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Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and affects approximately 25% of the general global adult population. The prognosis of NAFLD patients with advanced liver fibrosis is known to be poor. It is difficult to assess disease progression in all patients with NAFLD; thus, it is necessary to identify patients who will show poor prognosis. Aim To investigate the efficacy of non-invasive biomarkers for predicting disease progression in patients with NAFLD. Methods We investigated biomarkers associated with mortality in patients with NAFLD who visited the Kawasaki Medical School General Medical Center from 1996 to 2018 and underwent liver biopsy and had been followed-up for > 1 year. Cumulative overall mortality and liver-related events during follow-up were calculated using the Kaplan-Meier analysis and compared using log-rank testing. We calculated the odds ratio and performed receiver operating characteristic curve analysis with logistic regression analysis to determine the optimal cut-off value with the highest prognostic ability. Results We enrolled 489 patients who were followed-up for a period of 1-22.2 years. In total, 13 patients died (2.7% of total patients enrolled); 7 patients died due to liver-related causes. Poor prognosis was associated with liver fibrosis on histological examination but not with inflammation or steatosis. Blood biomarkers associated with mortality were platelet counts, albumin levels, and type IV collagen 7S levels. The optimal cutoff index for predicting total mortality was a platelet count of 15 × 104/μL, albumin level of 3.5 g/dL, and type IV collagen 7S level of 5 mg/dL. In particular, only one-factor patients with NAFLD presenting with platelet counts ≤ 15 × 104/μL, albumin levels ≤ 3.5 g/dL, or type IV collagen 7S ≥ 5 mg/dL showed 5-year, 10-year, and 15-year survival rates of 99.7%, 98.3%, and 94%, respectively. However, patients with two factors had lower 5-year and 10-year survival rates of 98% and 43%, respectively. Similarly, patients with all three factors showed the lowest 5-year and 10-year survival rates of 53% and 26%, respectively. Conclusion A combination of the three non-invasive biomarkers is a useful predictor of NAFLD prognosis and can help identify patients with NAFLD who are at a high risk of all-cause mortality.

With recent technological advances in the field of endoscopic hemostasis, the prognosis of patients with gastrointestinal (GI) bleeding has improved. However, few studies have reported on the clinical course of patients with GI bleeding. This study aimed to evaluate the differences in clinical outcomes of patients with lower GI bleeding (LGIB) compared with upper GI bleeding (UGIB) and the factors related to their prognosis.Patients who had undergone emergency endoscopy for GI bleeding were retrospectively reviewed. The severity of GI bleeding was evaluated using the Glasgow-Blatchford (GB), AIMS65, and NOBLADS scores. Patients in whom obvious GI bleeding relapsed and/or iron deficiency anemia persisted after emergency endoscopy were considered to exhibit rebleeding.We reviewed 1697 consecutive patients and divided them into UGIB (1054 patients) and LGIB (643 patients) groups. The proportion of patients with rebleeding was significantly greater in the UGIB group than in the LGIB group; the mortality rate was significantly higher in the UGIB group than in the LGIB group. Multivariate analysis showed that a GB score ≥12 and an AIMS65 score ≥2 were significantly associated with rebleeding in the UGIB group, whereas a NOBLADS score ≥4 was significantly associated with rebleeding in the LGIB group. Notably, the influence of emergency endoscopy differed according to GI bleeding location.The clinical course was significantly worse in patients with UGIB than in patients with LGIB. The influence of emergency endoscopy differed according to GI bleeding location.

