Stress Ulcer Development Research Articles

Ischemic insular damage and stress ulcer in patients of acute ischemic stroke.

Stress ulcer (SU) is a common complication in patients with acute ischemic stroke. The relationship of infarction location and the incidence of SU was unclear. Herein, we aim to investigate the association between ischemic insular damage and the development of SU. Data were retrieved from the SPARK study (Effect of Cardiac Function on Short-Term Functional Prognosis in Patients with Acute Ischemic Stroke). We included the patients who had experienced an ischemic stroke within 7 days. The diagnosis of SU was based on clinical manifestations, including hematemesis, bloody nasogastric tube aspirate, or hematochezia. Evaluation of ischemic insular damage was conducted through magnetic resonance imaging. Cyclo-oxygenase regression analysis and Kaplan-Meier survival curves were used to assess the relationship between ischemic insular damage and the occurrence of SU. Among the 1357 patients analyzed, 110 (8.1%) developed SUs during hospitalization, with 69 (6.7%) experiencing infarctions in the anterior circulation. After adjusting for potential confounders, patients with ischemic insular damage exhibited a 2.16-fold higher risk of developing SUs compared to those without insular damage (p=.0206). Notably, among patients with infarctions in the anterior circulation, those with insular damage had a 2.21-fold increased risk of SUs (p=.0387). Moreover, right insular damage was associated with a higher risk of SUs compared to left insular damage or no insular damage (p for trend=.0117). Kaplan-Meier curves demonstrated early separation among groups, persisting throughout the follow-up period (all p<.0001). This study identified a significant independent correlation between ischemic insular damage, particularly on the right side, and the development of SU during hospitalization, indicating the need to consider prophylactic acid-suppressive treatment for patients with ischemic insular damage.

Assessment of the appropriateness of stress ulcer prophylaxis use and its determinants among admitted surgical patients at Debre Berhan University Hakim Gizaw Hospital, Ethiopia. A hospital-based cross-sectional study.

Pharmacological stress ulcer prophylaxis (SUP) has been recommended for many years to reduce the risk of clinically significant upper gastrointestinal (GI) bleeding caused by stress ulcers (SUs). Stress-related ulcer bleeding in surgical patients significantly increases morbidity and mortality. Therefore, preventing stress-induced hemorrhage is the most appropriate measure for patients who are at increased risk. However, the inappropriate use of SUP has increased in recent years, and its use in Ethiopian surgical patients has not been well studied. The aim of this study was to assess the appropriateness of SUP use and its determinants among admitted surgical patients at Debre Berhan University Hakim Gizaw Hospital (DBUHGH), Ethiopia. We randomly selected 230 patients from the whole cross-sectional group of all surgical patients at DBUHGH from 1 February to 30 June 2023. The risk of stress ulcer (SU) development was assessed using the modified American Society of Health-System Pharmacists (ASHP) guidelines. For data analysis, we used SPSS version 25. The mean age of study participants was 47.2 years (SD ± 20.4), and out of the total of 230, 130 (56.5%) were women. Approximately 66% of study participants took inappropriate SUP based on ASHP guidelines criteria. The most commonly used drug class for SUP was histamine-2 receptor blockers 115 (50%). Study participants who have a Charlson Comorbidity Index Score of moderate and GI bleeding have been significantly associated with the inappropriate use of SUP. In our study, inappropriate SUP use was common in the surgical ward of DBUHGH. This may be an area that requires further and more focused working together among clinical pharmacists and medical professionals in an institution-specific SUP protocol that aids clinicians in identifying appropriate candidates for SUP medication.

Current practice of stress ulcer prophylaxis in a surgical patient cohort in a German university hospital

IntroductionStress ulcer prophylaxis (SUP) has been a widespread practice both in intensive care units (ICU) and internal wards at the beginning of the twenty-first century. Clinical data suggests an important overuse of acid suppressive therapy (AST) for this indication. Data on current clinical practice of SUP in surgical patients in a non-ICU setting are spares. In the light of a growing number of reports on serious side effects of AST, this study evaluates the use of AST for SUP in a normal surgical ward in a German university hospital.MethodsBetween January 2016 and June 2016, SUP was analysed retrospectively in 1132 consecutive patients of the Department of Surgery of the Universitätsmedizin Greifswald.ResultsThe patients managed with and without SUP were similar with respect to demographic data and treatment with anticoagulants, SSRI and glucocorticoids. Patients with SUP were treated more frequently by cyclooxygenase inhibiting drugs (NSAID, COX2-inhibitors), were more frequently treated in the intermediated care unit and had a longer hospital stay. Risk factors for the development of stress ulcers were similarly present in patient groups managed with and without SUP. About 85.7–99.6% of patients were given SUP without an adequate risk for stress ulcer development, depending on the method used for risk assessment.DiscussionStill today, SUP is widely overused in non-ICU surgical patients. Information campaigns on risk factors for stress ulcer development and standard operating procedures for SUP are required to limit potential side effects and increased treatment costs.

