József Czimmer

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - A Hungarian nationwide observational study

BackgroundInfliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohns disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary.MethodsDuring a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy.ResultsThree hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%).ConclusionIFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Otilonium bromide enhances sensory thresholds of volume and pressure in patients with irritable bowel syndrome

UNLABELLED Visceral hyperalgesia has been suggested to play a role in the development of symptoms presented by irritable bowel syndrome patients. Otilonium bromide was developed to block smooth muscle Ca release to control cramping pain of these patients. AIMS to determine whether otilonium bromide can influence sensory thresholds of patients suffering from irritable bowel syndrome. METHODS 15 patients with Rome-II positive IBS were tested by Synectics Visceral Stimulator Barostat using rapid phasic distension (870 ml/min). The sensory threshold for first sensation, stool, pain and maximum tolerable volume and pressure were measured. All of the parameters were tested before and 1 week after the initiation of otilonium bromide (Spasmomen, Berlin Chemie, 3x40 mg) therapy. RESULTS The perceptual thresholds for first sensation, stool, pain and maximum tolerable distention were, 8.8+/-1.7 Hgmm, 19.2+/-2.1 Hgmm, 26.3+/-2.8 Hgmm, 28.7+/-2.8 Hgmm for pressure, 90+/-21 ml, 145+/-28 ml, 208+/-25 ml, 213+/-28 ml for volume, before treatment, respectively. Otilonium bromide treatment did not influence the thresholds for first sensation and stool, 7.4+/-1.4 Hgmm, 20.7+/-4.6 Hgmm and 83+/-21 ml, 178+/-35.8 ml, respectively. The pressure threshold of pain was significantly higher 1 week after treatment (26.3+/-2.8 Hgmm vs. 29.1+/-5.5 Hgmm, P<0.05), but the volume threshold of this sensation remained unchanged (208+/-25 ml vs. 234+/-39 ml, not significant). The pressure (28.7+/-2.8 Hgmm vs. 38.1+/-3.4 Hgmm, P<0.05) and volume (213+/-28 ml vs. 278+/-27 ml, P<0.05) thresholds for maximum tolerable volume were increased by 7 days otilonium bromide treatment. CONCLUSION These data suggest that otilonium bromide enhances sensory thresholds to recto-sigmoideal distention.

Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: A meta-analysis of clinical studies

Background Irritable bowel syndrome (IBS) and functional digestive tract disorders, e.g. functional bloating, carbohydrate maldigestion and intolerances, are very common disorders frequently causing significant symptoms that challenge health care systems. A low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet is one of the possible therapeutic approaches for decreasing abdominal symptoms and improving quality of life. Objectives We aimed to meta-analyze data on the therapeutic effect of a low-FODMAP diet on symptoms of IBS and quality of life and compare its effectiveness to a regular, standard IBS diet with high FODMAP content, using a common scoring system, the IBS Symptom Severity Score (IBS-SSS). Methods A systematic literature search was conducted in PubMed, EMBASE and the Cochrane Library as well as in the references in a recent meta-analysis. Adult patients diagnosed with IBS according to the Rome II, Rome III, Rome IV or NICE criteria were included in the analysis. Statistical methods Mean differences with 95% confidence intervals were calculated from studies that contained means, standard deviation (SD) or mean differences and SD of differences and p-values. A random effect model was used because of the heterogeneity (Q test (χ2) and I2 indicator). A p-value of less than 0.05 was chosen to indicate a significant difference. Results The literature search yielded 902 publications, but only 10 were eligible for our meta-analysis. Both regular and low-FODMAP diets proved to be effective in IBS, but post-diet IBS-SSS values were significantly lower (p = 0.002) in the low-FODMAP group. The low-FODMAP diet showed a correlation with the improvement of general symptoms (by IBS-SSS) in patients with IBS. Conclusions This meta-analysis provides high-grade evidence of an improved general symptom score among patients with irritable bowel syndrome who have maintained a low-FODMAP diet compared to those on a traditional IBS diet, therefore showing its superiority to regular IBS dietary therapy. These data suggest that a low-FODMAP diet with dietitian control can be a candidate for first-line therapeutic modality in IBS. Because of a lack of data, well-planned randomized controlled studies are needed to ascertain the correlation between improvement of separate key IBS symptoms and the effect of a low-FODMAP diet.

