 1000µg/kg daily for seven days, or 1000µg/kg for three days when given after TNB significantly decreased lesion formation in TNB-induced colitis. These treatments also significantly reduced colonic mucosal MPO levels. TNB enhanced colonic mucosal levels of PGE₂, LTB₄, and TxB₂, but these arachidonic acid derivatives were not affected by the present rhIL-11 treatments. TNB administration for three days caused a body weight loss that returned to normal after 14 days. The rhIL-11 significantly reduced colonic lesion severity and reduced colonic fecal blood loss. Given alone, rhIL-11 did not influence body weight. It can be concluded that rhIL-11 was protective against TNB-induced colitis and reactions of colonic MPO, but that these responses were not mediated through modulation of eicosanoid metabolism.Supported by Genetics Institute, Inc., Andover, Massachusetts.     

Role of superoxide dismutase in mechanism of diethyldithiocarbamate-induced gastric antral ulcer in rats: Protective effect of prostaglandin, cimetidine and pirenzepine

The role of superoxide radicals and the protective effects of superoxide dismutase (SOD), allopurinol, 16, 16-dimethyl-prostaglandin E₂ (dmPGE₂), cimetidine and pirenzepine in diethyldithiocarbamate (DDC)-treated rats were evaluated. Pretreatment with Cu,Zn-SOD (superoxide radical scavenger) 60 000 units/kg, allopurinol (competitive inhibitor of xanthine oxidase) 50 mg/kg, dmPGE₂ (prostaglandin analogue) 10 μg/kg, cimetidine (H₂-receptor antagonist) 10 mg/kg or pirenzepine (selective antimuscarinic drug) 10 mg/kg all significantly reduced the DDC-induced (800 mg/kg) gastric antral ulcer formation in rats. DDC treatment substantially decreases the gastric mucosal Cu, Zn-SOD activity. In this study treatment with DDC and SOD, DDC and dmPGE₂, DDC and cimetidine, and DDC and pirenzepine were demonstrated significantly to prevent the decrease of gastric mucosal Cu, Zn-SOD activity. However, allopurinol did not have this effect. The results suggest that SOD and/or superoxide radicals may play an important role in the mechanism of DDC-induced gastric antral ulcer. The protective property against ulcer formation of these drugs studied might be due to the action of SOD in the gastric mucosa.     

Diet of Paranthropus boisei in the early Pleistocene of East Africa

The East African hominin Paranthropus boisei was characterized by a suite of craniodental features that have been widely interpreted as adaptations to a diet that consisted of hard objects that required powerful peak masticatory loads. These morphological adaptations represent the culmination of an evolutionary trend that began in earlier taxa such as Australopithecus afarensis, and presumably facilitated utilization of open habitats in the Plio-Pleistocene. Here, we use stable isotopes to show that P. boisei had a diet that was dominated by C(4) biomass such as grasses or sedges. Its diet included more C(4) biomass than any other hominin studied to date, including its congener Paranthropus robustus from South Africa. These results, coupled with recent evidence from dental microwear, may indicate that the remarkable craniodental morphology of this taxon represents an adaptation for processing large quantities of low-quality vegetation rather than hard objects.     

Induction of cyclooxygenase protein and stimulation of prostaglandin E2 release by epidermal growth factor in cultured guinea pig gastric mucous cells

The present study was undertaken to investigate whether epidermal growth factor (EGF) could stimulate prostaglandin E₂ release, and if so, by what mechanism EGF would exert such an effect in gastric mucosal cells. In cultured guinea pig gastric mucous cells, EGF dosedependently stimulated prostaglandin E₂ release, with maximal stimulation observed at 10 ng/ml. EGF stimulated an increase in cyclooxygenase activity, which was reduced by protein synthesis inhibitor, actinomycin D, and cycloheximide. EGF also stimulated the enzyme protein synthesis estimated by Western blot analysis, whereas EGF did not stimulate phospholipase A₂ activity. These results suggest that such an effect of EGF onde novo synthesis of cyclooxygenase protein and prostaglandin E₂ release may be involved at least in part in the mechanism of EGF-induced local regulation of gastric mucosal integrity.     