A Retrospective Cohort Analysis of the Use of Enteral Nutrition Plus Pharmacologic Prophylaxis or Enteral Nutrition Alone.

Background: Due to the risk of development of stress ulcers in intensive care unit (ICU) patients, pharmacologic prophylaxis is often utilized. However, some literature describes the use of enteral nutrition instead as stress ulcer prophylaxis. Methods: The purpose of this study is to determine if enteral nutrition is similar to pharmacologic stress ulcer prophylaxis (SUP) with enteral nutrition for reduction of gastrointestinal (GI) bleeding, perforation, or ulceration in ICU patients. This was a retrospective, single-center cohort study that took place at an academic medical center. Adult ICU patients receiving enteral nutrition who had a risk factor for stress-related mucosal damage were included. The primary outcome was the incidence of GI bleeding, perforation, or ulcer formation. Results: Overall, 167 patients were included in the study, 147 in the pharmacologic prophylaxis plus EN group (PPEN) and 20 in the enteral therapy only (EN) group. Of 167 patients included, 22 patients (21 in the PPEN group and 1 in the EN group) developed a primary outcome of GI bleeding, perforation, or ulceration (14.3% vs 5%, P = .4781). Patients in the PPEN group had a higher incidence of pneumonia (42.2% vs 15%, P = .0194), but no difference was seen between groups when patients with pneumonia present on admission were excluded (20.6% vs 10.5%, P = .5254). Conclusion: In this small cohort of patients, enteral nutrition alone is as effective as pharmacologic therapy in addition to enteral nutrition for the reduction of stress-related GI bleeding, perforation, and ulceration.

Assessment of pharmacologic prophylaxis use against stress ulcer in the medical wards of University of Gondar Hospital.

Background:Critically ill patients with moderate-to-severe physiologically stressful event are at high risk of developing stress ulcers. The use of pharmacological prophylaxis significantly reduces the incidence of stress ulcer in high-risk patients.Objective:The aim of this study was to assess the use of pharmacological prophylaxis for stress ulcer in the medical wards of University of Gondar Hospital.Methods:A cross-sectional study design was used. In total, 234 patients were selected through simple random sampling technique. The risk of stress ulcer development was assessed using Evidence-Based Medicine Guideline for stress ulcer prepared by Orlando Regional Medical Center. SPSS version 21 was used for data analysis.Result:The most common acute risk factor to stress ulcer was coagulopathy (18.4%), followed by hypoperfusion (9.8%). The concomitant non-steroidal anti-inflammatory drug use (16.7%), mild-to-moderate brain or spinal cord injury (11.1%), and concomitant or recent corticosteroid use (9.4%) were frequently seen risk factors that necessitate administration of a prophylaxis. In total, 82 (35%) study participants were given stress ulcer prophylaxis, among which 52 (63.4%) were given without indication. The most commonly used drug class in the prevention of stress ulcer was proton pump inhibitors (76/82, 92.7%). In total, 43 (18.4%) study subjects were not given stress ulcer prophylaxis while there was clear indication. Patients with a long hospital stay and a diagnosis of central nervous system disorders had significant risk for inappropriate stress ulcer prophylaxis use.Conclusion:In this study, inappropriate use of prophylaxis for stress ulcer was common. The higher proportion of inappropriateness was due to the use of stress ulcer prophylaxis while there was no enough indication. We recommend future researchers to assess the cost and impact of inappropriate stress ulcer prophylaxis use, and the physicians should be adherent to the standard guidelines.

