下丘脑外侧区对大鼠胃缺血-再灌注损伤调控的神经机制

目的:观察电刺激下丘脑外侧区(LHA)对胃缺血-再灌注损伤(GI-RI)的影响,并初步分析其可能的神经机制。方法:用电和化学刺激、电损毁神经核团及切断外周神经等方法,观察LHA对大鼠胃缺血30min,再灌注60min所致损伤的影响并分析背侧迷走复合体(DVC)、迷走神经和交感神经在这一效应中的作用。结果:①电刺激LHA或LHA内注射L-谷氨酸(L-Glu),GI-RI均显著加重;②电损毁双侧LHA则减轻GI-RI;③损毁双侧DVC能取消电刺激LHA对GI-RI的加重;④分别切断膈下迷走神经和切除腹腔交感神经节后再电刺激LHA,GI-RI则减轻。结论:LHA是对GI-RI具有加重作用的特异性中枢部位,DVC以及迷走神经、交感神经均参与了LHA对GI-RI的调控作用。     

The protective effect of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats

The purpose of the present study is to investigate the protective effect of calcitonin gene-related peptide (CGRP) on gastric mucosa injury after focal cerebral ischemia reperfusion and gastric ischemia-reperfusion in rats. Wistar male rats (280-320g) were selected for this experiment. Focal cerebral ischemia and reperfusion rat model was established with left middle cerebral artery occlusion by using thread inserting. After regaining consciousness from the anaesthesia,rats were scored according to Zea longa 5 score system. Animals with scores 1-3 were randomly divided into two groups：CGRP group and normal saline group（NS group）. Sham-operated animals were stimulated only by the operation without occluding the middle cerebral artery. Ten rats were involved in each group. Reperfusion was given to the rats in CGRP group and NS group after 2 hours’ ischemia. Rats in CGRP group and NS group were injected intraperiloneally with CGRP (3μg/kg,1mg/L) or NS(3ml/kg) respectively. After 48 hours of the operation,the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method,detecting pathological changes of gastric mucosa tissue by light microscopy,determining mast cells by toluidine blue staining,and observing the expression of Gas, SST, AQP-4 and bFGF by immunohistochemical staining. One-way analysis of variance was used for statistical analysis. Difference between two groups was compared with qtest. Results：1. Under stereo microscope, focal cerebral ischemia and reperfusion rat more significant damage of gastric mucosa of NS group than that of CGRP group was observed,with diffuse edema,splinter hemorrhage and erosion. The injury index of gastric mucosa was lower in CGRP group as compared with that in NS group (P<0.05). 2. HE staining showed that under light microscope,gastric mucosa was damaged more pronouncedly with numerous endothelial cells necrosis,gastric mucosa dissociation,infiltration of inflammatory cells,and irregular arrangement of glands,while in CGRP group,the damage was less severe with partially dissociation of gastric mucosa,less irregular arrangement of glands,fewer mucosa hemorrhage and inflammatory cells infiltration. 3. The total number of mast cells and degranulation ratio of NS group in gastric mucosa was significantly higher than that of CGRP group (P<0.01). 4. Gas expression in gastric antrum mucosa was lower in CGRP group than that in NS group (P<0.01);SST expression in gastric antrum mucosa was higher in CGRP group than that in NS group (P<0.01). 5. AQP-4 expression in gastric mucosa was lower in CGRP group than that in NS group (P<0.05). 6. bFGF expression in gastric mucosa was higher in CGRP group than that in NS group (P<0.01). The results indicated that CGRP reduced the gastric mucosa injury index after brain ischemia and reperfusion,alleviated the damage of gastric mucosa and thus had protective effect on the stomach. An indirect protective effect of CGRP on gastric mucosa was also noted by the up-regulated SST expression and down-regulated Gas expression. CGRP down-regulated AQP-4 expression and up-regulated bFGF expression reduced gastric edema,regulated the secretion of gastric acid and exerted to promote gastric tissue repair. Besides,CGRP also inhibited mast cell degaranulation to reduce the infiltration of inflammatory cells and thus to alleviate the damage of gastric mucosa induced by ischemia and reperfusion.     