Impaired response of gastric vessels to prostaglandin E2 in rats with persistent obstructive jaundice

We investigated the response of gastric vessels to prostaglandin (PG) E₂ after intra-duodenal release of bile in rats with obstructive jaundice. The animals were divided into four groups according to duration of bile duct obstruction (BDO): control and 1 week (W), 2W, and 3W groups. Prolonged BDO decreased gastric mucosal blood flow (BF) significantly. The BF recovered after the release of BDO in the 1W and 2W groups, but not in the 3W group. BDO decreased PGE₂ content in gastric mucosa in the 1W, 2W, and 3W groups. PGE₂ decreased vascular perfusion pressure of the isolated stomach in the control and 2W groups, but not in the 3W group. The response of gastric vessels to PGE₂ was poor in the 3W group compared with the control and 2W groups. Decreased PGE₂ in the gastric mucosa and decreased response of gastric vessels to PGE₂ may affect gastric blood flow in obstructive jaundice.     

Effects of Leukotriene D4, the Antagonist L-649-923, and Arachidonic Acid on Duodenal Bicarbonate Secretion in the Rat in Vivo

Prostaglandins of the E type stimulate bicarbonate secretion by the duodenal mucosa and inhibit gastric acid secretion, effects that have been related to their anti-ulcer activity. Leukotrienes constitute a more recently discovered branch of the arachidonic acid cascade, and C₄ and D₄ have been suggested to be ulcerogenic in the stomach. We have studied the effects of luminal administration of leukotriene D₄ and the leukotriene C₄/D₄ antagonist L-649–923 on duodenal mucosal alkaline secretion in the anaesthetized rat. Leukotriene D₄ (10^?8-10^?6 M) had no significant effects, but the antagonist dose-dependently increased the bicarbonate secretion and also transiently increased the transmucosal electric potential difference. The precursor arachidonic acid (10^?7-10^?6 M) caused a small increase in secretion. The increase in bicarbonate secretion in response to 10^?3 M of the antagonist was of about the same magnitude as that observed with 10^?5 of prostaglandin E₂, and it was abolished by pretreatment with the cyclooxygenase inhibitor indomethacin. The gastroduodenal protective effects of L-649–923 in vivo may reflect an increase in mucosal prostaglandin production rather than leukotriene antagonism.     

Exaggerated prostaglandin production by colonic smooth muscle in rabbit colitis

Enhanced production of arachidonic acid metabolites by colonic mucosa has been reported in ulcerative colitis as well as in experimental models of colitis. However, production of these compounds by colonic smooth muscle from colitis subjects has not been described. To evaluate arachidonic acid metabolism in colonic tissue, we studied the production of prostaglandin E₂ (PGE₂) by mucosa and muscularis propria in two experimental models of acute colitis in which inflammation was virtually confined to the mucosa. Colitis was induced in New Zealand white rabbits by either of two methods, dinitrochlorobenzene (DNCB) sensitization or formalin followed by intravenous soluble immune complexes (F-IC). Arachidonic acid metabolites were identified from in vitro incubations of tissue with [¹⁴C]arachidonic acid by thin layer chromatography followed by autoradiography. The major eicosanoid metabolites of colitis mucosa and muscularis were¹⁴C-labeled prostaglandin E₂, prostaglandin F_2a and 6-keto prostaglandin f_1a. PGE₂ was quantitated from incubations without labeled arachidonic acid by radioimmunoassay. PGE₂, expressed as picograms per milligram protein per 20 min (mean±sem), was increased in F-IC mucosa (1093±141 vs 645±189, P < 0.05) and DNCB mucosa (1354±487 vs 527±222, P < 0.05) compared to normals. PGE₂ production by uninflamed colitis muscularis propria was also increased five-to eightfold compared to normals for F-IC muscularis (1594±329 vs 189±35, P < 0.005) and DNCB muscularis (1287±171 vs 225±72, P < 0.005). Thus, the adjacent inflammation in colonic mucosa may induce increased eicosanoid production by the uninflamed smooth muscle. Increased PGE₂, in turn, may contribute to the smooth muscle dysfunction seen in colitis.This work was supported by the National Institutes of Health through BRSG RR-05551, by the National Foundation for Ileitis & Colitis, and by the James L. Stamps Foundation, Inc.A preliminary report of this work was presented at the American Gastroenterological Association Meeting, New Orleans, Louisianna, in May 1984, and appeared in abstract form inGastroenterology 86:1129, 1984.