George Karamanolis

Selective Serotonin Reuptake Inhibitors for the Treatment of Hypersensitive Esophagus: A Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVES:Ambulatory 24-h pH–impedance monitoring can be used to assess the relationship of persistent symptoms and reflux episodes, despite proton pump inhibitor (PPI) therapy. Using this technique, we aimed to identify patients with hypersensitive esophagus and evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) on their symptoms.METHODS:Patients with normal endoscopy and typical reflux symptoms (heartburn, chest pain, and regurgitation), despite PPI therapy twice daily, underwent 24-h pH–impedance monitoring. Distal esophageal acid exposure (% time pH <4) was measured and reflux episodes were classified into acid or non-acid. A positive symptom index (SI) was declared if at least half of the symptom events were preceded by reflux episodes. Patients with a normal distal esophageal acid exposure time, but with a positive SI were classified as having hypersensitive esophagus and were randomized to receive citalopram 20 mg or placebo once daily for 6 months.RESULTS:A total of 252 patients (150 females (59.5%); mean age 55 (range 18–75) years) underwent 24-h pH–impedance monitoring. Two hundred and nineteen patients (86.9%) recorded symptoms during the study day, while 105 (47.9%) of those had a positive SI (22 (20.95%) with acid, 5 (4.76%) with both acid and non-acid, and 78 (74.29%) with non-acid reflux). Among those 105 patients, 75 (71.4%) had normal distal esophageal acid exposure time and were randomized to receive citalopram 20 mg (group A, n=39) or placebo (group B, n=36). At the end of the follow-up period, 15 out of the 39 patients of group A (38.5%) and 24 out of the 36 patients of group B (66.7%) continue to report reflux symptoms (P=0.021).CONCLUSIONS:Treatment with SSRIs is effective in a select group of patients with hypersensitive esophagus.

Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts

Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10−6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

Long-Term Acid Suppressive Therapy May Prevent the Relapse of Lower Esophageal (Schatzki's) Rings: A Prospective, Randomized, Placebo-Controlled Study

OBJECTIVES:Distal esophageal (Schatzkis) rings are a frequent cause of dysphagia. Bougienage is generally effective, but relapses are common. The aim of this study was to evaluate the effect of long-term antisecretory therapy on the relapse rate of lower esophageal rings after successful bougienage with Savary dilators.PATIENTS AND METHODS:The study was performed on 44 consecutive patients with symptomatic Schatzkis rings, detected endoscopically, and/or radiologically. Graded esophageal dilation was performed as an outpatient procedure in a single session. After appropriate assessment with esophageal manometry and 24-h ambulatory esophageal pH monitoring, patients with documented GERD (n = 14) were treated with long-term omeprazole therapy. The remaining patients were blindly randomized to receive maintenance treatment with either omeprazole (group A—15 patients) or placebo (group B—15 patients). The necessity for redilation after documentation of the ring with endoscopy and/or radiology was considered as a relapse of the ring. The relapse rate was evaluated in all groups.RESULTS:All bougienages were performed without significant side effects. Eight patients (8 of 44, 18.2%) had one or more relapses after a mean (SD) of 19.0 (10.1) months. Patients with (n = 14) or without (n = 30) GERD were comparable with respect to sex, age, body mass index, cigarette and alcohol consumption, diameter of the esophageal lumen at the level of the ring, resting lower esophageal sphincter pressure, duration of dysphagia, need for taking antacids during the follow-up period, and duration of follow-up. There were no recurrences of Schatzkis ring in the group of patients with documented GERD (follow-up [mean ± SD]: 43.8 ± 9.3 months, range: 27–62). In group A (follow-up [mean ± SD]: 37.1 ± 17.1 months, range: 11–66), one patient relapsed after 13 months, while in group B (follow-up [mean ± SD]: 34.3 ± 14.6 months, range: 10–58), seven patients relapsed after a mean (SD) of 19.9 (10.6) months. The actuarial probability of relapse was higher in patients without therapy (group B) (p= 0.008).CONCLUSIONS:Our data support the hypothesis that, in patients with symptomatic Schatzkis rings, acid suppressive maintenance therapy after bougienage may prevent relapse of the ring.