Objective To evaluate the prevalence of autoimmune gastritis in patients with histologically proven nonalcoholic steatohepatitis (NASH). Methods A total of 33 patients with NASH and 143 patients with chronic liver disease (66, 24, 22, 10, 1, and 21 patients with hepatitis C, hepatitis B, autoimmune hepatitis/primary biliary cholangitis, non-B/non-C hepatitis, fatty liver, and alcoholic disease, respectively) who underwent upper gastrointestinal endoscopy between January 2013 and August 2016 were retrospectively assessed to determine the prevalence of autoimmune gastritis. The clinical characteristics of these patients with NASH and autoimmune gastritis were examined, and the clinical characteristic and biomarkers were compared between patients with NASH with and without autoimmune gastritis. Results Six of the 33 patients with NASH (19.4%) were diagnosed with autoimmune gastritis. The prevalence of autoimmune gastritis was higher in patients with NASH than in those with other chronic liver diseases [4/143 (2.8%), p=0.002]. All six patients with NASH and autoimmune gastritis exhibited high serum gastrin levels; five of the patients were positive for anti-parietal cell antibodies, and one was negative for anti-parietal cell antibodies but positive for intrinsic factor antibody. Furthermore, 1 patient presented with iron-deficiency anemia (hemoglobin

A 44-year-old patient progressed from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) cirrhosis. She was diagnosed with NAFL via a liver biopsy. At 56 years old, she was diagnosed with NASH stage 3 via a second liver biopsy. One year later, she was diagnosed with NASH cirrhosis via a third liver biopsy. This is the first study to report the gradual deterioration of liver histology shown via three liver biopsies and fibrosis markers in a patient who progressed from NAFL to NASH cirrhosis. Following menopause, it is necessary to be aware of the rapid development of liver fibrosis.

We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.

Asians are known to be more likely than Westerners to develop fatty liver and lifestyle-related diseases in spite of their weight. However, the relationship between fat accumulation and lifestyle-related diseases in non-obese Asians is unknown. Therefore, this study aimed to analyze visceral fat and hepatic fat in participants with a normal body mass index (BMI) and examine their characteristics during a medical checkup. This cross-sectional study was conducted on 663 of 1142 patients who underwent abdominal ultrasonography and who had an alcohol intake (converted to ethanol) of &lt, 30 g/day for males and &lt, 20 g/day for females and a BMI of &lt, 25 kg/m2 during a health checkup. Participants were classified into four groups: group A, visceral fat accumulation (VFA) (&minus, ) and fatty liver (FL) (&minus, ) (n = 549), group B, VFA (+) and FL (&minus, ) (n = 32), group C, VFA (&minus, ) and FL (+) (n = 58), and group D, VFA (+) and FL (+) (n = 24). The frequencies of lifestyle-related disease complications, liver function tests, and liver fibrosis were evaluated among the four groups. Compared with group A (control), groups B, C, and D had a higher number of males, BMI, abdominal circumference, ALT, AST, &gamma, GTP, triglyceride, uric acid, fasting blood sugar levels, and incidence of hyperlipidemia. Groups C and D had higher ALT, HbA1c, cholinesterase, and triglyceride levels, FIB4 index, and the number of patients with diabetes mellitus (DM) than groups A and B, however, there was no difference between groups A and B. FL is a risk factor of DM and liver fibrosis in non-obese Japanese individuals, however, VFA only is not a risk factor of DM and liver fibrosis.

In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin (LDA) - 75 to 325 mg daily, dramatically reduces the risk of non-fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal (GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents (NSAIDs) and/or alcohol, or in patients with Helicobacter pylori (H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals (which we refer to as aging gastric mucosa or “aging gastropathy”) compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flow causing hypoxia, upregulation of PTEN, activation of pro-apoptotic caspase-3 and caspase-9, and reduced survivin (anti-apoptosis protein), importin-α (nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age ≥ 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine (PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations.

