Melatonin may have a role in the pathogenesis of functional dyspepsia in males.

OBJECTIVE: Pathogenesis of functional dyspepsia (FD) is complex. Melatonin is synthesized in enterochromaffin cells (EC) of the digestive system. It may influence gut function. The aim of this study is to evaluate the serum melatonin levels in FD patients. PATIENTS AND METHODS: A total of 57 FD patients, and 12 healthy controls were enrolled in this study between 2008-2010 years. Diagnosis of FD was established based on the Rome III Criteria. Blood samples were taken at 10 a.m. and serum samples were stored in -85°C. Serum melatonin levels were determined by an enzyme-linked immunosorbent assay (ELISA) kit. (polyclonal Kennaway G280 anti-melatonin antibody, Bühlmann Laboratories AG, Schönenbuch, Switzerland). RESULTS: Twenty-three (40.3%) patients were male, and, mean age was 44.3 ± 12.1 years. Mean age of control group was 38.5 ± 11.8 years, and 7 of them were male. The mean serum concentration of melatonin in patients and control group were 31.19 ± 43.4 pg/ml and 14.8 ± 20.9 pg/ml, respectively (p < 0.05). Melatonin levels were significantly higher in male patients (38.6 ± 55 pg/ml vs 12.8 ± 22 pg/ml, p < 0.05). However, melatonin levels were similar in females (p > 0.05). CONCLUSIONS: The serum melatonin levels were significantly higher in male patients with functional dyspepsia. High nocturnal melatonin secretion may play a role in the pathogenesis of functional dyspepsia, especially in males.

Clinical predictors of poor outcomes among patients with nonvariceal upper gastrointestinal bleeding in Europe.

BACKGROUND: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency associated with substantial morbidity and mortality. Despite advances in endoscopic and pharmacological treatment during the past two decades, the incidence of mortality associated with NVUGIB has remained relatively constant. AIM: To report outcomes and predictive factors for bleeding continuation/re-bleeding and mortality of NVUGIB in clinical practice in different European countries. METHODS: This observational, retrospective cohort study (NCT00797641; ENERGIB) was conducted in Belgium, Greece, Italy, Norway, Portugal, Spain and Turkey. Eligible patients were hospitalised (new admissions or inpatients), presenting with overt NVUGIB with endoscopy from 1 October to 30 November, 2008. Patients were managed according to routine care, and data regarding bleeding continuation/re-bleeding, pharmacological treatment, surgery and mortality during 30-days after the initial bleed were collected. A multivariate analysis of clinical factors predictive of poor outcomes was conducted. RESULTS: Overall, 2660 patients (64.7% men; mean age 67.7 years) were evaluable. Significant differences across countries in bleeding continuation/re-bleeding (range: 9-15.8%) or death (2.5-8%) at 30 days were explained by clinical factors (number of comorbidities, age > 65 years, history of bleeding ulcers, in-hospital bleeding, type of lesion or type of concomitant medication). Other factors (country, size of hospital, profile of team managing the event, or endoscopic/pharmacological therapy received) did not affect these outcomes. Similar predictors were observed in patients with high-risk stigmata. CONCLUSION: Differences in the outcomes of nonvariceal upper gastrointestinal bleeding in clinical practice across some European countries are explained mainly by patient-related factors, and not by management factors.

Crohn's disease; analysis of 105 patients.