胃缺血-再灌注损伤对胃窦黏膜D细胞内生长抑素含量的影响

目的:研究胃缺血-再灌注损伤(gastric ischemia-reperfusion injury,GI-RI)对大鼠胃窦黏膜D细胞内生长抑素(somatostatin SS)含量的影响。方法:实验组大鼠分为单纯缺血组(ISO)、GI-R1 h、6 h、24 h和72 h组(I／R1-4),用免疫组织化学法及图像分析法对SS进行定量研究。结果:正常大鼠胃窦黏膜中D细胞主要分布于幽门腺的中、下1／3处,形态多样;而ISC组和I／R1组D细胞多为圆形,很少见有长的胞质突起;在I／R2-4组,则可见D细胞形态多样,并可见分布于幽门腺上1／3处。ISC组和I／R1组D细胞的数目显著少于对照组,细胞平均灰度值极显著大于对照组;而I／R2-4组D细胞的数目均显著多于对照组,仅I／R2组细胞平均灰度值极显著低于对照组。结论:胃窦黏膜中D细胞的形态数量及细胞内SS的含量在大鼠GI-RI过程中有变化,提示SS参与了GI-RI过程。     

缺血预适应在大鼠肢体缺血再灌注后胃粘膜损伤中的作用

目的:观察肢体缺血再灌注(LIR)对胃粘膜的损伤,探讨肢体缺血再灌注对胃粘膜损伤的作用及其部分机制,以及短暂多次肢体缺血在胃粘膜损伤发生中的作用。方法:按Rosenthal方法复制大鼠LIR模型,观察并测定肢体缺血4h再灌注4h后以及应用缺血预适应干预对胃粘膜损伤的影响:取各组胃粘膜制作切片于光学显微镜和电子显微镜下进行观察,测定各组胃粘膜损伤指数、胃粘膜血流量(GMBF)、胃结合粘液量、胃粘液中磷脂、氨基己糖的含量、血浆和胃组织一氧化氮含量以及胃粘膜一氧化氮合酶(NOS)活性。结果:光学显微镜和电子显微镜观察结果显示大鼠LIR后胃粘膜损伤严重,IPC组各类细胞损伤较LIR组轻;LIR后GMBF及胃结合粘液量、胃粘液中磷脂、氨基己糖的含量均低于对照组,虽然IPC组大部分指标与对照组有差异,但与LIR组对比GMBF及胃结合粘液量、胃粘液中磷脂、氨基己糖的含量均较高于LIR组;LIR组血浆与胃粘膜组织NO含量及NOS活性显著高于对照组,而IPC组血浆与胃粘膜组织NO含量和胃粘膜的NOS活性又显著高于LIR组。结论:肢体缺血再灌注可导致胃粘膜损伤;缺血预适应可减轻肢体缺血再灌注后的胃粘膜损伤。     

丹酚酸A对缺血再灌注大鼠缺血期胃粘膜血流量及再灌注期胃粘膜脂质过氧化的影响

目的:探讨丹酚酸A(Sal.A)对缺血再灌注大鼠胃粘膜缺血期血流及再灌注期脂质过氧化的影响。方法:复制缺血-再灌注模型,用组织反射光谱法检测胃粘膜表面区域血液量(ΔEr)和血红蛋白氧饱和度(F)的变化,硫代巴比妥酸法测定胃粘膜丙二醛(MDA)含量和邻苯三酚自氧化法测定超氧化物歧化酶(SOD)活性。结果:与对照组比较,Sal.AI(1mg/Kg)组显著减少缺血期大鼠ΔEr和F下降程度(P<0.05),再灌注期MDA含量显著降低(P<0.05),SOD活性显著升高(P<0.05);与对照组和Sal.AI(1mg/Kg)组相比,Sal.AII(10mg/Kg)组显著减少缺血期大鼠胃粘膜ΔEr和F下降程度(P<0.01)再灌注期MDA含量显著降低(P<0.01),SOD活性显著升高(P<0.01)。结论:丹酚酸A能改善缺血期大鼠胃粘膜血流并且降低再灌注时胃粘膜脂质过氧化水平和提高抗氧化的活性,减轻胃粘膜的再灌注损伤。     