Background Gastrointestinal hemorrhage occurs frequently. We reviewed the tendency of occurrence of bleeding gastric and duodenal ulcers and their association with antithrombotic therapy before and after the widespread use of Evidence-Based Clinical Practice Guidelines for Peptic Ulcer 2009 (1st edition), which was published to improve treatment outcomes and prevent peptic ulcers. Methods The study enrolled 1105 patients with bleeding gastric and duodenal ulcers treated at our hospital between January 2000 and March 2016. They were divided into the preguideline group (807 patients treated between January 2000 and December 2010) and the postguideline group (298 patients treated between January 2011 and March 2016). The use of medications, severity, the incidence of Helicobacter pylori infection, the presence of any underlying disease, and other factors were compared between the pre- and postguideline groups. Results The number of patients receiving antithrombotic therapy was slightly higher in the postguideline group without a significant difference (P = 0.50). The incidence of H. pylori infection was significantly lower in the postguideline group (P

A 78-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric adenocarcinoma twice in 2009 and 2014. Between the procedures, he successfully completed Helicobacter pylori eradication therapy. In May 2015, upper endoscopy screening showed two elevated lesions on the gastric fundus, and en bloc resection by ESD was performed. We histopathologically diagnosed the patient to have gastric adenocarcinoma of the fundic gland type. In this case, the two lesions of gastric adenocarcinoma of the fundic gland type multifocally developed after ESD for metachronous gastric tubular adenocarcinoma. Furthermore, they appeared in the gastric fundus, where atrophy had been improved due to eradication therapy.

AIM To evaluate the usefulness of total colonoscopy (TCS) for patients undergoing gastric endoscopic submucosal dissection (ESD) and to assess risk factors for colorectal neoplasms. METHODS Of the 263 patients who underwent ESD at our department between May 2010 and December 2013, 172 patients undergoing TCS during a one-year period before and after ESD were targeted. After excluding patients with a history of surgery or endoscopic therapy for colorectal neoplasms, 158 patients were analyzed. Of the 868 asymptomatic patients who underwent TCS during the same period because of positive fecal immunochemical test (FIT) results, 158 patients with no history of either surgery or endoscopic therapy for colorectal neoplasms who were matched for age and sex served as the control group for comparison. RESULTS TCS revealed adenoma less than 10 mm in 53 patients (33.6%), advanced adenoma in 17 (10.8%), early colorectal cancer in 5 (3.2%), and advanced colorectal cancer in 4 (2.5%). When the presence or absence of adenoma less than 10 mm, advanced adenoma, and colorectal cancer and the number of adenomas were compared between patients undergoing ESD and FIT-positive patients, there were no statistically significant differences in any of the parameters assessed. The patients undergoing ESD appeared to have the same risk of colorectal neoplasms as the FIT-positive patients. Colorectal neoplasms were clearly more common in men than in women (P = 0.031). Advanced adenoma and cancer were significantly more frequent in patients with at least two of the following conditions: hypertension, dyslipidemia, and diabetes mellitus (P = 0.019). CONCLUSION In patients undergoing gastric ESD, TCS appears to be important for detecting synchronous double neoplasms. Advanced adenoma and cancer were more common in patients with at least two of the following conditions: hypertension, dyslipidemia, and diabetes mellitus. Caution is therefore especially warranted in patients with these risk factors.

Background Endoscopic sphincterotomy (EST) is currently recognized as the primary endoscopic treatment for common bile duct stones. However, it is difficult to remove multiple (≥3) or large (≥15 mm) common bile duct stones with EST alone. Recently, EST plus endoscopic papillary large-balloon dilation (EPLBD) was reported to be an effective treatment for such bile duct stones. We compared the results of EST and EST + EPLBD for multiple (≥3) or large (≥15 mm) stones that were difficult to treat using EST alone. We also compared the complication rates between the techniques. Methods Seventy patients with large (largest diameter, ≥15 mm) or ≥ 3 common bile duct stones treated in our department between April 2010 and March 2013 underwent EST + EPLBD (n = 34) or EST alone (n = 36). We compared final successful stone removal rates, rates of successful stone removal in the first session, procedure times, status of concurrent mechanical lithotripsy (ML), and complications between the EST + EPLBD and EST groups. Results The rates of final successful stone removal were similar between the two groups (EST + EPLBD: 100 % vs. EST: 89 %; p = 0.115). The rate of successful stone removal in the first session was significantly higher in the EST + EPLBD group (EST + EPLBD: 88 % vs. EST: 56 %; p = 0.03). Moreover, the procedure time was significantly shorter (EST + EPLBD: 42 min vs. EST: 67 min; p = 0.011) and the rate of ML use was significantly lower in the EST + EPLBD group (EST + EPLBD: 50 % vs. EST: 94 %; p