Evaluation of Stress Ulcer Prophylaxis Benefits and Outcomes: A Simple Literature Review

Background: One of the commonest complications in critically ill patients is stress related mucosal disease (SRMD). It can be associated with increase in the risk of development of overt gastrointestinal bleeding. As a result, a lot of literatures have been done to evaluate the pathogenesis that stands behind its development, and assessment of the measures that can be used to lower the risk of its 'occurrence. Aim of the Work: In this review we aimed at discussing the pathogenesis that stands behind stress ulcer development, Also, discussing the role of anta- acid as a prophylaxis against harms and benefits. In addition to providing an intensive study that analyzed the recent literatures considered this field of study. Methodology: A comprehensive search was done using biomedical databases; Medline, and Pubmed, for studies concerned with assessment of stress ulcer prophylaxis. Keywords used in our search through the databases were as; “stress ulcer”, “stress ulcer prophylaxis”, “stress ulcer in ICU patients”. Conclusion: Stress related mucosal disease is associated with increase in the risk of clinically overt gastrointestinal bleeding. As a result, patients who require mechanically ventilation for more than 48 h and those with a manifest of coagulopathy are highly recommended for having stress ulcer prophylaxis (SUP). Anta- acid such as Proton Pump Inhibitors (PPIs) and histamine 2 receptor antagonists (H2RA) help in prevention of gastrointestinal bleeding, but did not have any effect on mortality risk reduction. Still further prospective randomizes trials needs to be done to evaluate our scientific research survey to guide the physicians in making a decision about the use of SUP in ICU patients.

Evaluation of Stress Ulcer Prophylaxis Benefits and Outcomes: A Simple Literature Review

Background: One of the commonest complications in critically ill patients is stress related mucosal disease (SRMD). It can be associated with increase in the risk of development of overt gastrointestinal bleeding. As a result, a lot of literatures have been done to evaluate the pathogenesis that stands behind its development, and assessment of the measures that can be used to lower the risk of its 'occurrence. Aim of the Work: In this review we aimed at discussing the pathogenesis that stands behind stress ulcer development, Also, discussing the role of anta- acid as a prophylaxis against harms and benefits. In addition to providing an intensive study that analyzed the recent literatures considered this field of study. Methodology: A comprehensive search was done using biomedical databases; Medline, and Pubmed, for studies concerned with assessment of stress ulcer prophylaxis. Keywords used in our search through the databases were as; “stress ulcer”, “stress ulcer prophylaxis”, “stress ulcer in ICU patients”. Conclusion: Stress related mucosal disease is associated with increase in the risk of clinically overt gastrointestinal bleeding. As a result, patients who require mechanically ventilation for more than 48 h and those with a manifest of coagulopathy are highly recommended for having stress ulcer prophylaxis (SUP). Anta- acid such as Proton Pump Inhibitors (PPIs) and histamine 2 receptor antagonists (H2RA) help in prevention of gastrointestinal bleeding, but did not have any effect on mortality risk reduction. Still further prospective randomizes trials needs to be done to evaluate our scientific research survey to guide the physicians in making a decision about the use of SUP in ICU patients.

Stress ulcer prophylaxis in patients being weaned from the ventilator in a respiratory care center: A randomized control trial.

No data has been available on prophylaxis for stress ulcer development during the process of weaning patients off mechanical ventilators. We conducted a randomized study to evaluate the efficacy of stress ulcer prophylaxis with lansoprazole OD in patients being weaned from mechanical ventilators. A total of 120 patients were randomly allocated into two groups using blocked randomization, with 60 patients in each group. Group A was the treatment group, receiving lansoprazole OD 30mg from a nasogastric tube for 14 days, while Group B, the control group, received no proton pump inhibitors or other medications for treating peptic ulcers. The primary end point of our study was apparent upper gastrointestinal bleeding within 2 weeks of enrollment. Apparent upper gastrointestinal bleeding occurred in zero patients and five patients in Groups A and B, respectively (Group A: 0% vs. Group B: 8.3%, p=0.057). There was no significant difference between the two groups in ventilator-associated pneumonia (Group A: 6.7% vs. Group B: 10.0%, p=0.509) and 30-day survival rates (Group A: 96.7% vs. Group B: 100%, p=0.496). Stress ulcer prophylaxis with lansoprazole in patients being weaned from mechanical ventilators led to a lower but not statistically significant incidence of apparent upper gastrointestinal bleeding. There was no significant increase of incidence of ventilator-associated pneumonia in the prophylaxis group. Further larger scale studies are needed to clarify the benefit of stress ulcer prophylaxis in such patients.

