Carditis: a relevant marker of gastroesophageal reflux disease. Data from a prospective central European multicenter study on histological and endoscopic diagnosis of esophagitis (histoGERD trial).

The columnar-lined mucosa at the gastroesophageal junction may contain an inflammatory infiltrate, commonly referred to as carditis (or cardia gastritis). The etiology of carditis is not entirely clear since published data are conflicting. Some authors believe it to be secondary to gastroesophageal reflux disease (GERD) and others to Helicobacter pylori gastritis. This prospective study aims at clarifying the relationship between carditis and the histological, clinical, and endoscopic findings of GERD, in a large cohort of individuals negative for H. pylori infection. Eight hundred and seventy-three individuals (477 females and 396 males, median age 53 years) participated in this study. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Reflux-associated changes of the esophageal squamous epithelium were assessed according to the Esohisto consensus guidelines. Grading of carditis was performed according to the Updated Sydney System, known from the histological evaluation of gastritis. In total, 590 individuals (67.5%) had chronic carditis. Of these, 468 (53.6%) had mild chronic inflammation, with 321 individuals (68.6%) showing no or minimal changes on endoscopic examination (Los Angeles Categories N and M). The presence of chronic carditis was associated with several GERD-related parameters of the esophageal squamous epithelium (P < 0.0001), and data retained statistical significance even when analysis was restricted to individuals with mild chronic carditis and/or endoscopically normal mucosa. Chronic carditis was also associated with the presence of intestinal metaplasia (P < 0.0001). In addition, chronic carditis had a statistically significant association with patients' symptoms of GERD (P = 0.0107). This observation remained valid for mild chronic carditis in all patients (P = 0.0038) and in those with mild chronic carditis and normal endoscopic mucosa (P = 0.0217). In conclusion, chronic carditis appears to be the immediate consequence of GERD, correlating with patients' symptoms and endoscopic diagnosis. These results are valid in individuals with nonerosive reflux disease, which indicates a higher sensitivity of histological diagnosis. Our findings may impact the routine assessment of reflux patients.

Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study.

OBJECTIVES: The lower esophageal sphincter (LES), surrounded by diaphragmatic muscle, prevents gastroesophageal reflux. When these structures become incompetent, gastric contents may cause gastroesophageal reflux disease (GERD). For treatment, lifestyle interventions are always recommended. We hypothesized that by actively training the crura of the diaphragm as part of the LES using breathing training exercises, GERD can be positively influenced. METHODS: A prospective randomized controlled study was performed. Patients with non-erosive GERD or healed esophagitis without large hernia and/or previous surgery were included. Patients were randomized and allocated either to active breathing training program or to a control group. Quality of life (QoL), pH-metry, and on-demand proton pump inhibitor (PPI) usage were assessed at baseline and after 4 weeks of training. For long-term follow-up, all patients were invited to continue active breathing training and were further assessed regarding QoL and PPI usage after 9 months. Paired and unpaired t-test was used for statistical analysis. RESULTS: Nineteen patients with non-erosive GERD or healed esophagitis were randomized into two groups (10 training group and 9 control group). There was no difference in baseline patient characteristics between the groups and all patients finished the study. There was a significant decrease in time with a pH<4.0 in the training group (9.1±1.3 vs. 4.7±0.9%; P<0.05), but there was no change in the control group. QoL scores improved significantly in the training group (13.4±1.98 before and 10.8±1.86 after training; P<0.01), but no changes in QoL were seen in the control group. At long-term follow-up at 9 months, patients who continued breathing exercise (11/19) showed a significant decrease in QoL scores and PPI usage (15.1±2.2 vs. 9.7±1.6; 98±34 vs. 25±12 mg/week, respectively; P<0.05), whereas patients who did not train had no long-term effect. CONCLUSIONS: We show that actively training the diaphragm by breathing exercise can improve GERD as assessed by pH-metry, QoL scores and PPI usage. This non-pharmacological lifestyle intervention could help to reduce the disease burden of GERD.

The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis.