In this paper, 105 patients with Crohn's disease, (47 M, 58 F), mean age 37.4 +/- 42 years were evaluated clinically, demographically and epidemiologically. Mean age of patients at the time of diagnosis was 26.5 +/- 10.9 years. Follow-up period was 2.7 +/- 2.1 years on average. On admission, symptoms or signs were as follows: right lower quadrant pain 90.5%, abdominal mass 18.1%, enterocutaneous fistula 11.4% and subileus 9.5%. Diagnosis of Crohn's disease was established during appendectomy in 14 patients (13.3%). Family history of inflammatory bowel disease was determined only in six patients (5.7%). Intestinal localization were as follows: ileo colonic 52%, ileal 38%, colonic 10%. Clinical forms were inflammatory (68%), fistulous (23%) and obstructive (9%). Sacroiliitis (7.6%), ankylosing spondylitis (4.7%), erythema nodosum (2.9%), pyoderma gangrenosum (1%) were detected as extraintestinal manifestations. Of the patients, 12.4% underwent surgical intervention due to abscess drainage in 6.6%, fistulectomy in 3.8%, stricture resection in 1.9%. Medical therapy alone was sufficient in 75.3% of patients. As a result, our cases mentioned in this paper reflect the general characteristics of Crohn's disease and prominence of regular visits and treatment.

Tuberculous peritonitis--reports of 26 cases, detailing diagnostic and therapeutic problems.

OBJECTIVE: To evaluate the clinical presentation, biochemical (ascites and serum) and laparoscopic findings, and to assess the efficacy of triple antituberculous therapy without rifampicin for 6 months in patients with tuberculous peritonitis. METHODS: Twenty-six tuberculous peritonitis patients (11 male, 15 female) with a mean age of 34.8 +/- 3.4 years (range 14-77) were assessed with regard to diagnostic and therapeutic features. RESULTS: The most common symptoms and signs were abdominal pain (92.3%) and ascites (96.2%), respectively. Tuberculin skin test (TST) was positive in all patients. An abnormal chest radiography suggestive of previous tuberculosis was present in five patients (19.2%), and two patients (7.7%) had extra-peritoneal (cerebral, pericardial) active tuberculous involvement. In 24 of the 25 patients who underwent laparoscopy with directed biopsy, whitish nodules suggested tuberculous peritonitis; 76% of the biopsy specimens revealed caseating, 20% non-caseating granulomatous inflammation, and 4% non-specific findings. The ascitic fluid of one patient (3.8%) was positive for acid-resistant bacilli, and culture was positive in two patients (7.7%). Twenty-four of the patients were treated for 6 months with isoniazid, streptomycin (total dose 40 g) and pyrazinamide (for the first 2 months and then substituted with ethambutol). Eighteen patients also received methyl prednisolone, initially 20 mg/day, for 1 month. The follow-up period was 19 +/- 1.7 months after the end of therapy (range 6-36). Ascites and abdominal pain abated earlier in patients on steroid therapy. All but two of the 24 patients responded to treatment. CONCLUSION: Non-invasive tests such as acid-fast stain and culture of the ascitic fluid are usually insufficient, hence invasive laparoscopy and peritoneal biopsy are necessary for the diagnosis of tuberculous peritonitis if non-invasive tests such as ascites adenosine deaminase activity measurement are not easily available. Triple therapy without rifampicin for 6 months is sufficient to treat tuberculous peritonitis.

Helicobacter pylori eradication lowers esophageal sphincter pressures in functional dyspepsia patients.

BACKGROUND/AIMS: Helicobacter pylori infection is the most common cause of gastroduodenal diseases. The role H. pylori eradication in functional dyspepsia patients is contradictory. We performed this study to determine the effects of H. pylori eradication in functional dyspepsia patients with respect to physiological and histological parameters including esophageal sphincter functions. METHODOLOGY: We studied 20 functional dyspepsia patients, whose H. pylori infection was confirmed by histology and urease test. We also confirmed eradication using the same methods after three months. We performed 24-hour esophageal pH monitoring, esophageal manometry, meal stimulated gastrin release test and measured dyspepsia severity score and gastric emptying time before and three months after eradication. Eradication regimen consisted of omeprazol 20 mg b.i.d., clarithromycin 500 mg b.i.d. and metranidazol 500 mg b.i.d., for two weeks. Gastric inflammation and H. pylori density within biopsy samples from the antrum (n = 4), corpus (n = 4), cardia (n = 2), fundus (n = 2), duodenum (n = 2) and distal esophagus (n = 1) were assessed. RESULTS: Dyspepsia severity score (P < 0.001), meal stimulated gastrin levels, upper (P = 0.01) and lower (P = 0.06) sphincter pressures were decreased after eradication irrespective of gastric histology; but gastric emptying times (P = 0.87) and pH < 4.5% reflux (P = 0.91) were not changed significantly. CONCLUSIONS: H. pylori eradication results in decreased esophageal sphincter pressures irrespective of gastric histology in functional dyspepsia patients. These decreases are not associated with increased objective reflux or reflux symptomatology. The clinical significance of these finding deserves further evaluations.

