Chronic Alcohol Abuse Leads to Gastric Atrophy and Decreased Gastric Secretory Capacity: A Histological and Physiological Study

We performed morphological and physiological studies in 43 male patients with alcohol dependence (ALC) who had no other apparent lesions in the upper gastrointestinal tract except atrophic and erosive gastritis. A gastric secretory study in which tetragastrin was used as the stimulant revealed that acid and pepsin secretion was less in ALC patients than in hospital controls (p less than 0.001). Endoscopic biopsy specimens of gastric mucosa from ALC patients revealed that atrophy of the gastric mucosa advanced with age. A strong negative correlation was also found between the secretory capacity of the stomach and the degree of atrophy. Possibly, the interval between recurrent episodes of acute mucosal damage was too short to allow complete healing of mucosal lesions. Failure to regenerate denuded epithelium would result in a decrease in the gastric secretory area. Thus, chronic alcohol abuse seems to be an etiological factor in atrophic gastritis.     

Role of mucosal blood flow in duodenal ulcer formation induced by dulcerozine

To clarify the role of mucosal blood flow in the pathogenesis of ulcer formation, the authors investigated dulcerozine-induced duodenal ulcers in rats. Administration of dulcerozine, 500 mg/kg by intragastric route or 250 mg/kg given intraperitoneally, induced acute ulcers in the duodenum, but not the stomach, in all rats. Using the pyloric ligation method, it was determined that although dulcerozine significantly increased gastric acid secretion, no duodenal ulcers were observed in these animals. The administration of 1 ml of 0.1 N HC1 every hour for 6 hours did not induce duodenal ulceration. The mucus glycoprotein content of the corpus, antrum and proximal duodenum did not differ following dulcerozine administration. Duodenal mucosal blood flow, which was measured by an electrolytically generated hydrogen gas clearance technique, decreased significantly following dulcerozine administration even in pylorus-ligated rats. In contrast, there was an increase in the gastric mucosal blood flow following administration of the drug. Therefore, not only an increase in gastric acid secretion but also a decrease in duodenal mucosal blood flow are suggested to be responsible for dulcerozine-induced duodenal ulceration.     

Tolerability,pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor,in healthy subjects

Aims

Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Methods

Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18–55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18–55 years), 25, 50, 100 and 150 mg (Japanese males, 18–55 years). Study 2: Caucasian males (18–55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21–28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.

Results

Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92–99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.

Conclusions

TA-8995 is a potent CETP inhibitor and warrants further investigation.     

Germinal center-associated nuclear protein (GANP) has a phosphorylation-dependent DNA-primase activity that is up-regulated in germinal center regions

Antigen stimulation induces a rapid proliferation of B cells for expansion of specific B cell clones and their further differentiation into antibody-producing cells in germinal centers of T-dependent antigen-immunized mice. Previously, we identified a 210-kDa germinal center-associated nuclear protein (GANP) that is up-regulated selectively in germinal centers and carries an MCM-binding domain in the carboxyl-terminal side. In addition, here, we found a region (from 414 to 550 aa) in GANP molecule that is slightly similar to the known DNA-primase component p49. The recombinant GANP fragment covering this region synthesizes RNA primers for extension by DNA polymerase I with single-stranded DNA templates in vitro. GANP DNA-primase activity is controlled by phosphorylation at Ser(502) that is induced by CD40-mediated signaling in vitro and in the germinal center B cells stimulated with antigen in vivo. Overexpression of ganp cDNA in Daudi B cells caused the increased DNA synthesis more than the levels of the mock-transfectants. These evidences suggested that the novel DNA-primase GANP is involved in regulation of cell proliferation of antigen-driven B cells in germinal centers.     

