Detailed esophageal function and morphological analysis shows high prevalence of gastroesophageal reflux disease and Barrett's esophagus in patients with cervical inlet patch.

Although the pathogenesis of cervical inlet patch (CIP) is not fully understood, most authors consider it as a congenital abnormality, whereas others surmise it to be related to gastroesophageal reflux disease (GERD). We aimed to evaluate esophageal function and the prevalence of GERD and Barrett's esophagus in patients with CIP. GERD is defined by the presence of erosive esophagitis or an abnormal pH monitoring. Seventy-one consecutive patients with endoscopic and histological evidence of CIP were prospectively evaluated. Esophageal symptom analysis, 24-hour simultaneous biliary reflux and double-channel pH-monitoring, and esophageal manometry were carried out in 65/71 (92%) patients and in 25 matched controls. Six patients were not suitable for testing and were, therefore, excluded. The histological evaluation of the heterotopic islands showed cardia and/or oxyntic mucosa in 64/65 (98%) patients and specialized intestinal metaplasia (SIM) in one patient (2%). The cardia and/or oxyntic mucosa was accompanied by focally appearing pancreatic acinar metaplasia and pancreatic ductal metaplasia in 7/64 (11%) and in 1/64 (2%), superficial mucous glands in 6/64 (9%), and SIM in 2/64 (3%) cases. In total, SIM was present in three patients (5%), and one of them had low-grade dysplasia. At the gastroesophageal junction, 28 (43%) patients had columnar metaplasia, including nine (14%) patients with SIM. Erosive esophagitis was present in 37 (57%) cases. Thirty-two patients (49%) had abnormal acid reflux in the distal and 25 (38%) in the proximal esophagus. Abnormal biliary reflux was present in 25 (38%) cases. On the basis of endoscopic and pH studies, GERD was established in 44/65 (68%) patients. Typical reflux symptoms were common (33/65, 51%). The combined 24-hour biliary and double-channel pH-monitoring detected significantly more significant acidic reflux at both measurement points and significantly longer bile exposure time in the distal esophagus in patients with CIP. Acid secretion in the CIP was detected in three (5%) cases. Esophageal manometry revealed decreased LES pressure and prolonged relaxation with decreased peristaltic wave amplitude, and an increased number of simultaneous contractions in the esophageal body. The detailed evaluation of the esophageal morphology and function in subjects with CIP showed a high prevalence of GERD and Barrett's esophagus. Further studies are needed to evaluate whether combined acidic and biliary reflux is able to promote similar histomorphological changes in the CIP, as it is shown distally in patients with Barrett's esophagus.

A renewed insight into Barrett's esophagus: comparative histopathological analysis of esophageal columnar metaplasia.

Specialized intestinal metaplasia (SIM) is considered as a premalignant condition of the esophagus, but other types of esophageal metaplasia are commonly neglected. A standardized histopathological analysis was focused not only on SIM but also on the presence of metaplastic processes typical of additional glands. A morphological study using standardized histopathological tests was carried out between 2004 and 2007, with biopsies taken from esophageal mucosa of 826 consecutive patients. Mean age and male : female ratio of patients were 55.6 ± 14.7 and 1.1 : 1, respectively. Only 4.1% (n = 34) of all cases proved to have SIM. The remainder of the cases (n = 615; 74.4%) contained cardiac-fundic mucosa without SIM. Some samples exhibited superficial mucous glands, pancreatic acinar metaplasia (PAM), and ciliated metaplasia accounting for 24% (n = 198), 14.9% (n = 123), and 0.2% (n = 2), respectively. SIM was colocalized with superficial mucous glands (103/198 superficial mucous gland cases; P < 0.001). Low-grade dysplasia (n = 51; 6.2%) and high-grade dysplasia (n = 9; 1.1%) were found mainly in SIM (37/51; 9/9; P = 0.071) with male preponderance (3 : 1 at low-grade and 2 : 1 at high-grade dysplasia). PAM was found mainly in cases without dysplasia (103 of 123 pancreatic metaplasias; P < 0.001). SIM alone in the esophagus is rare, and its frequent association with cardiac mucosa-type metaplasia testifies to transition of mucinous-goblet cell through pseudogoblet cells. PAM rather indicates absence of dysplasia, but superficial mucous glands predicts that SIM follows dysplasia.

Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging.