The Distressing Overuse of Gastric Acid Inhibitors

Gastric acid secretion by parietal cells is an energy consuming process that concentrates H? one million-fold. The energy required is produced by abundant mitochondria. High gastric acidity in combination with the proteolytic enzyme, pepsin, and the lipolytic enzyme, lipase, plays a key role in killing ingested microorganisms including bacteria [1, 2], viruses [3], and prions [4]. This corrosive juice can, however, overwhelm mucosal defense mechanisms leading to erosion and ulceration. Stress ulcers and less severe damage to the gastric mucosa may develop in critically ill patients. The damage, which occurs predominantly in the oxyntic mucosa, is thought to be caused by tissue hypoxia [5, 6]. Hypovolemic or hypotensive patients are at obvious risk of developing such ulcers, but severe illness also increases the risk of stress ulcers [7, 8], particularly in patients requiring mechanical ventilation. Experimental studies have suggested that antisecretory medications, e.g. proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs), reduce development of ulcers in the oxyntic mucosa by decreasing energy expenditure as well as raising intragastric pH [9, 10]. In this issue of Digestive Diseases and Sciences, Koczka et al. [11] report the overuse of stress ulcer prophylaxis in a large medical center. This adds to a large body of literature reporting the inappropriate overprescription of PPIs. Although the use of gastric acid inhibitors may reduce the risk of stress ulcers, it is important to target the therapy to patients at significant risk since PPIs have recently been associated with numerous adverse events, including infections. Gastric hypoacidity leads to bacterial overgrowth in the stomach and small intestine, in particular, an increase in gram negative and anaerobic bacteria [12, 13]. PPIs also increase the risk for Clostridium difficile infection (CDI) [14] and may predispose cirrhotic patients for spontaneous bacterial peritonitis [15, 16]. PPIs may also be associated with increased risk for respiratory infections, although the data are less clear [17, 18]. Nevertheless, in patients disposed to develop stress ulcers (that is patients with hypovolemia and/or hypoxia), it seems justified to prescribe prophylaxis with PPIs since the benefits of preventing a significant bleed in these very sick patients outweigh potential risks [19]. Critically ill patients probably profit from PPI stress ulcer prophylaxis, whereas in less ill patients with a minute risk of development of stress ulcers, the side effects may represent a greater risk for the patients than a possible small reduction in the risk of stress ulcer bleeding. In the present issue Koczka et al. [11] compared the attitude to stress ulcer prophylaxis between attending physicians and residents in a medical center in New York, reporting that half of the attending physicians thought that stress ulcer prophylaxis was indicated outside critical care settings. Perhaps even more problematic than short-term overuse of PPIs during the hospital stay is the fact that most of these patients are discharged on PPIs and thus probably remain on these drugs for prolonged periods without a proper indication [20, 21]. After patients are on PPIs for more than 3 months, stopping may be difficult due to rebound acid hypersecretion-induced dyspepsia [22, 23]. In conclusion, stress ulcer prophylaxis with PPIs is indicated in critically ill patients with hypovolemia and/or R. Fossmark H. Waldum (&) Department of Gastroenterology and Hepatology, St. Olavs Hospital, Prinsesse Kristinas Gate 1, 7006 Trondheim, Norway e-mail: helge.waldum@ntnu.no

