Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.

BACKGROUND: Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated. METHODS: After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform. KEY RESULTS: Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. CONCLUSIONS & INFERENCES: In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.

Diagnostic performance of the endoscopic pressure study integrated system (EPSIS): a novel diagnostic tool for gastroesophageal reflux disease.

BACKGROUND: The endoscopic pressure study integrated system (EPSIS) is a prototypic system for monitoring intragastric pressure (IGP) fluctuations that result from opening of the cardia during gastric distension. The performance of EPSIS for the diagnosis of gastroesophageal reflux disease (GERD) was evaluated. METHODS: A retrospective analysis was conducted of data prospectively collected over a 2-year period from 59 patients who underwent gastroscopy, EPSIS, and 24-hour pH monitoring. Using a dedicated electronic device and a through-the-scope catheter, maximum IGP (IGPmax) and IGP waveform pattern (uphill/flat) were recorded. RESULTS: The optimal IGPmax cutoff was 18.7 mmHg. IGPmax < 18.7 mmHg (sensitivity 74.2 %, 95 % confidence interval [CI] 56.8 - 86.3; specificity 57.1 %, 95 %CI 39.1 - 73.5) and flat pattern (sensitivity 71.0 %, 95 %CI 53.4 - 83.9; specificity 82.1 %, 95 %CI 64.4 - 92.1) were associated with GERD. "Double" EPSIS positivity (IGPmax < 18.7 mmHg and flat pattern) provided maximum specificity (85.7 %, 95 %CI 68.5 - 94.3), whereas "any" EPSIS positivity (IGPmax < 18.7 mmHg or flat pattern) provided maximum sensitivity (80.6 %, 95 %CI 63.7 - 90.8). Maximum specificity and sensitivity for nonerosive reflux disease (NERD) was > 70 %. In multivariate analysis, "double" EPSIS positivity was the strongest predictor of GERD (odds ratio [OR] 16.05, 95 %CI 3.23 - 79.7) and NERD (OR 14.7, 95 %CI 2.37 - 90.8). CONCLUSION: EPSIS emerges as a reliable adjunct to routine gastroscopy for GERD diagnosis, and might prove helpful for the stratification and management of patients with reflux disorders.

2007-2019: a "Third"-Space Odyssey in the Endoscopic Management of Gastrointestinal Tract Diseases.

PURPOSE OF REVIEW: The main scope of this review article is to introduce readers to the innovative field of third-space endoscopy and offer a closer look at its history, milestones, and procedure spectrum while discussing ongoing and future challenges arising from its increasing adoption worldwide. RECENT FINDINGS: Over the past few years, third-space endoscopy has been utilized in various diagnostic and interventional procedures performed throughout the gastrointestinal tract: obliteration of Zenker's diverticulum, myotomy for achalasia, gastroparesis or Hirschsprung's disease, biopsy or removal of subepithelial tumors, stricture management, post-per-oral endoscopic myotomy endoscopic fundoplication, and mediastino-, thoraco-, and peritoneoscopy. Third-space endoscopic interventions have revolutionized the management of esophageal motility disorders, gastroparesis, and gastrointestinal tract subepithelial tumors. Despite the high efficacy and safety of such interventions, some common (e.g., the high level of necessary endoscopic skill) and unique for each procedure (e.g., post-procedure gastroesophageal reflux or poor outcomes in patient subgroups) challenges still remain. Through a dedicated endoscopic training, a rigorous pre-procedure patient evaluation and selection, and the application of modified or new techniques, challenges can be overcome thus establishing existing procedures and paving the way for additional breakthroughs in the field of third-space endoscopy.

Effect of citalopram on esophageal motility in healthy subjects-Implications for reflux episodes, dysphagia, and globus.