抑郁模型大鼠胃窦部变态反应及超微结构改变

目的：观察抑郁模型大鼠胃窦部变态反应及超微结构改变。方法:将慢性、不可预见性、非同质性应激原作为抑郁模型,通过免疫荧光组织化学及超微结构形态学观察抑郁模型组(n=10)和正常对照组 (n=10)大鼠胃窦部的免疫变态反应及形态学的变化。结果:抑郁模型组大鼠胃窦黏膜组织肥大细胞胰蛋白酶1（MCP-1）平均免疫荧光强度值(37.4±7.7), 显著高于对照组（24.8±5.6）,P＜0.05。抑郁模型大鼠胃窦黏膜组织肥大细胞激活、增殖及颗粒增生。超微电镜观察发现,抑郁模型组大鼠胃窦黏膜组织肥大细胞表现为：肥大细胞向血管、神经和单核细胞周围渗透,肥大细胞膜折皱,细胞内含有非同质的、非均匀、低电子密度颗粒,部分颗粒到达膜表面、成为丝状物、空颗粒及脂质体,细胞核呈梭形;肥大细胞周围白细胞、单核细胞、巨噬细胞渗出;肥大细胞激活脱颗粒,脱落的颗粒趋化到巨噬细胞表面;白细胞颗粒与肥大细胞膜黏附形成桥接;巨噬细胞吞噬肥大细胞激活脱落的颗粒。结论:抑郁模型大鼠胃窦部发生免疫变态反应,肥大细胞对微环境的变化一方面表现肥大细胞细胞数显著增加,另一方面表现为其表型的变化。     

Lateral hypothalamic area mediated the protective effects of microinjection of glutamate into interpositus nucleus on gastric ischemia-reperfusion injury in rats

We investigated the protective effects of chemical stimulation of cerebellar interpositus nucleus (IN) on gastric ischemia-reperfusion injury (GI-RI) and its possible regulatory mechanisms in rats. Gastric mucosal damage index (GMDI) indicated the severity of gastric mucosal injuries. Transferase dUTP nick end labeling (TUNEL) staining and proliferating cell nuclear antigen (PCNA) were performed to assess gastric mucosal cell apoptosis and proliferation. Microinjection of glutamate into IN markedly attenuated GI-RI. Either chemical lesion of IN or electrical ablation of the decussation of superior cerebellar peduncle (DSCP) obviously aggravated GI-RI. The protective effects of IN were reversed with the pretreatments of microinjection of 3-mercaptopropionic acid into IN or Bicuculline into lateral hypothalamic area (LHA), individually. The discharge frequency and intensity of greater splanchnic nerve (GSN) decreased and gastric mucosal blood flow increased after chemical stimulation of IN. The apoptosis of positive cells of gastric mucosa was decreased by chemical stimulation of IN, whereas proliferation increased. The gastric juice volume, acidity, and total acid output were all decreased after the chemical stimulation of IN. These results indicated that IN participates in regulation of GI-RI and is a specific area in central nervous system for exerting protective effects on GI-RI. DSCP, LHA and GSN may involve in this process. Apoptosis and proliferation may mediate this protective process in rats too.     

CGRP和NGF对全脑缺血再灌注大鼠脑组织PKC表达的调节作用

目的　研究大鼠脑缺血再灌注后蛋白激酶C(proteinkinaseC ,PKC)在海马和顶叶皮质的表达 ,探讨降钙素基因相关肽 (CGRP)和神经生长因子 (NGF)对脑组织缺血再灌注的保护作用及机制。方法　采用颈动脉负压分流法制作大鼠脑缺血再灌注模型 ,采用免疫组织化学SABC法及显微图像分析检测海马及皮质内PKC的表达。结果　大鼠缺血再灌注海马CA1区及顶叶皮质内PKC阳性产物平均灰度值较正常组低 (P <0 .0 5 ) ,注射CGRP或NGF后PKC阳性产物平均灰度值明显高于缺血再灌注组 (P <0 .0 1) ,二者联合应用时平均灰度值比单独应用高 (P <0 .0 1)。结论　CGRP及NGF参与缺血神经元PKC的调节 ,二者对缺血神经元有协同保护作用     