Comparative performance of novel solutions for submucosal injection in porcine stomachs: An ex vivo study

BACKGROUND Submucosal injection of normal saline (NS) is commonly used during endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) but is quickly absorbed. Sodium hyaluronate (SH) produces longer lasting mucosal elevation but is expensive. AIMS To evaluate the performance of novel solutions for submucosal injection in comparison with NS and SH. METHODS One ml of the following solutions was injected in the submucosa of fresh specimens of porcine stomachs: NaCl 0.9%, SH 0.4%, human albumin 25%, two artificial tears solutions, namely, hydroxypropyl methylcellulose (HPMC) 0.3%/dextran 70.1% and polyvinyl alcohol (PVA) 1.4%, hydroxyethyl starch (HES) 6% and polyethylene glycol (PEG) 50%. The time until the disappearance of the mucosal elevation was recorded in a blind manner. RESULTS The median duration of mucosal elevation was significantly longer with HPMC/dextran, PVA, HES, PEG and SH (29, 26, 38, 31.5, and 41.5min, respectively) compared with NS (12min) (p<0.05 for each comparison). There were no significant time differences between SH and HPMC/dextran, HES and PEG (p>0.05). CONCLUSIONS Novel viscous or hypertonic solutions for submucosal injection, perform better than normal saline and equally well as sodium hyaluronate in porcine stomachs in vitro.

Gastroesophageal Reflux Disease: Medical or Surgical Treatment?

Background. Gastroesophageal reflux disease is a common condition with increasing prevalence worldwide. The disease encompasses a broad spectrum of clinical symptoms and disorders from simple heartburn without esophagitis to erosive esophagitis with severe complications, such as esophageal strictures and intestinal metaplasia. Diagnosis is based mainly on ambulatory esophageal pH testing and endoscopy. There has been a long-standing debate about the best treatment approach for this troublesome disease. Methods and Results. Medical treatment with PPIs has an excellent efficacy in reversing the symptoms of GERD, but they should be taken for life, and long-term side effects do exist. However, patients who desire a permanent cure and have severe complications or cannot tolerate long-term treatment with PPIs are candidates for surgical treatment. Laparoscopic antireflux surgery achieves a significant symptom control, increased patient satisfaction, and complete withdrawal of antireflux medications, in the majority of patients. Conclusion. Surgical treatment should be reserved mainly for young patients seeking permanent results. However, the choice of the treatment schedule should be individualized for every patient. It is up to the patient, the physician and the surgeon to decide the best treatment option for individual cases.

Effect of sleep on excessive belching: a 24-hour impedance-pH study.

In patients with repetitive and troublesome belching an organic cause is seldom found, indicating the presence of an acquired abnormal behavior. The aim of our study was to investigate the incidence and pattern of belching during a 24-hour period. Methods Combined 24-hour pH and intraluminal impedance monitoring was performed in 14 patients (9 female; mean age: 43 y) with excessive belching and 10 patients (6 women, mean age 42 y; range 28 to 56) with noncardiac chest pain. Thereafter, we counted the number of belching events and differentiated the number of supragastric and gastric belches. Results During the 24-hour study, the hourly rate of belching was 38.7±6.0; rate of supragastric belches were significantly higher compared to gastric belches (37.7±6.0 vs 1.0±0.5, P<0.001). Patients with noncardiac chest pain showed a lower average hourly rate of belching (3.1±0.6, P<0.001). Dividing the recording into 2 periods (daily-upright and night-supine), there was a significant decrease in the hourly rate at night (37.8±6.1 vs. 0.9±0.5, respectively, P<0.001); mostly due to decrease in supragastric belches, where as the rate of gastric belches remained unchanged. None of the patients showed pathological acid reflux and none of the supragastric belches was associated with acid or nonacid reflux events. Conclusions Supragastric belch is the prominent belching pattern in patients with excessive belching. Supragastric belches almost ceased at night suggesting the presence of a behavioral disorder. There were no diurnal changes in the rate of gastric belches.

Endoscopic treatments for chronic radiation proctitis

Chronic radiation proctitis is a complication that occurs in patients who receive radiation therapy for pelvic malignancies. The common presentation is with rectal bleeding, but also rectal pain, diarrhea, tenesmus and even passage of mucus can occur. The optimal treatment of bleeding due to radiation proctitis remains unclear. Among various therapeutic options, medical management is generally ineffective and surgical intervention has a high incidence of morbidity. Promising advances have been made in endoscopic therapy, including argon plasma coagulation (APC), formalin application as well as new techniques such as radiofrequency ablation and cryoablation. APC is a safe, highly effective and long-lasting therapy in patients with rectal bleeding associated with radiation proctitis. It has been shown that several sessions of APC reduce the rate of bleeding and therefore the blood transfusion requirements. Moreover, the effect of treatment is long lasting. However, best results are achieved in patients with mild to moderate radiation proctitis, leaving space for alternative treatments for patients with more severe disease. In patients with severe or refractory radiation proctitis intra rectal formalin application is an appropriate treatment option. Radiofrequency ablation and cryoablation have shown efficacy as alternative methods in a limited number of patients with refractory chronic radiation proctitis.