Xiaotan Tongfu granules contribute to the prevention of stress ulcers

To investigate the efficacy and potential mechanism of Xiaotan Tongfu granules (XTTF) in stress ulcers. One hundred sixty rats were randomly divided into 4 groups (n = 10) as follows: the model group (MP group), the control group (CP group), the ranitidine group (RP group) and the XTTF granule group (XP group). Rats in the MP group received no drugs, rats in the CP group received 0.2 mL of a 0.9% sodium chloride solution via oral gavage, and rats in the RP and XP groups received the same volume of ranitidine (50 mg/kg) or XTTF granule (4.9 g/kg). The cold-restraint stress model was applied to induce stress ulcers after 7 consecutive days of drug administration. Afterwards, rats were sacrificed at 0, 3, 6 and 24 h. Gastric pH was measured by a precise pH meter; gastric emptying rate (GER) was measured by using a methylcellulose test meal; myeloperoxidase activity (MPO), macrophage migration inhibitory factor (MIF), proliferating cell nuclear antigen (PCNA), and heat shock protein 70 (HSP70) were measured by immunohistochemical staining; and mucosal cell apoptosis was measured by transferase dUTP nick end labeling. In the cold-restraint stress model, the development of stress ulcers peaked at 3 h and basically regressed after 24 h. Gastric lesions were significantly different in the RP and XP groups at each time point. Interestingly, although this index was much lower in the RP group than in the XP group immediately following stress induction (7.00 ± 1.10 vs 10.00 ± 1.79, P < 0.05. Concerning gastric pH, between the RP and XP groups, we detected a statistically significant difference immediately after stress induction (0 h: 4.56 ± 0.47 vs 3.34 ± 0.28, P < 0.05) but not at any of the subsequent time points. For GER, compared to the RP group, GER was remarkably elevated in the XP group because a statistically significant difference was detected (3 h: 46.84 ± 2.70 vs 61.16 ± 5.12, P < 0.05; 6 h: 60.96 ± 6.71 vs 73.41 ± 6.16, P < 0.05; 24 h: 77.47 ± 3.17 vs 91.31 ± 4.34, P < 0.05). With respect to MPO and MIF, comparisons between the RP and XP groups revealed statistically significant differences at 3 h (MPO: 18.94 ± 1.20 vs 13.51 ± 0.89, P < 0.05; MIF: 150.67 ± 9.85 vs 122.17 ± 5.67, P < 0.05) and 6 h (MPO: 13.22 ± 1.54 vs 8.83 ± 0.65, P < 0.05; MIF: 135.50 ± 9.46 vs 109.83 ± 6.40, P < 0.05). With regard to HSP70, HSP70 expression was significantly increased in the RP and XP groups at 3 and 6 h compared to the MP and CP groups. In addition, comparing the RP and XP groups also showed statistically significant differences at 3 and 6 h. The expression of PCNA was higher in the RP and XP groups 3 h after stress induction. Between these two groups, small but statistically significant differences were observed at all of the time points (3 h: 69.50 ± 21.52 vs 79.33 ± 15.68, P < 0.05; 6 h: 107.83 ± 4.40 vs 121.33 ± 5.71, P < 0.05; 24 h: 125.33 ± 5.65 vs 128.50 ± 14.49, P < 0.05) except 0 h. With regard to apoptosis, the apoptotic activity in the RP and XP groups was significantly different from that in the MP and CP groups. The XP group exhibited a higher inhibition of cell apoptosis than the RP group at 3 h (232.58 ± 24.51 vs 174.46 ± 10.35, P < 0.05) and 6 h (164.74 ± 18.31 vs 117.71 ± 12.08, P < 0.05). The Xiaotan Tongfu granule was demonstrated to be similar to ranitidine in preventing stress ulcers. It exhibited multiple underlying mechanisms and deserves further study.

The Impact of Valvular Oxidative Stress on the Development of Venous Stasis Ulcer Valvular Oxidative Stress and Venous Ulcers

It is widely believed that venous ulcers result from venous insufficiency related to venous valve damages. To further investigate the pathogenesis of venous ulcers, we compared the influence of oxidative stress in venous valvular tissue on stasis ulcer formation in patients with venous ulcers secondary to superficial venous reflux disease. Thirty-nine consecutive patients with superficial venous reflux who underwent saphenectomy were included in the study. Patients were divided into 2 groups: with healed venous ulcers (group 1, n = 15) and without ulcers (group 2, n = 24). All patients were preoperatively evaluated with duplex ultrasound scanning and their blood samples were obtained to examine leukocyte count, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) levels. All patients underwent standard above-knee saphenectomy. Extracted saphenous vein segments were from the saphenofemoral junction, the first valve along. The biochemical analysis of the valve tissues included matrix metalloproteinase (MMP)-9, MMP-2, IL-6, TNF-alpha, superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO) studies. There was no significant difference between patients in terms of age, gender, hospital stay, and preoperative blood levels of leukocyte, IL-6, TNF-alpha, and CRP (P > .05). Biochemical examination of valve tissue showed that the levels of MMP-9, MMP-2, IL-6, TNF-alpha, SOD, MDA, and NO in patients with healing venous ulcer were higher than those of the second group. A higher oxidative stress in the valvular tissue may contribute to venous stasis ulcer formation.