孤束核参与室旁核加压素能神经元对大鼠胃缺血-再灌注损伤的调控作用

目的：探讨孤束核（NTS）在下丘脑室旁核（PVN）加压素能神经元对大鼠胃缺血-再灌注损伤（GI-RI）调控中的作用。方法：复制夹闭大鼠腹腔动脉30 min，松开动脉夹血流复灌1 h的GI-RI模型，观察核团内微量注射、电刺激、损毁等对其影响。结果：PVN内注射精氨酸加压素（AVP）能明显减轻GI-RI，且具有剂量-效应依赖关系（r=-0.477, P<0.05）；损毁双侧NTS或NTS内给予AVP受体阻断剂均能取消电刺激PVN对GI-RI的减轻作用；NTS内注射AVP的作用与PVN内注射AVP的效应相似。结论：NTS参与下丘脑室旁核加压素神经元对大鼠胃缺血-再灌注损伤的调控作用，并且是通过其中的AVP受体来实现的。     

柴胡疏肝散对胃溃疡大鼠血浆、胃、蓝斑中胃泌素及生长抑素的影响

目的研究柴胡疏肝散对急性应激胃溃疡大鼠血浆、胃、蓝斑中胃泌素及生长抑素含量的干预作用。方法将32只大鼠随机分为正常对照组、胃溃疡模型组、柴胡疏肝散组、雷尼替丁组,采用不可预知性刺激造成大鼠急性胃溃疡模型,观察各组大鼠血浆、胃、蓝斑中胃泌素及生长抑素含量的变化。结果与模型组相比,柴胡疏肝散不仅能明显降低血浆、胃中胃泌素含量,而且能降低胃组织中的生长抑素含量,差异均有统计学意义（P〈0.05）,血浆中生长抑素未见明显降低（P〉0.05）,蓝斑中两者差异均无统计学意义（P〉0.05）,但雷尼替丁能显著降低蓝斑中胃泌素含量、血浆中生长抑素含量,差异均有统计学意义（均P〈0.05）,而对蓝斑中生长抑素含量则无影响。结论柴胡疏肝散改善外周或中枢胃泌素及生长抑素含量可能是治疗应激性胃溃疡的作用机制之一。     

降钙素基因相关肽和神经生长因子对短暂性全脑缺血后再灌注大鼠纹皮质c-jun mRNA及蛋白表达的影响

目的探讨外源性降钙素基因相关肽（CGRP）和神经生长因子（NGF）对短暂性全脑缺血后再灌注大鼠纹皮质c-jun mRNA及蛋白表达的影响。方法原位杂交和免疫组织化学结合显微图像分析方法。结果假手术组大鼠纹皮质c-jun mRNA表达弱；缺血组较假手术组c-jun mRNA表达显著强（P〈0．01）；CGRP组和NGF组c-jun mRNA表达弱于缺血组（P〈0．05）；CGRP和NGF合用组c-jun mRNA表达明显弱于缺血组（P〈0．01），分别弱于CGRP组和NGF组（P〈0．05）。假手术组大鼠纹皮质未见c-Jun蛋白表达；缺血组较假手术组c-Jun蛋白表达明显强（P〈0．01），缺血后再灌注3h强，1d、3d时弱；CGRP组和NGF组c-Jun蛋白表达较缺血组弱（P〈0．05）；CGRP和NGF合用组较缺血组c-Jun蛋白表达明显弱（P〈0．01），分别弱于CGRP组和NGF组（P〈0．05）；CGRP和NGF合用组缺血后再灌注3h时强，1d、3d时弱。结论CGRP和NGF分别抑制全脑缺血后再灌注大鼠纹皮质c-jun mRNA及蛋白表达，联合应用显著抑制全脑缺血后再灌注大鼠纹皮质c-jun mRNA及蛋白表达，两者对保护缺血神经元可能有协同作用。     

硒对大鼠腺胃癌的作用及其对腺胃、胰CGRP阳性细胞的影响

目的：探讨硒在机体自然抗肿瘤发生过程中的作用。方法：用ＭＮＮＧ（２０ｍｇ／ｋｇ）灌胃诱导大鼠腺胃粘膜异倍形成（大鼠腺胃癌模型形成）。用流式细胞仪测定硒对大鼠腺胃幽门粘膜异倍体形成的影响。用免疫组织化学ＡＢＣ法观察硒在大鼠腺胃粘膜异倍体形成过程中,大鼠腺胃、胰ＣＧＲＰ阳性细胞的变化。并对以上结果进行图像分析及统计学处理。结果：（１）硒能掏所致大鼠腺胃粘膜细胞异倍体的形成。（２）在ＭＮＮＧ所致大鼠异倍     