BACKGROUND: Faecal microbiota transplantation is an experimental approach for the treatment of patients with ulcerative colitis. Although there is growing evidence that faecal microbiota transplantation is effective in this disease, factors affecting its response are unknown. AIMS: To establish a faecal microbiota transplantation treatment protocol in ulcerative colitis patients, and to investigate which patient or donor factors are responsible for the treatment success. METHODS: This is an open controlled trial of repeated faecal microbiota transplantation after antibiotic pre-treatment (FMT-group, n = 17) vs antibiotic pre-treatment only (AB-group, n = 10) in 27 therapy refractory ulcerative colitis patients over 90 days. Faecal samples of donors and patients were analysed by 16SrRNA gene-based microbiota analysis. RESULTS: In the FMT-group, 10/17 (59%) of patients showed a response and 4/17 (24%) a remission to faecal microbiota transplantation. Response to faecal microbiota transplantation was mainly influenced by the taxonomic composition of the donor's microbiota. Stool of donors with a high bacterial richness (observed species remission 946 ± 93 vs no response 797 ± 181 at 15367 rps) and a high relative abundance of Akkermansia muciniphila (3.3 ± 3.1% vs 0.1 ± 0.2%), unclassified Ruminococcaceae (13.8 ± 5.0% vs 7.5 ± 3.7%), and Ruminococcus spp. (4.9 ± 3.5% vs 1.0 ± 0.7%) were more likely to induce remission. In contrast antibiotic treatment alone (AB-group) was poorly tolerated, probably because of a sustained decrease of intestinal microbial richness. CONCLUSIONS: The taxonomic composition of the donor's intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in ulcerative colitis patients. The design of specific microbial preparation might lead to new treatments for ulcerative colitis.

Immunohistochemical localization and characterization of a protein from the basolateral membrane of rat small intestine epithelium using monoclonal antibody GZ-1.

The proteins of the basolateral membrane (BLM) of small intestine epithelial cell in rat have been less precisely described than those of the microvillus membrane (MVM). To identify BLM-specific proteins, Balb/c mice were immunized with isolated intestinal epithelial cells and monoclonal antibodies (MAb) to their cell membrane, produced with the hybridoma technique. One of the MAb so obtained (GZ-1), a class 1 IgG, is specifically directed to a surface membrane protein of intestinal epithelium (GZ-1-Ag). The MAb served to characterize the protein as follows. Light microscopic immunohistochemical FITC labeling and, still more clearly, electron microscopic labeling with colloidal gold on Lowicryl sections of small intestinal tissue, show that the GZ-1-Ag occurs only in BLM of the absorptive cell and the goblet cell. It is not present in the MVM, the tight-junction area, and probably in the desmosomal sections of the membrane. The crypt cells are more markedly labeled with GZ-1 than are the villus cells; the villus cells are also more clearly labeled from the duodenum to the ileum. Gross analysis of the position of the gold marker on the BLM indicates that GZ-1-Ag is probably integrated into the lipid bilayer. With immunoblotting (with HRP as marker), a single band of MW 42,000 D can be identified as the corresponding GZ-1-Ag from the protein band pattern obtained with SDS-PAGE from BLM isolated in the presence of protease inhibitors (PI). In BLM fractions isolated without protease inhibition, a band of MW 30,000 D can be labeled with GZ-1. These results are interpreted as follows: GZ-1-Ag is a protein of MW 42,000 D. On isolation of the BLM without PI, a piece of this protein is broken off by proteolysis. The larger piece of the molecule (30,000 D) is not accessible to the proteolytic enzyme owing to its localization in the BLM, and therefore remains intact (and recognizable by the Ab). The preferred position of the gold marker on the BLM is in agreement with this explanation.

Absorption of hydrolysed bovine serum albumin from the human jejunum over a 6-hour period.

OBJECTIVE: Quantitative assessment of intestinal absorption of total and single amino acids in a hydrolysed bovine serum albumin solution over a 6-h period. DESIGN: Ten healthy volunteers underwent segmental jejunal perfusion using a multi-lumen tube assembly with a proximal occluding balloon. Prehydrolysed bovine serum albumin served as protein source. In one set of experiments we used a washout phase before the equilibration period to eliminate any contents present in the test segment. In another set we started directly with the equilibration period. Absorption rates of total and single amino acids were measured over a period of 6 h. RESULTS: Absorption rates remained constant throughout this period and there was no significant difference in absorption rates whether a washout phase was used or not. Absorption rates of total amino acids ranged from 6.4 +/- 1.9 (mean +/- SEM) to 10.7 +/- 0.7 g/h and 30 cm, when a washout phase was used. Percentage absorption of the perfusion load per hour was 24 +/- 7% to 40 +/- 2% with a washout phase. Although a highly concentrated perfusion load was used there was a correlation (r = 0.66, P < 0.05) between absolute concentration in the perfusion solution and the amount of individual amino acid absorbed. Individual amino acids showed a wide range of percentage absorption. Percentage absorption of 50% or more of the perfusion load was seen for alanine, phenylalanine, arginine, leucine, methionine and tyrosine. The highest absorption rate was seen for methionine with 86%, the lowest for cysteine with 3%. CONCLUSION: When hydrolysed bovine serum albumin is used, amino acid absorption is constant over a period of 6 h in the human jejunum. A washout phase has no influence on total and single amino acid absorption.