BACKGROUND: Gastrointestinal symptoms, particularly constipation, increase with aging, but their underlying mechanisms are poorly understood due to lack of experimental models. Previously we established the progeric klotho mouse as a model of aging-associated anorexia and gastric dysmotility. We also detected reduced fecal output in these animals; therefore, the aim of this study was to investigate in vivo function and cellular make-up of the small intestinal and colonic neuromuscular apparatus. METHODS: Klotho expression was studied by RT-PCR and immunohistochemistry. Motility was assessed by dye transit and bead expulsion. Smooth muscle and neuron-specific gene expression was studied by Western immunoblotting. Interstitial cells of Cajal (ICC) and precursors were analyzed by flow cytometry, confocal microscopy, and three-dimensional reconstruction. HuC/D(+) myenteric neurons were enumerated by fluorescent microscopy. KEY RESULTS: Klotho protein was detected in neurons, smooth muscle cells, and some ICC classes. Small intestinal transit was slower but whole-gut transit of klotho mice was accelerated due to faster colonic transit and shorter intestinal lengths, apparent only after weaning. Fecal water content remained normal despite reduced output. Smooth muscle myosin expression was reduced. ICC, ICC precursors, as well as nitrergic and cholinergic neurons maintained their normal proportions in the shorter intestines. CONCLUSIONS & INFERENCES: Progeric klotho mice express less contractile proteins and develop generalized intestinal neuromuscular hypoplasia mainly arising from stunted postweaning growth. As reduced fecal output in these mice occurs in the presence of accelerated colonic and whole-gut transit, it likely reflects reduced food intake rather than intestinal dysmotility.

Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity.

OBJECTIVES: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is characterised by elevated colonic lumenal serine protease activity. The aims of this study were (1) to investigate the origin of this elevated serine protease activity, (2) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity, and (3) to examine the role of the proteinase-activated receptor-2 (PAR-2) activation and signalling cascade in this process. PATIENTS AND METHODS: Faecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhoea. Following mucosal exposure to supernatants from control subjects and IBS-D patients, electromyographic response to colorectal balloon distension was recorded in wild-type and PAR-2(-/-) mice, and CPP was evaluated on colonic strips in Ussing chambers. Zonula occludens-1 (ZO-1) and phosphorylated myosin light chain were detected by immunohistochemistry. RESULTS: The threefold increase in faecal serine protease activity seen in IBS-D patients compared with constipation-predominant IBS (IBS-C) or infectious diarrhoea is of neither epithelial nor inflammatory cell origin, nor is it coupled with antiprotease activity of endogenous origin. Mucosal application of faecal supernatants from IBS-D patients in mice evoked allodynia and increased CPP by 92%, both of which effects were prevented by serine protease inhibitors and dependent on PAR-2 expression. In mice, colonic exposure to supernatants from IBS-D patients resulted in a rapid increase in the phosphorylation of myosin light chain and delayed redistribution of ZO-1 in colonocytes. CONCLUSIONS: Elevated colonic lumenal serine protease activity of IBS-D patients evokes a PAR-2-mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS.

Regional differences in the manifestation of gastrointestinal motor disorders in type 1 diabetic patients with autonomic neuropathy.

OBJECTIVE: The aim of this work was to establish the prevalence and severity of different gastrointestinal symptoms and their relationships to esophageal, gastric and recto-anal motor disturbances by manometry in patients with Type 1 diabetes mellitus and autonomic neuropathy. PATIENTS AND METHODS: Sixteen patients (mean age: 53.4 +/- 14.9 years) with long standing type 1 diabetes mellitus (mean diabetes duration: 22.1 +/- 14.7 years) and autonomic neuropathy (mean Ewing score: 5.73 +/- 2.34) were investigated. The gastrointestinal symptom scores were established by using the Talley dyspepsia questionnaire. The motor function of the digestive tract was tested in the esophagus, in the stomach, and in the ano-rectum by perfusion manometry. RESULTS: Manometric evaluation of the esophagus did not reveal significant abnormalities in the region of the upper sphincter in patients with diabetes mellitus. In contrast, diabetic patients had decreased peristaltic wave amplitude, prolonged duration, decreased wave propagation velocity, and increased number of simultaneous contractions in the esophageal body, and decreased lower esophageal sphincter pressures with prolonged relaxation compared to the age- and sex-matched controls. Symptom analysis showed correlations between reflux symptoms and LES relaxation times, and between dysphagia scores and esophageal body peristaltic wave duration, propagation velocity and the rate of simultaneous contractions. In the gastric antrum, frequent, and often severe, fasting motility disorders were observed, which had no correlation with dyspeptic symptoms. In the ano-rectal region the diabetic patients had a lower squeezing-resting pressure difference, and impaired fecal expulsive function. Motility disorders were simultaneously present at multiple parts of the gastrointestinal tract in 13/16 cases. CONCLUSIONS: In patients with type 1 diabetes mellitus and autonomic neuropathy gastrointestinal motility disorders were observed frequently, and in most of the cases simultaneously. While esophageal and ano-rectal symptoms correlated better with the manometric abnormalities, the lack of correlation between the impaired fasting gastric motility and dyspeptic symptoms shows that, on the basis of the clinical symptom analysis, the prevalence of such motor disorders could be underestimated. The early recognition of gastrointestinal motility disorders may be important for the better long-term management of patients with type 1 diabetes mellitus.

Impaired accommodation of proximal stomach in patients with alcoholic liver cirrhosis.