炎性胃痛幽门括约肌内VIP和CGRP能神经的变化

目的：研究大鼠幽门括约肌内肠神经系统的分布与胃肠运动功能的相互关系。方法：30只大鼠，设对照组，实验组，采用免疫组织化学技术，显示括约肌内VIP－和CGRP－ir神经元成分，结果：（1）正常幽门括约肌肌层可见个别的CGRP－和VIP－ir神经元胞体，阳性纤维丰富，于肌纤维增厚的括约肌部位神经元成分特别丰富，（2）甲醛致胃炎性痛鼠，肌间神经丛VIP神经元胞体和肌层内神经纤维的活性（图像分析，平均光密度）降低，甲醛组比对照组均显著降低（P＜0．01），但CGRP的甲醛组较对照组升高（P＜0．01），结论：肠神经系统中这两种神经元成分参与幽门括约肌活动与胃肠运动的调控机制。     

降钙素基因相关肽和神经生长因子对短暂性脑缺血后再灌注大鼠纹皮质c-fos mRNA及蛋白表达的影响

目的：探讨外源性降钙素基因相关肽(CGRP)和神经生长因子(NGF)对短暂性脑缺血后再灌注大鼠纹皮质c-fos mRNA及蛋白表达的影响。方法：在脑缺血后再灌注模型上，应用原位杂交和免疫组织化学结合显微图像分析方法检测c-fos mRNA及蛋白表达。结果：缺血组大鼠纹皮质较假手术组c-fos mRNA和蛋白表达非常显著增加；CGRP组和NGF组c-fos mRNA和蛋白表达分别显著弱于缺血组；CGRP和NGF合用组c-fos mRNA和蛋白表达非常明显弱于缺血组、CGRP组和NGF组。结论：CGRP和NGF分别抑制脑缺血后再灌注大鼠纹皮质c-fos mRNA及蛋白表达，联合应用则能显著抑制脑缺血后再灌注大鼠纹皮质c-fos mRNA及蛋白表达，二者对保护缺血神经元可能有协同作用。     

CGRP和NGF对短暂性全脑缺血后再灌注大鼠纹皮质Caspase-3蛋白表达的影响

为了探讨外源性降钙素基因相关肽 ( CGRP)和神经生长因子 ( NGF)对短暂性全脑缺血后再灌注大鼠纹皮质 Caspase-3蛋白表达的影响 ,在全脑缺血后再灌注模型上 ,应用免疫组织化学结合显微图象分析方法检测了 Caspase-3蛋白表达。结果发现 ,假手术组大鼠纹皮质未见 Caspase-3表达 ;缺血组较假手术组 Caspase-3表达显著增加 ( P<0 .0 1) ;CGRP组和 NGF组 Cas-pase-3表达均弱于缺血组 ( P<0 .0 5 ) ;CGRP和 NGF合用组 Caspase-3表达明显弱于缺血组 ( P<0 .0 1) ,分别弱于 CGRP组 ( P<0 .0 5 )和 NGF组 ( P<0 .0 5 )。缺血组缺血后再灌注 3 h Caspase-3开始表达 ,1d达高峰 ,3 d时减弱 ,CGRP和 NGF合用组 Cas-pase-3表达随着缺血后再灌注时间的延长而逐渐减弱。以上结果提示 :CGRP和 NGF分别抑制全脑缺血后大鼠纹皮质 Caspase-3蛋白表达 ,联合应用则能显著抑制全脑缺血后大鼠纹皮质 Caspase-3蛋白表达 ,二者对保护缺血神经元可能有协同作用     

丹参提取物F抗大鼠胃窦部粘膜再灌注损伤作用的研究

目的：探讨丹参提取物Ｆ（ＤＳＥＦ）抗大鼠胃窦部粘膜再灌注损伤的作用。方法：大鼠随机分为假手术组（ＳＣ）,单纯失血组（ＨＥ）,生理盐水组（ＮＳ）及丹参提取物Ｆ组（ＤＳＥＦ）;ＳＣ组大鼠除未行放血及血液回输外,行所有操作步骤,ＨＥ组大鼠经２０ｍｉｎ的失血性休克后处死,ＮＳ及ＤＥＦ组在休克２０ｍｉｎ后处死。     