Laryngeal manifestation of gout: a case report of a subglottic gout tophus.

A subglottic tophaceous deposition of urate crystals is a rare finding. We report on a case of a male Caucasian who had a moderate dysphonia without any further laryngeal symptoms. The laryngoscopy revealed a hemispheric lesion on the left subglottic region. An excision biopsy was performed, and the histopathological examination of the dissected specimen showed a tophus. Diagnostic and therapeutic strategies are discussed.

Ex juvantibus approach for chronic posterior laryngitis: results of short-term pantoprazole therapy.

The aim of this study was to investigate whether patients with chronic posterior laryngitis and symptoms of gastro-pharyngeal reflux benefit from a six-week therapy with pantoprozole. Twenty-nine out-patients with voice disorders (case history of at least two months) and simultaneous symptoms of gastro-pharyngeal reflux were recruited for this study. At the entry to the study a symptom questionnaire and a video-laryngo/stroboscopy were completed. The symptom questionnaire and the video-laryngo/stroboscopy were repeated after the six weeks of therapy with pantoprazole 40 mg once a day and again six weeks and three months after this follow-up, during which time the patient was without therapy. Hoarseness, globus pharyngeus, sore throat, heartburn, and coughing were the symptoms which showed a significant (p < 0.05) recovery at the follow-ups (mean of hoarseness index: 7.28 to 0.92; mean of globus pharyngeus index: 3.14 to 0.58; mean of heartburn index: 2.86 to 0.5; mean of cough index: 1.72 to 0.25; mean of throat soreness index: 1.72 to 0.15). Laryngoscopy scores of the posterior laryngeal region, the glottic and the supraglottic region showed statistically significant improvement (p < 0.05) after the treatment with pantoprazole. The therapeutic effect exceeded the drug administration until the last follow-up (after three months). The medication was tolerated without side-effects in all patients. A primary (ex juvantibus) therapy with proton pump inhibitors seems to be a therapeutic option for patients with long-lasting chronic inflammation of the larynx not responding to common therapy. In this case a six-week course of treatment has been shown to be sufficient.

Fecal osmotic gap and pH in experimental diarrhea of various causes.

Although the osmotic gap of fecal fluid is often used to distinguish osmotic diarrhea from secretory diarrhea, there has never been a scientific evaluation of the validity of this concept. Similarly, although a low fecal fluid pH value is used to indicate that diarrhea is mediated by carbohydrate malabsorption, the validity of this method is unproven. Therefore, in the present study, diarrhea was induced in normal subjects by different mechanisms and fecal fluid osmotic gap (using an assumed fecal fluid osmolality of 290 mOsm/kg) and pH were measured. In secretory diarrhea caused by phenolphthalein, the osmotic gap was always less than 50 mOsm/kg, whereas in osmotic diarrhea caused by polyethylene glycol, magnesium hydroxide, lactulose, and sorbitol, the osmotic gap always exceeded 50 mOsm/kg. In osmotic diarrhea caused by sodium sulfate, the fecal fluid osmotic gap was less than 50 mOsm/kg, but phenolphthalein-induced secretory diarrhea could be distinguished from sodium sulfate-induced osmotic diarrhea by the fecal chloride concentration. When diarrhea was caused by carbohydrate malabsorption (lactulose or sorbitol), the fecal fluid pH was always less than 5.6 and usually less than 5.3; by contrast, other causes of diarrhea rarely caused a fecal pH as low as 5.6 and never caused a pH less than 5.3. It is concluded that measurement of fecal fluid osmotic gap and pH can distinguish various mechanisms of experimental diarrhea in normal subjects. The concepts on which these tests are based are therefore verified experimentally.