After the eradication of Helicobacter pylori infection, relapse is a serious problem in Turkey.

Eradication of Helicobacter pylori (Hp) infection is strongly recommended in duodenal and gastric ulcer. In developed countries the recurrence rate is low; however, in Turkey, the Hp recurrence rate is suspected to be high as the prevalence of Hp infection is--as high as 70-80% in the asymptomatic population. We planned this study to determine the relapse rate of Hp infection after successful eradication therapy in Turkey. Fifty-two cases including 24 patients with duodenal ulcer and 28 patients with nonulcer dyspepsia were examined in this study. The eradication regimen was omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg three times a day for 1 week. All patients underwent upper gastrointestinal tract endoscopy. At least four samples from antrum and corpus were taken to enable histologic diagnosis of Hp infection. After the eradication therapy, endoscopy was repeated at 1, 3, 6, and 12 months, and Hp-positive patients were dropped from study. With the use of this regimen, the Hp eradication rate was 92.3% (48/52). After the eradication of Hp infection, relapse rates were 6.97%, 27.5%, and 11.11% at 3, 6, and 12 months, respectively. The cumulative relapse rate for 1 year was 41.46%. The results of this study revealed that after the eradication of Hp infection, recurrence is encountered very often as a problem in Turkey. We concluded that hygienic and environmental factors can affect these high relapse rates.

Effect of PACAP on gastric acid secretion in rats.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a new VIP-like brain-gut peptide. Its effects on the motility and secretory functions of the gastrointestinal system have been shown in previous studies. In this study we investigated the effect of intravenous PACAP on gastric acid secretion in conscious pylorus-ligated rats and in gastric fistula rats. PACAP showed significant inhibitory effects on pentagastrin- and histamine-stimulated gastric acid secretion, but no effect on basal or carbachol-stimulated secretion in pylorus-ligated rats. It did show dose-related inhibitory effects both on basal gastric acid secretion and on secretion stimulated by pentagastrin, histamine, or carbachol in gastric fistula rats. PACAP did not alter serum gastrin levels. Inhibition of prostaglandin synthesis with indomethacin and immunoneutralization of somatostatin with anti-somatostatin serum did not prevent the inhibitory effect of PACAP on gastric acid secretion in pylorus-ligated rats. We conclude that PACAP most likely has a direct effect on parietal cells and that this effect may be mediated, at least partially, by inhibition of the action of histamine on parietal cells.

Galanin: structure-dependent effect on pancreatic amylase secretion and jejunal strip contraction.

Rat and porcine galanin and their fragments inhibited cholecystokinin-8 (CCK-8)-stimulated amylase secretion with the following activities: rat galanin-(1-29) = porcine galanin-(1-29) = galanin-(1-15) = rat galanin-(3-29) > rat galanin-(2-29) = porcine galanin-(2-29) > galanin-(1-10). Fragments of rat galanin-(9-29) and N alpha-acetyl-galanin-(9-29) were able to inhibit CCK-8-stimulated pancreatic amylase secretion but only at higher dose levels. Porcine galanin-(15-29) and rat galanin-(21-29) were unable to produce significant inhibition. Rat and porcine galanin-(1-29), galanin-(1-15) and rat N alpha-acetyl-galanin-(9-29) also inhibited basal pancreatic amylase secretion. In the rat jejunal strip contraction model, rat galanin-(1-29) and porcine galanin-(1-29) have similar potencies. Galanin-(1-15) and galanin-(1-10) stimulate rat jejunal strip contraction with decreasing potencies. Elimination of Gly1 from the N-terminus of both rat and porcine galanin had no significant effect either on pancreatic amylase secretion or on jejunal strip contraction. The rat galanin-(3-29) and (9-29) are not active in the stimulation of rat jejunal strip contraction. Acetylation of porcine galanin-(9-29) created a peptide that was a powerful stimulator of rat jejunal strip contraction. The present data indicate that N-terminal rat galanin amino acid residues are crucial for rat jejunal strip contraction but are not required for inhibition of pancreatic amylase. These results suggest that the galanin amino acid sequence contains several specific domains, which can be recognized by specific galanin receptor subsets.