In sicker hearts, right atrial pressure (an estimation of right ventricle preload) are not equivalent to left atrial pressure (an estimation of left ventricle preload). Both right and left atrial pressures are frequently estimated using invasive techniques and also transthoracic echocardiography. While right atrial pressure is easy to obtain with transthoracic echocardiography, the assessment of left ventricle preload or filling pressures is not simple. In relation to the study of Sasai et al. (J Intensive Care 2(1):58, 2014), this paper discusses in a succinct manner how to think and assess the left ventricle preload by transthoracic echocardiography.

Background: The relationship between Helicobacter pylori infection and gastric cancer has been demonstrated, and the risk of gastric cancer occurrence is known to increase with the progression of atrophic changes associated with chronic gastritis. Endoscopic evaluation of the degree and extent of atrophy of the gastric mucosa is a simple and very important means of identifying a group at high risk for gastric cancer. This study aimed to clarify the carcinogenic risk in relation to the degree of atrophy. Methods: A total of 27,777 patients (272 with early gastric cancer and 135 with advanced gastric cancer) were included in this study. Endoscopically evaluated atrophy of the gastric mucosa was classified as C-0 to O-3 according to the Kimura and Takemoto classification system. Results: The cancer detection rate in relation to the degree of gastric mucosal atrophy was 0.04% (2/4,183 patients) for C-0, 0% (0/4,506) for C-1, 0.25% (9/3,660) for C-2, 0.71% (21/2,960) for C-3, 1.32% (75/5,684) for O-1, 3.70% (140/3,780) for O-2 and 5.33% (160/3,004) for O-3. As to the proportions of differentiated and undifferentiated cancers, the latter were relatively frequent in the C-0 to C-2 groups, but differentiated cancers became predominant as atrophy progressed. On the other hand, the number of both differentiated and undifferentiated cancers detected increased as gastric mucosal atrophy progressed. In addition, open-type atrophy was found in 29 (96.7%) of 30 patients with synchronous multiple gastric cancers and in all 20 patients with metachronous multiple gastric cancers. Conclusion: Endoscopic evaluation of gastric mucosal atrophy can provide a simple and reliable predictive index for both current and future carcinogenic risk.

Background Initial fluid resuscitation is an important hemodynamic therapy in patients with septic shock. The Surviving Sepsis Campaign Guidelines recommend fluid resuscitation with volume loading according to central venous pressure (CVP). However, patients with septic shock often develop a transient decrease in cardiac function; thus, it may be inappropriate to use CVP as a reliable marker for fluid management. Methods We evaluated 40 adult patients with septic shock secondary to intra-abdominal infection who received active treatment and were monitored using transthoracic echocardiography (TTE) and CVP for 2 days after admission to our intensive care unit (ICU). We measured left ventricular end-diastolic diameter (LVEDD), left atrial diameter (LAD), and the pressure gradient of tricuspid regurgitation (TR∆P). The shock status was treated with volume loading and inotrope/vasopressor administration according to the TTE findings. We assessed left ventricular fractional shortening (LVFS) as an index of left ventricular contractility and TR∆P as an index of right ventricular afterload and then examined the correlation between CVP and LVEDD/LAD/TR∆P. Results LVFS decreased to ≤30% in 42.5% and 27.5% of patients with septic shock, and severe left ventricular dysfunction with LVFS ≤20% developed in 12.5% and 15.0% of patients on the first and second ICU days, respectively, despite the use of inotropes/vasopressors. Mild pulmonary hypertension as indicated by TR∆P ≥30 mmHg was present in 27.5% and 30.0% of patients on their first and second ICU days, respectively. There was no significant correlation between CVP and LVEDD/LAD/TR∆P. The hospital mortality rate in this study was 10.0%, although the predicted mortality based on the Acute Physiology and Chronic Health Evaluation II score was 58.7%. Conclusions Our results suggest that CVP is not a reliable marker of left ventricular preload for fluid management during the initial phase of septic shock. Assessment of left ventricular preload, right ventricular overload, and left ventricular contractility using TTE seems to be more informative than the measurement of CVP for fluid resuscitation since some patients developed left ventricular dysfunction and/or right ventricular overload.