Gastric adenocarcinoma mimicking achalasia in a 15-year-old patient: a case report and review of the literature.

Although adenocarcinoma of the cardia is extremely rare in adolescent patients, the endoscopist should be alert to this disease in patients of any age with dysphagia, even if symptoms, and results of a barium study, upper endoscopy, and esophageal manometry are suggestive of primary achalasia, especially if family history is negative for achalasia. In addition, secondary achalasia should be suspected in patients who do not respond to therapy with botulinum toxin within 2 months. Because none of the mentioned tests can distinguish between primary achalasia and secondary forms due to carcinoma of the cardia, biopsy specimens should be obtained. It appears that, although there is a minimal risk for complications, a diagnostic procedure such as biopsy would be appropriate when the information obtained could be essential. In some cases EUS can be an additional diagnostic tool, because lesions of the submucosa and the surrounding area can be identified by EUS.

Cyclosporin for the treatment of severe ulcerative colitis.

The effect of cyclosporin was evaluated in six patients with severe ulcerative colitis not responding to at least 8 days of standard therapy with intravenous corticosteroids. Cyclosporin (5-7.5 mg/kg/day intravenously) was added while steroid therapy was continued. Five of 6 patients responded after a mean of 7 days and colectomy was not necessary. After 4 weeks three patients achieved clinical remission or had mild symptoms and were weaned from cyclosporin and corticosteroids without exacerbation within the next 7-15 months. Two patients improved and they were put on oral cyclosporin. One of them relapsed after 2 weeks and then responded to high dose corticosteroids. This patient is doing well at 8 months of followup on azathioprine and steroids. One patient stopped oral cyclosporin after 3 months abruptly and then had a relapse. He subsequently improved while refusing any medical therapy. Side effects of cyclosporin occurred in 2 patients but were mild and self limited and did not necessitate discontinuation of the drug. Cyclosporin appears to be effective in a large portion of patients with severe ulcerative colitis who failed to improve on corticosteroids and in whom colectomy would otherwise be considered.

Effect of neuropeptide Y on jejunal water and ion transport in humans.

Neuropeptide Y is a neurotransmitter in enteric and postganglionic sympathetic neurons. In animal models of intestinal water and ion transport, neuropeptide Y decreases stimulated secretion but has no consistent effect on basal transport. In the present study, the effect of neuropeptide Y on jejunal water and electrolyte transport in healthy volunteers was investigated under basal conditions and during intestinal secretion induced by intraluminal administration of prostaglandin E2. The triple-lumen tube technique was used for perfusion of the small intestine with a plasmalike electrolyte solution containing polyethylene glycol as a nonabsorbable volume marker. After an initial control period (saline IV) neuropeptide Y was administered IV at a dose of 400 pmol.kg-1.h-1. Neuropeptide Y significantly increased net absorption of water, sodium, potassium, and chloride under basal conditions. The peptide significantly reduced the secretion of these electrolytes induced by an intraluminal prostaglandin E2 concentration of 5 mumol/L and reduced net water secretion by 36%. The results of the current study suggest that neuropeptide Y can change intestinal water and ion transport from secretion toward absorption.

Effect of psyllium, calcium polycarbophil, and wheat bran on secretory diarrhea induced by phenolphthalein.

BACKGROUND: Fiber and water-holding agents are used for the treatment of constipation. In what may appear to be a paradox, they are sometimes also used for the treatment of diarrhea; it has been proposed that they sequester water from liquid stools and/or increase the ratio of fecal solids to fecal water and thereby improve stool consistency. The purpose of the present study was to test the validity of this hypothesis in normal subjects in whom secretory diarrhea was induced by phenolphthalein. METHODS: In random sequence, 9 subjects with phenolphthalein-induced diarrhea were treated with placebo, psyllium, calcium polycarbophil, or wheat bran. RESULTS: Calcium polycarbophil and wheat bran had no effect on fecal consistency or on fecal viscosity. By contrast, psyllium made stools firmer and increased fecal viscosity. In a dose-response study in 6 subjects, doses of 9, 18, and 30 g of psyllium per day caused a near linear increase in fecal viscosity. CONCLUSION: Psyllium, but not calcium polycarbophil or wheat bran, improves fecal consistency and viscosity in subjects with experimentally-induced secretory diarrhea.

Effect of 5-hydroxytryptamine antagonists on cholera toxin-induced secretion in the human jejunum.