Development of a potent bombesin receptor antagonist with prolonged in vivo inhibitory activity on bombesin-stimulated amylase and protein release in the rat.

Of the various types of potent bombesin(Bn)/gastrin releasing peptide receptor antagonists that have been discovered, the desMet14-methyl ester peptides are devoid of residual agonist activity and are among the most potent in terms of in vitro receptor blockade and also in terms of their prolonged inhibition of bombesin-stimulated amylase and protein release in the rat. We have now examined the in vitro and in vivo properties of a new series of methyl ester analogues, [D-Phe6]Bn(6-13)OMe, [D-Phe6,D-Ala11]Bn(6-13)OMe, N alpha-propionyl-[D-Ala24]GRP(20-26)OMe, and [D-pentafluoro-Phe6,D-Ala11]Bn(6-13)OMe, which have an additional D-amino acid substituent and some highly lipophilic moieties at the N-terminus. All analogues were able to potently antagonize the ability of Bn to stimulate amylase release from rat acinar cells, with IC50 values of 2.4, 2.5, 0.6, and 1.3 nM, respectively. The four peptides were found to have binding affinities for these cells comparable to Bn itself, with K(i)s of 10.3, 2.8, 5.5, and 3.6 nM, respectively, but all had little or no affinity for neuromedin B receptors on murine C6 cells. Single bolus IV injections of these peptides were found to potently inhibit amylase and protein release caused by IV infusion of bombesin into the rat. Generally the peptides containing the D-Ala substituent were longer acting than [D-Phe6]Bn(6-13)OMe, so that [D-Phe6,D-Ala11]Bn(6-13)OMe and N alpha-propionyl-[D-Ala24]GRP(20-26)OMe displayed significant inhibitory effects for up to 1.5 h after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary adenylate cyclase-activating polypeptide relaxes rat gastrointestinal smooth muscle.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a new member of the secretin/glucagon peptides family, being most homologous to vasoactive intestinal peptide (VIP). The present study was designed to investigate a possible effect of PACAP on the rat gastrointestinal smooth muscle in vitro. We demonstrated that 1) PACAP reduced basal smooth-muscle contractions in all portions of the gastrointestinal tract, but the effect of VIP was region-specific. The inhibitory effect of PACAP in midcolon was approximately 100 times greater than that of VIP. 2) PACAP significantly inhibited smooth-muscle contractions induced by acetylcholine or carbachol. The inhibitory effect of PACAP was not affected by hexamethonium and was additive to the inhibitory effect of atropine and pirenzepine. 3) PACAP inhibited smooth-muscle contractions induced by substance P, cholecystokinin, and galanin, even after atropine treatment. Although the exact mechanism of the inhibitory action of PACAP remains to be clarified, PACAP appears to exert its effect in the rat at a site other than muscarinic receptors, probably through a direct effect on gastrointestinal smooth muscle in vitro.

Reduced gastric acid inhibitory effect of a pGIP(1-30)NH2 fragment with potent pancreatic amylase inhibitory activity.