Stress ulcer prophylaxis in hospitalized patients not in intensive care units

A review is presented of the evidence behind the current use of therapies for the prevention of stress-related mucosal disease and bleeding in the nonintensive care unit (ICU), general medicine population. The use of proton pump inhibitors and histamine H2-receptor antagonists for the prevention of stress ulcers has been well-defined in critical care patients. In 1999, the American Society of Health-System Pharmacists (ASHP) published guidelines on the use of stress ulcer prophylaxis in medical, surgical, respiratory, and pediatric ICU patients. In recent years, the practice of stress ulcer prophylaxis has become increasingly more common in general medicine patients, with little to no evidence to support it. Multiple risk factors have been identified for the development of stress ulcers, such as major trauma, severe head injury, multiple organ failure, burns covering more than 25-30% of the body, and major surgical procedures. Multiple studies have demonstrated the overuse of acid-suppressive therapy (AST), with as many as 71% of patients admitted to the hospital receiving some form of treatment. While many practitioners view AST to be harmless, its use is not without risks. Subsequently, a significant number of patients are discharged home on these medications, increasing economic cost and potentially increasing the risk of pneumonia or Clostridium difficile-associated disease. AST is commonly misused in hospitals, with as many as 71% of patients in general medicine wards receiving some sort of AST without an appropriate indication. Anticoagulant therapy has been identified as a risk factor for GI bleeding in hospitalized patients, but prophylaxis with AST has not been found to lower that risk. Although PPIs, H2-antagonists, and antacids are often viewed as safe, patients--particularly those with complicated disease states and complex drug regimens--should not be unduly exposed to the adverse effects and drug interactions associated with those agents. Many such patients treated with the drugs while hospitalized continue to receive AST as outpatients. The cost of inappropriate stress ulcer prophylaxis in medicine patients was found in one trial to exceed $111,000 for one year. The use of AST for the prevention of stress ulcers in general medicine patients is currently not recommended or supported in the clinical literature.

Preface

In 1969, Skillmann et al. reported that the disruption of the gastric mucosal barrier to hydrogen ions (H+) was a causative factor in the development of stress ulcers, and it was called ‘H+ back-diffusion theory’. In the 1970s, the attention was focused on the defensive mechanisms of gastric mucosa. In 1974, Cimetidine, the first histamine-2 receptor antagonist (H2-blocker), was developed in the UK. H2-blocker made it possible to decrease drastically the number of elective surgeries. However, the factors associated with relapse of peptic ulcers or acute gastric mucosal lesions were the main topics in the 1980s. The first meeting of the Taisho International Symposium on Gastroenterology was held in 1987. Disruption of the gastric defensive mechanisms as a causative factor of relapse of peptic ulcers or acute gastric mucosal lesions was enthusiastically discussed in the first meeting of the Taisho International Symposium on Gastroenterology. In 1994, the National Institutes of Health in USA recommended the eradication of Helicobacter pylori as a first-line treatment of gastroduodenal ulcers, which opened ‘the era of Helicobacter pylori’. Factors related to H. pylori became important topics in the Taisho International Symposium in the middle of the 1990s. The 11th Taishotoyama International Symposium on Gastroenterology was held from 22 to 23 April 2005. The topics discussed in the 11th Symposium were growth factors, H. pylori, PG and Cox, cancer, IBD, GERD and brain–gut peptides. This shows that Helicobacter research connected the pathogenesis of ulcers with that of cancers. As H. pylori was related with gastric ulcers and gastric cancers, the stream of the change in gastric mucosal character resulted in cancer development is now the interest of investigators. The majority of papers reported in the meeting were related to the change in gastric mucosal character. In a broad point of view, the data on Helicobacter research have linked the pathogenesis of ulcers with cancers. It has been about 20 years since the first meeting of this symposium was held. Now the incidence of H. pylori infection is rapidly decreasing in Japan. This tendency will be followed by East Asian countries. H. pylori-negative diseases or conditions, e.g. H. pylori-negative GERD, acid secretion, cancers, ulcers and metabolic syndrome will be major interests in the next 20 years. Finally, I wish to express my sincere appreciation to those who made efforts for submitting, reviewing and publishing these papers. I also deeply thank Taishotoyama Pharmaceutical Co. for supporting this symposium.