Background Gastric endoscopic submucosal dissection (ESD) has gradually come to be recommended as the optimal treatment for early gastric cancer; however, one of the primary issues is postoperative bleeding. Although second-look endoscopy is conventionally performed to reduce the risk of postoperative bleeding, its benefit has not yet been clearly elucidated. The objective of this study was to elucidate the benefit of second-look endoscopy. Methods A total of 459 lesions in patients were underwent gastric ESD from May 2004 to April 2013 at our hospital were included in the analysis. The patients were divided into those who had bleeding within 24 hours after ESD (immediate bleeding) and those in whom bleeding occurred 24 hours or more after the procedure (delayed bleeding); the underlying disease, age, lesion site, diameter of the resected specimen, and lesion diameter were analyzed to identify the risk factors for postoperative bleeding after ESD. Results Post-ESD immediate or delayed bleeding occurred in 23 of the 459 cases (5.0%). Second-look endoscopy was performed in 210 of 447 cases (47.0%) excluding 12 cases with immediate bleeding; in the remaining 237 of the 447 cases (53.0%), it was not performed. Post-ESD delayed bleeding occurred in 6 of the 210 cases (2.9%) and 5 of the 237 cases (2.1%), with no statistically significant difference between the two groups. Overall, the following factors were identified as the risk factors for postoperative bleeding: young age (P = 0.005), lesions in the L segment (P = 0.042), and large size of the resected specimen (P = 0.005). The risk factors identified in the immediate bleeding group were lesions in the L segment (P = 0.032), large size of the resected specimen (P

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treatment of orthopedic diseases, inflammatory diseases, etc., and low-dose aspirin is a common antiplatelet therapy given mainly for secondary prevention of atherothrombosis (e.g., myocardial infarction and cerebral infarction). As to the history of NSAID-induced gastric mucosal injury in Japan, the first case of an aspirin-induced gastric ulcer was reported as early as 1934. Based on a meta-analysis of risk factors for peptic ulcers, Helicobacter pylori infection and NSAIDs are the main etiologies of peptic ulcers. NSAIDs alone increase the odds ratio for ulcer development to 19.4 and that for ulcer bleeding to 4.85. In fact, the Japan Rheumatism Foundation reported in 1991 that active gastric ulcers and active duodenal ulcers were detected in 15.5 and 1.9 % of 1008 patients, respectively, taking oral NSAIDs for 3 months or longer. In Japan, which is becoming an increasingly aged society, the numbers of patients taking NSAIDs and low-dose aspirin are expected to increase dramatically in the future. It is hoped that accumulation of evidence on gastrointestinal risk will allow many patients to rationally avoid gastrointestinal complications while receiving the benefits of NSAIDs and low-dose aspirin.

Several nonsurgical approaches to the treatment of postradiation proctitis have been described, but no effective conservative treatment has yet been established. As an alternative to the usual treatment, three cases of chronic postradiation proctitis with hemorrhage were successfully treated with oral administration of sucralfate, with resultant decreased bleeding in long term follow-up period. Oral sucralfate may provide a novel approach to the treatment of intractable postradiation proctitis.