Gastric inhibitory polypeptide (GIP) strongly stimulates insulin secretion in the presence of glucose and also stimulates somatostatin release from gastric mucosa. It was reported recently that both stimulatory activities can be dissociated by removing the C-terminal 12 amino acid residues. Since insulin and somatostatin are involved in regulation of exocrine pancreatic and gastric secretion in rats, we compared the inhibitory effects of pGIP and the pGIP(1-30)NH2 fragment on pancreatic amylase and gastric acid secretion. pGIP(1-30)NH2 displayed full activity on inhibition of bombesin (BN)-stimulated amylase release relative to GIP itself, but was about 10-fold less potent in inhibiting gastric acid secretion. These results suggest that the receptors involved in these two events have quite different ligand binding requirements and that more specific analogues of GIP can be designed which should be of value in elucidating the physiological roles of this hormone.

Structural requirements for galanin inhibition of pentagastrin-stimulated gastric acid secretion in conscious rats.

The effects of rat galanin, together with a number of its N- and C-terminal fragments, on pentagastrin-stimulated gastric acid secretion were studied in conscious rats equipped with chronic gastric fistulas. Similarly to its porcine counterpart studied previously, at a dose of 3 nmol/kg per h rat galanin was a potent inhibitor of gastric acid secretion. The N-terminal fragments, rat galanin-(1-10) and -(1-15), retained about 60% of the inhibitory potency of the whole galanin sequence whilst the C-terminal fragments, rat galanin-(2-29), -(3-29) and -(9-29), were unable to produce significant inhibition over comparable dose ranges. Surprisingly, however, simply acetylating the alpha-amino group in position 9 of rat galanin-(9-29) restored almost full gastric acid inhibitory activity in a homologous rat model. We speculate that this could be due to a favorable conformational effect on the C-terminal region produced by alpha-acetylation. These results also suggest that structural features within either the N-terminal or C-terminal regions of rat galanin are able to elicit this particular biological response. One possible explanation for this could be the involvement of more than one rat galanin receptor having different ligand recognition requirements.

Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) inhibits pentagastrin-stimulated gastric acid secretion in conscious rats.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel neuropeptide and has two amidated forms, PACAP-27 and PACAP-38. Its chemical structure is similar to that of vasoactive intestinal peptide (VIP). In our previous studies, we found that PACAP has a stimulatory effect on rat exocrine pancreas secretion and an inhibitory effect on rat gastrointestinal motility. These effects of PACAP-27 were greater than those of PACAP-38 and VIP. In the present study, we examined the effect of PACAP-27 on basal and pentagastrin (PG)-stimulated gastric acid secretion in conscious rats and compared its effect with that of VIP. Rats were equipped with a chronic gastric fistula and a permanent IV line and separately housed in metabolic cages. The effects of PACAP-27 and VIP at doses of 1.25, 2.5, 5 and 10 nmol/kg/h on basal and PG (24 micrograms/kg/h)-stimulated gastric acid secretion were tested. Our results showed that: (1) VIP had no significant effect on basal and PG-stimulated gastric acid secretion at the tested doses. (2) PACAP-27 had no effect on basal acid secretion but had a dose-dependent inhibitory effect on PG-stimulated gastric acid secretion. The highest inhibition by PACAP-27, 68.2 + 8.1%, was achieved at 5 nmol/kg/h. We suggest that PACAP may have a regulatory role in gastric acid secretion.

Effect of pituitary adenylate cyclase activating polypeptide on rat pancreatic exocrine secretion.

A novel neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), which has been isolated from ovine hypothalami, shows 68% homology with vasoactive intestinal peptide (VIP). Since VIP stimulates amylase secretion from the pancreas, we investigated the effect of PACAP and VIP on rat pancreatic exocrine secretion after intravenous injections of PACAP-27, PACAP-38, or VIP at doses of 2.5, 5 or 10 nmol/kg. Results showed: 1) Bolus injection of PACAP stimulated pancreatic amylase and protein secretions in a dose-dependent manner; and 2) Stimulation of amylase secretion with 10 nmol/kg of PACAP-27 was greater than that induced with the same dose of VIP or PACAP-38 (p less than 0.05).