Dynamic functional and ultrastructural changes of gastric parietal cells induced by water immersion-restraint stress in rats

To investigate the dynamic functional and ultrastructural changes of gastric parietal cells induced by water immersion-restraint stress (WRS) in rats. WRS model of Sprague-Dawley (SD) rats was established. Fifty-six male SD rats were randomly divided into control group, stress group and post-stress group. The stress group was divided into 1, 2 and 4 h stress subgroups. The post-stress group was divided into 24, 48 and 72 h subgroups. The pH value of gastric juice, ulcer index (UI) of gastric mucosa and H(+), K(+)-ATPase activity of gastric parietal cells were measured. Ultrastructural change of parietal cells was observed under transmission electron microscope (TEM). The pH value of gastric juice decreased time-dependently in stress group and increased in post-stress group. The H(+), K(+)-ATPase activity of gastric parietal cells and the UI of gastric mucosa increased time-dependently in stress group and decreased in post-stress group. Compared to control group, the pH value decreased remarkably (P = 0.0001), the UI and H(+), K(+)-ATPase activity increased significantly (P = 0.0001, P = 0.0174) in 4 h stress subgroup. UI was positively related with stress time (r = 0.9876, P < 0.01) but negatively with pH value (r = -0.8724, P < 0.05). The parietal cells became active in stress group, especially in 4 h stress subgroup, in which plenty of intracellular canalicular and mitochondria were observed under TEM. In post-stress group, the parietal cells recovered to resting state. The acid secretion of parietal cells is consistent with their ultrastructural changes during the development and healing of stress ulcer induced by WRS and the degree of gastric mucosal lesions, suggesting gastric acid play an important role in the development of stress ulcer and is closely related with the recovery of gastric mucosal lesions induced by WRS.

Gastric blood flow, mast cell degranulation and micromorphology of gastric mucosa following experimental haemorrhagic shock in dogs.

Ischaemia of the gastric mucosa in haemorrhagic shock appears to be one of the principal factors underlying acute bleeding from the upper gastrointestinal tract. In the present experimental study on dogs the changes of blood flow in the upper gastrointestinal tract were recorded by direct flow measurement in the pertinent vessels. Fourteen mongrel dogs were subjected to haemorrhagic shock lasting for 3 and 4 h. A decline of 46 per cent cardiac output was observed while coeliac artery blood flow decreased by 40 per cent and gastric artery blood flow by 60 per cent. All stages of stress ulcers were documented by light and electron microscopy. In addition, pronounced degranulation of mast cells preceding major tissue damage was observed. In the light of these findings a cascade of events is thought to be present resulting in the development of stress ulcer.

Changes in endothelin‐1 gene expression in the gastric mucosa of rats under cold‐restraint‐stress

To investigate in rats the role of endothelin (ET)-1 gene expression in the development and progression of acute gastric mucosal lesions (AGML) induced by stress, and the effect of BQ-123 (a special ETA receptor antagonist) on the AGML. A rat model of gastric ulcer induced by cold-restraint-stress (CRS) was used. ET-1 concentrations in the plasma and gastric mucosa were determined by radioimmunoassay (RIA), gastric mucosa blood flow (GMBF) was measured with a laser Doppler flow meter, the ulcer index (UI) was used to estimate the degree of gastric mucosa damage and the expression levels of ET-1 mRNA in the gastric mucosa were measured using dot blot and reverse transcription polymerase chain reaction (RT-PCR). Different doses of BQ-123 were administered via the left femoral vein prior to the stress in order to observe the effects of BQ-123 on the ET-1 concentrations in the plasma and gastric mucosa, the GMBF and the UI. Compared with the normal controls, the ET-1 concentrations in the plasma and gastric mucosa of the stressed rats were increased significantly (P < 0.05), the GMBF was decreased markedly (P < 0.01), and the UI increased dramatically (P < 0.01). There was a significant positive correlation between the gastric mucosal EF-1 concentration and the UI (r = 0.98, P < 0.01), and a significant negative correlation between the gastric mucosal ET-1 concentration and GMBF (r = -0.89, P < 0.01) and also between the UI and GMBF (r = -0.98, P < 0.01). The expression level of ET-1 mRNA in the gastric mucosa of the stressed rats increased significantly compared with that of the normal controls (P < 0.01), and there was a positive correlation between the expression of ET-1 mRNA and the ET-1 concentration in the gastric mucosa (r = 0.93, P < 0.01). Compared with the untreated animals, the GMBF was increased (P < 0.01) and the UI decreased significantly (P < 0.01) in the BQ-123-treated rats, and the dose of BQ-123 correlated with the degree of change in the GMBF and UI; however, the ET-1 concentrations of either the plasma or the gastric mucosa did not change markedly in the BQ-123-treated animals (P > 0.05). The present study showed that the level of expression of ET-1 mRNA and the synthesis of ET-1 in the gastric mucosa both increased significantly, which suggests that the increased concentration of endogenous ET-1 may be involved in the development and progression of stress ulcer (acute gastric mucosa lesion). The mechanism of action may be associated with a reduction of GMBF induced by ETAR-mediated vasoconstriction. BQ-123 can dose-dependently attenuate significantly the degree of damage to the gastric mucosa induced by stress, and may have therapeutic benefits for stress ulcer.