Background: Endoscopic variceal banding ligation (EVL) and sclerotherapy (EVS) have been used to prevent variceal hemorrhage. However, the rate of recurrence of esophageal varices after EVL or EVS is considerably high. Argon plasma coagulation (APC) is a new modality of electrosurgery to apply high frequency electric current into tissue to cause defined thermal effects. This study was conducted to determine whether APC is beneficial for eradication of residual esophageal varices after EVL or EIS. Methods: Cirrhotic patients with endoscopically assessed high-risk esophageal varices but no history of bleeding underwent EVL or EIS to reduce the risk of hemorrhage. When the size of varices was reduced 1 week later, the entire esophageal mucosae 4-5 cm proximal to the esophagogastric junction was coagulated with one session of APC in a total of 15 patients.APC was performed with the use of argon source APC300 and high frequency generator ICC 200 (ERBE, Germany). Follow-up endoscopy was performed 7 days and 1 month after the initial procedure and thereafter every 3 months, to check for recurrent/residual esophageal varices and its complications. Results: Ten to 14 days after APC, ulcerations with white coating were noted in all cases, whereas varices were completely eradicated. One month after APC, while the varices remained eradicated, coagulated esophageal mucosae became whitish and the ulcerations were nearly completely healed. During the course, no patients complained of dysphagia or retrosternal pain. Furthermore, neither development of gastric varices nor aggravation of portal hypertensive gastropathy was observed endoscopically. No serious complication such as bleeding necessitating endoscopic therapy and perforation or stricture of the esophagus was encountered. Over a maximum follow-up period of 5 months, neither recurrence of nor hemorrhage from esophageal varices was observed. Conclusions: APC ablation of residual esophageal varices in patients who have undergone prior EVL or EIS is safe and may be a novel approach to eradicate esophageal varices. It requires a long term follow-up of the eradicated varices to further evaluate its efficacy.

that endoscopically negative patients with GER-related symptoms may have enhanced protective mechanisms. Aims: 1. To assess bicarbonate, non-bicarbonate, protein, transforming growth factor ct (TGFtx) and prostaglandin E 2 (PGE2) in salivary secretion in patients with endoscopically negative [E(-)] GERD. 2. To compare the obtained results with corresponding values in asymptomatic controls (C) and patients with RE~ Subjects & Methods: The study was conducted in 30 patients with RE (12F & 18M, mean age of 49), in 39 asymptomatic volunteers (16F & 23M, mean age of 40), and in 10 patients with E(-) GERD (SF & 5M, mean age of 40). Salivary secretions were collected under basal conditions, daring mastication, and during intraesophageal mechanical and chemical stimulation, mimicking the GER scenario, using an esophageal perfusion catheter. Salivary bicarbonate and non-bicarbonate were measured using Titra-Lab (Radiometer America, IL). Salivary protein was quantitated using Lowry method, whereas TGFot, and PGE z by RIA (Amersham, IL and Biomed. Technol. Inc. MA). Statistical analysis was implemented by E-Stat (Jandel Sci. CA) software. Results: Salivary bicarbonate in patients with E(-) GERD was significantly higher than in C and in RE during intraesophageal chemical stimulation (P < 0.05). Salivary protein was significantly higher in GERD E(-) than in and RE during intraesophageai mechanical and chemical stimulation (P < 0.05). Salivary TGFot output in GERD E(-) was significantly higher than in RE (P < 0.05) but not controls during intraesophageal mechanical stimulation. Salivary PGE z output, on the other hand, in GERD E(-) was significantly higher than in C (P < 0.05) but not RE during intraesophageal chemical stimulation. Conclusion: . A strong salivary secretory response to intraesophageal mechanical and chemical stimuli in patients with GERD E(-) in terms of bicarbonate, protein, TGFa, and PGE z seem to mediate resistance to the development of endoscopic mucosal changes by GER. ° This could explain t he lack of endoscopic esophagitis in the majority of GERD patients and could be a therapeutic target in future treatment strategies.