短暂性脑缺血后再灌注大鼠丘脑C-jun mRNA表达及CGRP和NGF的影响

目的探讨外源性降钙素基因相关肽(CGRP)和神经生长因子(NGF)对短暂性脑缺血后再灌注大鼠丘脑c-jun mRNA表达的影响。方法在脑缺血后再灌注模型上,应用原位杂交结合显微图像分析方法检测c-jun mRNA表达。结果缺血组大鼠丘脑较假手术组c-jun mRNA表达显著增加(P<0.01),CGRP组和NGF组c-jun mRNA表达分别低于缺血组(P<0.05),CGRP+NGF合用组c-jun mRNA表达明显低于缺血组(P<0.01)和分别低于CGRP组和NGF组。结论CGRP和NGF分别抑制脑缺血后再灌注大鼠丘脑c-jun mRNA表达,二者联合应用对保护缺血神经元可能有协同作用。     

海洛因依赖对大鼠胃窦生长抑素和白细胞介素2阳性细胞表达的影响

目的:探讨海洛因依赖对大鼠胃窦生长抑素(SS)、白细胞介素2(IL-2)阳性细胞表达的影响。方法:应用免疫组织化学SABC法及图像分析技术。结果:海洛因依赖组大鼠胃窦SS阳性细胞染色强度增强,细胞数量显著高于空白和盐水对照组,平均灰度值低于正常及盐水对照组;IL-2阳性细胞的数量及染色强度显著降低,平均灰度值升高。结论:大鼠胃窦中SS、IL-2阳性细胞通过形态数量及细胞内的SS、IL-2的含量改变参与了在海洛因依赖期间机体的调节过程。     

CGRP和NGF对全脑缺血再灌注大鼠脑组织Erk表达的调节作用

目的 :检测大鼠脑缺血再灌注后细胞外调节蛋白激酶 (Erk)的表达 ,探讨降钙素基因相关肽 (CGRP)和神经生长因子 (NGF)对脑组织的保护作用及机制。方法 :采用颈动脉负压分流法制作大鼠脑缺血再灌注模型 ,采用免疫组织化学SABC法及显微图像分析检测海马及皮质内Erk的表达。结果 :大鼠缺血再灌注海马及皮质内Erk免疫反应阳性产物较正常组增多 (P <0 .0 5 ) ,而注射CGRP或NGF后阳性产物明显高于缺血再灌注组 (P <0 .0 1 ) ,二者联合应用效果更加显著 (P <0 .0 5 )。结论 :CGRP及NGF参与缺血神经元Erk的调节 ,二者对缺血神经元有协同修复作用     

Acute gastric lesions induced by the administration of histamine to rats with partial vascular occlusion: evidence for the gastroprotective effect of prostaglandin

Introduction

Histamine is not only a potent stimulator of gastric acid secretion, but it also plays a central role in gastroduodenal ulcerogenesis. In the present study we tested the effect of pre-treatment with exogenous prostaglandin E₂ (PGE₂) in a new rat model of experimental gastric ulcers induced by combination of histamine and gastric ischemia.

Methods

In male Wistar rats, a chronic ischemia of gastric mucosa was induced via the clamping of the left gastric artery and vein (L-AV) in combination with pylorus ligation. The following treatment groups of rats (6 rats/group) were investigated: 1) histamine alone (40 mg/kg twice s.c.); 2) vehicle (saline) followed 30 min later by gastric mucosal L-AV ischemia and pylorus ligation combined with histamine (40 mg/kg twice s.c.) and 3) PGE₂ (5 µg/kg i.g.) followed 30 min later by gastric mucosal L-AV ischemia combined with histamine (40 mg/kg twice s.c.) and pylorus ligation. At 4 hr after the clamping of L-AV and pylorus ligation, the area of gastric lesions and gastric acid secretion was determined.

Results

Histamine treatment failed to produce gastric lesions, but when it was combined with ischemia, the widespread gastric lesions in the corpus mucosa, but not in the antrum, were observed. This damaging effect and decrease in the GBF were significantly attenuated by pretreatment with PGE₂.

Conclusion

The present study demonstrates that gastric hypersecretion induced by histamine in combination with gastric mucosal ischemia results in gastric lesions which progress into chronic gastric ulcers.