Stress responses, pressure ulcer development and adaptation

This case study explores the possible psychosocial concepts underpinning a spinal cord-injured patients' pressure ulcer development, his response to the treatment offered and subsequent self-discharge. By examining both the physiological and psychological reactions of stress through conceptual models, it was possible to depict that there is a close relationship between autonomic responses and an individual's emotional and appraisal attributes. The effect of stress on the immune system was reviewed, with particular focus placed on the wound-healing process and the inflammatory phase. This identified a probable correlation between emotional stress and pressure ulcer development. An individual's reaction to emotional stressors is frequently associated with his/her unique coping strategies and their interplay with social support mechanisms. This case study will depict both positive and negative coping strategies and how the lack of social support influenced the final outcome. Through the provision of an anonymous patient history, investigation will be made into the effects of stress experienced by a patient. Models of stress and the patient's related physiological and psychological reactions will be discussed. Examination will be made into how the use of social support could have influenced the patient's coping mechanisms.

Effect of acute verapamil treatment on cold restraint-induced gastric lesions in rats with lesioned nucleus basalis magnocellularis

Our recent studies suggested that there were no differences in the number and type of cold restraint-induced gastric lesions (petechiae and erosions) between control and nucleus basalis magnocellularis (NBM)-lesioned rats. Having in mind that calcium antagonists can prevent the development of gastric stress ulcer in control rats, the aim of the present study was directed to compare the effect of verapamil in the prevention of cold restraint-induced gastric lesions in control and NBM-lesioned rats. Therefore, 30 min before the stress, control (intact control and sham-operated) rats as well as rats with bilateral electrolytic lesions of NBM were treated with saline (1 ml/kg s.c.) or verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg s.c.) and exposed to cold restraint for 2 hr. Verapamil, in doses of 5.0 and 10.0 mg/kg, significantly decreased the number and length of gastric erosions (p < 0.05) in control rats, while in NBM-lesioned rats, the same doses of verapamil significantly decreased the number of gastric petechiae (p < 0.01). Since the antiulcer treatment with verapamil express different effects in the prevention of the two types of gastric lesions in control and NBM-lesioned rats, it can be concluded that in NBM-lesioned rats there may exist an alteration of the mechanisms involved in stress-induced gastric petechiae and erosions.

Lateralized Effects of Medial Prefrontal Cortex Lesions on Neuroendocrine and Autonomic Stress Responses in Rats

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.

Cold Restraint-Induced Gastric Lesions in Individual- and Group-Stressed Rats

The aim of the present study was to 1) determine the intensity of cold restraint-induced gastric lesions and core body temperature in single- and group-stressed rats, and establish a correlation between them; and 2) determine the influence of visual contact among animals during cold restraint on development of gastric stress ulcer. Therefore, adult male Wistar rats were put into individual or group restraint boxes (composed of two, three, six or nine single boxes) with or without possibility of visual contact and then exposed 2 hr to the cold (4°C). Core body temperature was measured just before and after cold restraint using a digital rectal thermometar. The results showed that: 1) single stressed animals expressed significantly higher ulcer index than those stressed in group of three, six and nine rats; 2) there was no significant difference in degree of hypothermia among rats exposed to various group paradigms; and 3) there was no significant difference in ulcer index among animals stressed in conditions with or without visual contact. An absence of significant difference in ulcer index between single and paired stressed rats implies that three is the lowest number of animals per group at which an influence of group size on behavioral and adaptive mechanisms in rats exposed to cold restraint becomes manifest.