BACKGROUND: Impaired gastric emptying has previously been detected by ultrasonography in cirrhotic patients, and the role of the type of meal has also been discussed. While these earlier studies dealt with the distal part of the stomach, the aim of our study was to examine the effects of three different types of meal on the proximal stomach in cirrhotic patients. METHODS: The proximal stomach was examined by ultrasonography in 15 healthy volunteers and in 21 alcoholic cirrhotic patients. The subjects received a liquid meal with a low calorie content and two different semisolid test meals with a low calorie content or high calorie and fat contents. The proximal gastric size was assessed by ultrasonography in a sagittal area and a frontal diameter. On the basis of assessment of the autonomic nervous function, the cirrhotic patients were divided into two groups: autonomic neuropathy positive and autonomic neuropathy negative. RESULTS: The postcibal gastric size immediately after ingestion of the liquid test meal was significantly lower in the cirrhotic patients than in the healthy controls. In the healthy volunteers, the measures of the proximal gastric size were significantly higher than in either group of cirrhotic patients at to, and at 10, 20 or 30 min after ingestion of a semisolid test meal with low calorie and fat contents. The proximal gastric sizes in the three groups of investigated subjects did not differ when the meal with high fat and calorie contents was tested. When the liquid meal was administered, the proximal gastric size was significantly lower in the cirrhotic patients with autonomic neuropathy. A significant intragroup difference was not observed when the semisolid meals were tested. CONCLUSIONS: This study reveals an impairment of the proximal stomach in alcoholic cirrhotic patients. The low calorie liquid meal distinguishes between the two groups of cirrhotic patients and healthy controls.

Opposite effects of acute and chronic administration of alcohol on gastric emptying and small bowel transit in rat.

The effects of acute and chronic administration of a large dose of alcohol on gastric emptying and small bowel transit were studied in rats. The development of tolerance to the acute effect of alcohol on gastrointestinal motility during chronic alcohol administration was also investigated. Gastric emptying and small intestinal transit were assessed by the Phenol Red recovery method. Acutely, ethanol was given in a dose of 2.5 g/kg body wt by gavage 30 min before the test meal. Chronically, ethanol was administered by two different methods: (1) a dose of 2.5 g/kg body wt was administered by gavage daily for 10 days; (2) animals received 15% ethanol in their drinking water for 30 days. A single large dose of alcohol inhibited gastric emptying and small bowel transit. Treatment with a large dose of alcohol for 10 days did not change the gastric emptying significantly, but inhibited the small intestinal transit. Alcohol consumption in drinking water for 30 days accelerated gastric emptying and small bowel transit. Tolerance to the acute inhibitory effect of a single large dose of alcohol on gastrointestinal motility did not develop during chronic alcohol treatment.

Effects of oxytocin-related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists.

The hormonally and behaviorally active nonapeptide oxytocin (OXT), its behaviorally active N-terminal octapeptide desglycinamide9-OXT and Z-prolyl-D-leucine, a synthetic analog of the C-terminal prolyl7-leucine8 sequence, inhibited the development both of a moderate and of a strong tolerance to morphine. N-alpha-Acetyl-(2-0-methyltyrosine)-OXT and (penicillamine1-2-0-methyltyrosine)- lysine8-vasopressin, both OXT receptor antagonists, facilitated the development of a moderate morphine tolerance. The i.c.v. injection of either antagonist prevented the effects of i.c.v. and s.c. OXT treatment on the development of tolerance. The effect of desglycinamide9-OXT, but not that of Z-prolyl-D-leucine was also prevented by N-alpha-acetyl-(2-0-methyltyrosine)-OXT. It is concluded that OXT and desglycinamide9-OXT, but not Z-prolyl-D-leucine, attenuate morphine tolerance by affecting putative oxytocinergic binding sites in the mouse brain. The fact that i.c.v. injection of the receptor antagonist also blocked the effect of s.c. OXT treatment argues in favor of the possibility that a minor proportion of s.c. OXT (or behaviorally active fragments thereof) may reach central nervous system target sites.

Effects of oxytocin and a derivative (Z-prolyl-D-leucine) on morphine tolerance/withdrawal are mediated by the limbic system.

Recent data indicate that the neurohypophyseal hormone oxytocin (OXT) and Z-prolyl-D-leucine (Z-Pro-D-Leu), a synthetic dipeptide derived from the C-terminal part of OXT, attenuate the development of tolerance to and dependence on morphine in the mouse. Biochemical and behavioral data raise the possibility that these effects of the peptides might be associated with their effects on the central nervous system and in particular on limbic brain structures. The present results confirm this hypothesis, since intracerebroventricular (i.c.v., 50 ng) and local (0.5 ng) injections of OXT and Z-Pro-D-Leu into the dorsal hippocampus and the mesolimbic nucleus accumbens attenuate morphine tolerance/dependence, similarly to systemic injections of these peptides in higher amounts (5-50 micrograms). Local injections of these peptides into other brain sites (e.g. the nucleus caudatus, ventral tegmental area and the external cortical surface) are without effect. Lesion of the nucleus accumbens by the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) completely prevents the effects of Z-Pro-D-Leu and partially those of OXT on morphine tolerance/dependence. The data point to the role of limbic structures as mediators of the effects of neuropeptides on morphine addiction.