Association of endoscopic appearances with dyspeptic symptoms

Background The relationship between endoscopic appearances such as endoscopic gastritis and duodenitis and dyspeptic symptoms has not been clearly demonstrated. We aimed to clarify the association of endoscopic appearances with Helicobacter pylori infection, histological severity of gastritis, and dyspeptic symptoms in a Japanese population. Methods We enrolled 87 dyspeptic and 93 nondyspeptic subjects in this study. All subjects underwent gastroscopy, and patients with active peptic ulcer disease, reflex esophagitis with erosion, polyps >1 cm, or cancer were excluded. Endoscopic appearances in patients with dyspeptic symptoms and in those without were assessed retrospectively on the basis of endoscopic images. The degree of atrophy by the Kimura-Takemoto classification system was also assessed. Helicobacter pylori infection status was examined by histology or antibody against H. pylori. Histological severity of inflammation and glandular atrophy in the antrum were assessed according to the updated Sydney System. The odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression using the variables age, sex, H. pylori infection status, and all endoscopic appearances. Results The degree of atrophy tended to be lower among dyspeptic patients (P = 0.06). Among all endoscopic appearances, the liner redness (friability) in the antrum (OR = 3.90, 95% CI = 1.20−12.64) and duodenal ulcer (DU) scarring (OR = 3.41, 95% CI = 1.08−10.79) were independently associated with dyspepsia. Histological severity of inflammation and glandular atrophy were not associated with dyspeptic symptoms. Also, no correlation was found between endoscopic appearances and any of the different subgroups of dyspeptic symptoms. Patients with friability in the antrum and DU scar, which correlated with dyspeptic symptom showed some of communal symptoms such as epigastric pain, epigastric discomfort, hypochondriac pain, early satiation/postprandial fullness, and belching, but they differed considerably with respect to H. pylori positivity and the histological severity of gastritis. Conclusions Some endoscopic appearances such as friability in the antrum and DU scarring may be associated with dyspeptic symptoms, and endoscopic appearances may be useful markers to perform clinical implementation reflecting an individual’s pathophysiology of dyspeptic symptoms.     

Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes

Objective

Bilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes.

Materials and Methods

We measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2 ± 0.9 years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria.

Results

During follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76; 95% CI, 1.65 to 24.93).

Conclusions

Low serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes.     

Functional polymorphisms in the promoter region of macrophage migration inhibitory factor and chronic gastritis

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify associations of the functional polymorphisms of the MIF gene promoter with the development of chronic gastritis. The study was performed with 290 stocked DNAs from subjects with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Both the 7/7-CATT repeat at position -794 and the -173 C/C genotypes were significantly associated with a risk of developing severe gastric mucosal atrophy (OR, 9.69; 95% CI, 1.29-72.5; and OR, 4.60; 95% CI, 1.05-20.2, respectively). In subjects younger than 60 years old, the number of 7-CATT alleles was significantly correlated with both the activity and inflammation scores (p=0.0079 and 0.0080, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene might be associated with the severity of gastric mucosal inflammation in younger subjects and with the subsequent development of mucosal atrophy.     

Adenocarcinoma of the minor duodenal papilla: report of a case

We report a case of adenocarcinoma of the minor duodenal papilla, a rare type of duodenal neoplasm. A 76-year-old man with a history of surgery for rectal cancer and gastric cancer was referred to us after a follow-up upper gastrointestinal endoscopy revealed an abnormal elevation in the minor duodenal papilla. The pathological diagnosis of a biopsy specimen was adenocarcinoma. Preoperative examination of other organs revealed a tumor in the ascending colon, which was also identified as adenocarcinoma. We performed synchronous pancreatoduodenectomy and ileocecal resection with lymph node dissection. Histopathological examination of the resected specimen revealed that the papilla tumor arose from the duodenal mucosa and infiltrated the submucosa of the duodenal wall, but not the pancreatic parenchyma. Based on these findings, we diagnosed primary adenocarcinoma of the minor duodenal papilla. To our knowledge, this is only the sixth such case reported in the English-language literature, and we review all six cases after this case report.