Peculiar antibody reactivity to human connexin 37 and its microbial mimics in patients with Crohn's disease

BACKGROUND/AIMS We found that pooled Crohns disease (CD) sera strongly react with a human gap-junction connexin 37 (Cx37) peptide and tested for anti-Cx37 antibody reactivity in sera from CD patients and controls. We also investigated whether peptide-recognition is due to Cx37/microbial molecular mimicry. METHODS The PSI-BLAST program was used for Cx37(121-135)/microbial alignment. Reactivity to biotinylated human Cx37(121-135) and its microbial mimics was determined by ELISA using sera from 44 CD, 30 ulcerative colitis and 28 healthy individuals. RESULTS Anti-Cx37(121-135) reactivity (1/200 dilution) was present in 30/44 (68%) CD cases and persisted at 1/1000 dilution. Database search shows that Cx37(121-135) contains the -ALTAV- motif which is cross-recognized by diabetes-specific phogrin and enteroviral immunity. Testing of 9 Cx37(121-135)-microbial mimics revealed 57-68% reactivity against human enterovirus C, Lactococcus lactis, coxsackie virus A24 and B4. Anti-Cx37(121-135) was inhibited by itself or the microbial mimics. No reactivity was found against the poliovirus, rubella, and Mycobacterium tuberculosis mimics, or the beta cell phogrin autoantigen. Microbial/Cx37 reactivity was not able to differentiate CD patients from UC or healthy controls, in terms of overall prevalence and antibody titres, but microbial mimics were unable to inhibit reactivity to human Cx37 in the majority of the controls. CONCLUSIONS Sera from CD patients react with connexin 37 and cross-react with specific Cx37-mimicking enteroviral peptides. Microbial/self reactivity can be seen in UC and healthy controls. The lack of responses to other Cx37(121-135) microbial mimics and the inability of the reactive microbes to inhibit reactivity to self is intriguing and warrants further investigation.

Gene polymorphisms associated with functional dyspepsia

Functional dyspepsia (FD) is a constellation of functional upper abdominal complaints with poorly elucidated pathophysiology. However, there is increasing evidence that susceptibility to FD is influenced by hereditary factors. Genetic association studies in FD have examined genotypes related to gastrointestinal motility or sensation, as well as those related to inflammation or immune response. G-protein b3 subunit gene polymorphisms were first reported as being associated with FD. Thereafter, several gene polymorphisms including serotonin transporter promoter, interlukin-17F, migration inhibitory factor, cholecystocynine-1 intron 1, cyclooxygenase-1, catechol-o-methyltransferase, transient receptor potential vanilloid 1 receptor, regulated upon activation normal T cell expressed and secreted, p22PHOX, Toll like receptor 2, SCN10A, CD14 and adrenoreceptors have been investigated in relation to FD; however, the results are contradictory. Several limitations underscore the value of current studies. Among others, inconsistencies in the definitions of FD and controls, subject composition differences regarding FD subtypes, inadequate samples, geographical and ethnical differences, as well as unadjusted environmental factors. Further well-designed studies are necessary to determine how targeted genes polymorphisms, influence the clinical manifestations and potentially the therapeutic response in FD.

The contribution of long non-coding RNAs in Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood. While they are widely investigated in cancers, little is known about their contribution in other diseases. There is growing evidence that lncRNAs play critical role in regulation of immune system and that they interfere in the pathogenetic mechanisms of autoimmune diseases, like IBDs. Recent studies have identified lncRNAs in the proximity of IBD-associated genes and single nucleotide polymorphisms within IBD-associated lncRNAs as well. Furthermore, blood samples and pinch biopsies were also analyzed and a plethora of lncRNAs are found to be deregulated in Crohns disease (CD), Ulcerative colitis (UC) or both. (Especially in UC samples the lncRNAs INFG-AS1 and BC012900 were found to be significantly up-regulated. Similarly, ANRIL, a lncRNA that nest different disease associated SNPs, is significantly down-regulated in inflamed IBD tissue.) This review aims at recording for the first time recent data about lncRNAs found to be deregulated in IBDs and discussing suggestive pathogenetic mechanisms and future use of lncRNAs as biomarkers.