In rats, the combined administration of the 5-HT2 antagonist ketanserin and the 5-HT3 antagonist tropisetron inhibits cholera toxin-induced intestinal secretion. We investigated whether these agents and the 5-HT3 antagonist ondansetron can inhibit cholera toxin-induced secretion in the human jejunum using a segmental perfusion technique. In a first control period the subjects' jejunums were perfused continuously with a plasma-like electrolyte solution. In a second control period they either received a combination of tropisetron plus ketanserin, or tropisetron or ondansetron alone. Cholera toxin 6.25 micrograms was then administered intrajejunally and the experiments were continued for 4 h. Net water movements during the 4th hour after CT administration minus net water movement during the first control period was used for further calculation and was referred to as net luminal gain. In perfusion studies with tropisetron plus ketanserin resp. ondansetron the net luminal gain of water (+ 161 +/- 26 resp. 189 +/- 28 ml 30 cm-1 h-1, mean +/- SEM) was significantly higher compared to perfusion studies with cholera toxin alone (+ 94 +/- 30). Treatment with tropisetron did not change the CT-induced net luminal gain of water (+ 108 +/- 41). Movements of sodium, chloride, bicarbonate and potassium paralleled the movement of water. In agreement with these observations we found a deterioration of clinical parameters after the end of the perfusion studies in four of five subjects treated with CT 25 micrograms plus ketanserin and tropisetron.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute respiratory acidosis on water and electrolyte transport in the human ileum.

Animal experiments have shown that acute respiratory acidosis stimulates water, Na and Cl absorption and HCO3 secretion in the ileum. The aim of this study was to investigate whether the human ileum also responds to changes in systemic acid-base balance. Seven healthy volunteers (mean age 24, range 21-29 years) underwent segmental ileal perfusion using a multi-lumen tube assembly with a proximal occluding balloon. A 30 cm test segment was perfused under steady state conditions with a plasma-like electrolyte solution containing PEG as a non-absorbable volume marker. After a control period, respiratory acidosis (blood pCO2 56.2 mmHg, pH 7.29 and [HCO3] 26.4 mmol l-1) was induced by CO2-breathing over a period of 50 min. Acute respiratory acidosis stimulated net HCO3 secretion in patients secreting HCO3 and reduced absorption in patients exhibiting net HCO3 absorption. These changes were immediate and appeared to be at least partly reversible. Net water, Na, K and Cl movement were not affected. The data suggest that HCO3 transport in the human ileum responds to acute respiratory acidosis.

Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders.

BACKGROUND AND AIMS: Sildenafil blocks phosphodiesterase type 5 which degrades nitric oxide (NO) stimulated 3'5'-cyclic monophosphate (cGMP), thereby relaxing smooth muscle cells in various organs. We used sildenafil as a tool to investigate the role of the NO-cGMP pathway in the oesophagus of healthy volunteers and patients with hypercontractile oesophageal motility disorders. METHODS: Six healthy male volunteers participated in a randomised double blind study on two separate days before and one hour after oral intake of either sildenafil 50 mg or placebo. Oesophageal manometry was performed to determine vector volume of the lower oesophageal sphincter (LOS) and pressure amplitudes of the oesophageal body. Four of the volunteers underwent 12 hour ambulatory oesophageal manometry on two separate days, once with sildenafil 50 mg and once with placebo. An activity index for spontaneous swallowing was calculated for every hour of the study. Eleven patients with hypercontractile oesophageal motility disorders took part in an open study of the effect of 50 mg sildenafil on manometric features of their disorder and on the clinical response to sildenafil taken as required. RESULTS: In healthy subjects, sildenafil significantly reduced LOS pressure vector volume and pressure amplitudes in the distal half of the oesophageal body. In three of four subjects the inhibitory effect of sildenafil lasted at least eight hours. In nine of 11 patients, manometric improvement after sildenafil was observed but only four had an improvement in oesophageal symptoms with sildenafil taken as required. Two of these four patients however experienced side effects and did not want to continue treatment. CONCLUSIONS: Sildenafil lowers LOS pressure and propulsive forces in the body of the oesophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia. The effect of sildenafil on the oesophageal body may last for up to eight hours in healthy volunteers. A subset of patients with hypertensive LOS or nutcracker oesophagus may benefit from sildenafil but side effects are a limiting factor.