Failure of capsaicin-containing red pepper sauce suspension to induce esophageal motility response in patients with Barrett’s esophagus

UNLABELLED The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barretts esophagus. METHODS The diagnosis of Barretts esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. RESULTS Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barretts esophagus. CONCLUSION Impaired esophageal sensory motor function may serve as one etiologic role in the development of Barretts esophagus.

Prospective, Multicentre, Nationwide Clinical Data from 600 Cases of Acute Pancreatitis

Objective The aim of this study was to analyse the clinical characteristics of acute pancreatitis (AP) in a prospectively collected, large, multicentre cohort and to validate the major recommendations in the IAP/APA evidence-based guidelines for the management of AP. Design Eighty-six different clinical parameters were collected using an electronic clinical research form designed by the Hungarian Pancreatic Study Group. Patients 600 adult patients diagnosed with AP were prospectively enrolled from 17 Hungarian centres over a two-year period from 1 January 2013. Main Results With respect to aetiology, biliary and alcoholic pancreatitis represented the two most common forms of AP. The prevalence of biliary AP was higher in women, whereas alcoholic AP was more common in men. Hyperlipidaemia was a risk factor for severity, lack of serum enzyme elevation posed a risk for severe AP, and lack of abdominal pain at admission demonstrated a risk for mortality. Abdominal tenderness developed in all the patients with severe AP, while lack of abdominal tenderness was a favourable sign for mortality. Importantly, lung injury at admission was associated with mortality. With regard to laboratory parameters, white blood cell count and CRP were the two most sensitive indicators for severe AP. The most common local complication was peripancreatic fluid, whereas the most common distant organ failure in severe AP was lung injury. Deviation from the recommendations in the IAP/APA evidence-based guidelines on fluid replacement, enteral nutrition and timing of interventions increased severity and mortality. Conclusions Analysis of a large, nationwide, prospective cohort of AP cases allowed for the identification of important determinants of severity and mortality. Evidence-based guidelines should be observed rigorously to improve outcomes in AP.

Molecular pharmacological approaches to effects of capsaicinoids and of classical antisecretory drugs on gastric basal acid secretion and on indomethacin-induced gastric mucosal damage in human healthy subjects (mini review)

BACKGROUND Actions of various drugs have been tested on the gastric acid basal secretion and on the drug (Indomethacin)- induced gastric mucosal damage; however their physiological and pharmacological mechanisms have not been compared. AIMS The effects of capsaicinoids, atropine, cimetidine, omeprazole, famotidine and ranitidine were studied on gastric basal acid output, whereas the gastric mucosal preventive effects of capsaicinoids (capsaicin), atropine and cimetidine were tested on the indomethacin-induced gastric mucosal microbleedings in human healthy subjects. Results were presented by molecular pharmacological method; affinity (pD) and intrinsic activity (α-values) were calculated. Intrinsic activity curves are based on comparison to atropine effect (α(atropine)= 1.00). For evaluation of physiological and pharmacological effects of compounds molar doses of pD(2) (necessary doses to produce 50% inhibition) and pA(2) (50% inhibion on intrinsic activity) were calculated from affinity and intrinsic activity curves. RESULTS The pD(2) values for compounds were as follows: 5.88 for capsaicinoids, 5.40 for atropine , 2.23 for cimetidine, 3.33 for ranitidine, 3.77 for famotidine and 3.97 for omeprazole. α - value results for compounds were: 0.76 for capsaicinoids, and 1.00 for atropine, cimetidine, ranitidine, famotidine and omeprazole all equal to 1.00 on gastric acid basal secretion. The pD(2) values on indomethacin-induced gastric mucosal microbleeding were found as follows: 6.00 for capsaicinoids, 5.50 for atropine, and 3.50 for cimetidine, meanwhile α-values resulted 0.76 for capsaicinoids, 1.00 for atropine and cimetidine. CONCLUSIONS Comparison classical antisecretory drugs acting on different pathways but in much more higher molar concentrations. The atropine and capsaicinoids act in about the same molar concentration which suggests a significant physiological role for capsaicin sensitive afferent nerves in the regulation of gastric basal acid secretion and in the prevention of chemically- induced gastric mucosal protection in human healthy subjects, suggesting a novel physiological pathway in regulation. These results clearly indicate the molecular pharmacological backgrounds of actions of classical antisecretory drugs and physiological role of capsaicin- sensitive afferent nerves in human healty subjects on the gastric basal secretion and on the prevention of drug-induced gastric mucosal damage.

Leiden mutation (as genetic) and environmental (retinoids) sequences in the acute and chronic inflammatory and premalignant colon disease in human gastrointestinal tract.

BACKGROUND Tumor, calor, dolor, pallor and functio laesa are together involved in the different acute and chronic inflammatory processes. The processes involved in the inflammation are determined by differently acquired and hereditary factors. Recently the presence of a new genetic marker (Leiden point mutation) was found in Crohns disease and ulcerative colitis. On the other hand, the GI mucosal integrity was proven on gastrointestinal mucosal damage to be produced by different chemicals, xenobiotics, drugs. In human observations, the serum level of retinoids (vitamin A, lutein, zeaxanthin, alpha-, beta-carotene) was proven in patients with chronic gastrointestinal inflammatory bowel disease. The aims of this study were (1) to measure the prevalence of Leiden mutation; (2) to identify the changes in the serum retinoid level in patients with Helicobacter pylori infection of the stomach (n=24), hepatitis C infection (n=75), ileitis terminalis (Crohns disease; n=49), ulcerative colitis (n=35), colon polyposis (n=59) and adenocarcinoma in colon polyps (n=9), and 57 healthy persons were used in the control group; (3) to compare the directions of the changes in the measured parameters in the acute (H. pylori and hepatitis C infections), chronic (ileitis terminalis, ulcerative colitis) GI inflammatory diseases and in colon polyposis without and with malignisation. METHODS The Leiden mutation was measured by the method of polymerase chain reaction, the retinoid level in the patients serum was measured by high liquid cromathografic method (HPCL). RESULTS (1) It has been found that the prevalence of Leiden mutation increased significantly in patients with ileitis terminalis (P<0.001), ulcerative colitis (P<0.001), colon polyposis (P<0.001) and with colon polyps with malignisation (P<0.01). (2) Serum level of vitamin A and zeaxantin were decreased significantly in all group of patients except for the group with H. pylori infections. (3) alpha- and beta-carotenes were found to be practically at the same level as those in the control groups, except in patients of colon polyps with malignisation. (4) The vitamin A, lutein, zeaxantin, alpha- and beta-carotenes were decreased in patients with ileitis terminalis. CONCLUSIONS (1) The essential role of retinoids (carotenoids) as environmental factors are suggested for keeping GI mucosal integrity in human healthy subjects and patients. (2) Leiden mutation, as a genetic marker, can be used in the screening of patients with ileitis terminalis, ulcerative colitis and colon polyposis (without and with malignisation). (3) An opposite direction can be found between the increased prevalence of Leiden mutation and decrease of serum levels of retinoids in group of patients with ileitis terminalis, ulcerative colitis and colon polyposis (without and with malignisation).

Meta-analysis of the long term success rate of different interventions in benign biliary strictures

Background Benign biliary stricture is a rare condition and the majority of the cases are caused by operative trauma or chronic inflammation based on various etiology. Although the initial results of endoscopic, percutaneous and surgical treatment are impressive, no comparison about long term stricture resolution is available. Aims The goal of this study was to compare the long term disease free survival in benign biliary strictures with various etiology after surgery, percutaneous transhepatic—and endoscopic treatment. Methods PubMed, Embase, and Cochrane Library were searched by computer and manually for published studies. The investigators selected the publications according to the inclusion and exclusion criteria, processed the data and assessed the quality of the selected studies. Meta-analysis of data of 24 publications was performed to compare long term disease free survival of different treatment groups. Results Compared the subgroups surgery resulted in the highest long term stricture resolution rate, followed by the percutaneous transhepatic treatment, the multiple plastic stent insertion and covered self-expanding metal stents (SEMS), however the difference was not significant. All compared methods are significantly superior to the single plastic stent placement. Long term stricture resolution rate irrespectively of any therapy is still not more than 84%. Conclusions In summary, the use of single plastic stent is not recommended. Further randomized studies and innovative technical development are required for improving the treatment of benign biliary strictures.

Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

BACKGROUND AND AIMS Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. METHODS The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. RESULTS Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. CONCLUSION We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.