BACKGROUND: Drugs such as citalopram, "targeting" the serotonin pathway, can alter esophageal mechano-chemical sensitivity and gastrointestinal motility. The aim of this study was to clarify the effect of citalopram on esophageal motility and sphincter function, transient lower esophageal sphincter relaxations (TLESRs), and reflux events. METHODS: Sixteen healthy volunteers (HV) receiving 20 mg citalopram or placebo intravenously, in a randomized cross-over fashion, underwent two high-resolution impedance manometry studies involving liquid swallows and a high-fat, high-caloric meal. Manometric, reflux, and symptom-related parameters were studied. KEY RESULTS: A lower distal contractile integral was recorded under citalopram, compared with placebo (P = 0.026). Upper esophageal sphincter (UES) resting pressure was significantly higher after citalopram administration throughout the study (P < 0.05, all periods). Similarly, the UES postswallow mean and maximum pressures were higher in the citalopram condition (P < 0.0001, in both cases) and this was also the case for the 0.2 s integrated relaxation pressure (P = 0.04). Esophagogastric junction resting pressures in the citalopram visit were significantly higher during swallow protocol, preprandial period, and the first postprandial hour (P < 0.05, in all cases). TLESRs and total reflux events were both reduced after citalopram infusion (P = 0.01, in both cases). During treatment with citalopram, five participants complained about globus sensation (P = 0.06). This citalopram-induced globus was associated with higher UES postswallow mean and maximum pressure values (P = 0.01 and P = 0.04, respectively). CONCLUSIONS AND INFERENCES: Administration of citalopram exerts a diversified response on esophageal motility and sphincter function, linked to clinically relevant phenomena: a reduction in postprandial TLESRs and the induction of drug-induced globus.

α2-Heremans-schmid glycoprotein (fetuin A) downregulation and its utility in inflammatory bowel disease.

AIM: To investigate the impact of inflammatory bowel disease (IBD) on α2-Heremans-Schmid Glycoprotein (AHSG/fetuin A) and potential associations with disease and patient characteristics. METHODS: AHSG serum levels were determined in treatment-naïve newly-diagnosed patients, 96 with ulcerative colitis (UC), 84 with Crohn's disease (CD), 62 with diarrhea-predominant or mixed irritable bowel syndrome (IBS, D- and M- types) and 180 healthy controls (HC), by an enzyme linked immunosorbent assay (ELISA). All patients were followed for a minimum period of 3 years at the Gastroenterology Department of the University Hospital of Larissa, Greece. C-reactive protein (CRP), anti-glycan antibodies, anti-Saccharomyces cerevisiae mannan antibodies IgG, anti-mannobioside carbohydrate antibodies IgG, anti-laminariobioside carbohydrate antibodies IgG and anti-chitobioside carbohydrate antibodies IgA were also determined via immunonephelometry and ELISA, respectively. RESULTS: The mean ± SE of serum AHSG, following adjustment for confounders, was 0.32 ± 0.02 g/L in IBD, 0.32 ± 0.03 g/L in CD and 0.34 ± 0.03 g/L in UC patients, significantly lower than in IBS patients (0.7 ± 0.018 g/L) and HC (0.71 ± 0.02 g/L) (P < 0.0001, in all cases). AHSG levels were comparable between the CD and UC groups. Based on AHSG levels IBD patients could be distinguished from HC with about 90% sensitivity and specificity. Further adjusted analysis verified the inverse association between AHSG and penetrating, as well as stricturing CD (partial correlation coefficient: -0.45 and -0.33, respectively) (P < 0.05). After adjusting for confounding factors, inverse correlations between AHSG and CRP and the need for anti-TNFα therapy or surgery, were found (partial correlation coefficients: -0.31, -0.33, -0.41, respectively, P < 0.05, in all cases). Finally, IBD individuals who were seropositive, for at least one marker, had AHSG levels falling within the two lower quartiles (OR = 2.86, 95%CI: 1.5-5.44, P < 0.001) while those with at least two serological markers positive exhibited AHSG concentrations within the lowest quartile (OR = 5.03, 95%CI: 2.07-12.21, P < 0.001), after adjusting for age, sex and smoking. CONCLUSION: AHSG can be used to distinguish between IBD and IBS patients or HC while at the same time "predicting" complicated disease behavior, need for therapy escalation and surgery. Moreover, AHSG may offer new insights into the pathogenesis of IBD, since it is involved in key processes.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Epidermal growth factor in the treatment of diabetic foot ulcers: an update.

Management of diabetic foot ulcers remains a rather challenging task. Epidermal growth factor (EGF) plays a central role in wound healing. It acts on epithelial cells and fibroblasts promoting restoration of damaged epithelium. However, its bioavailability is impaired in chronic diabetic foot ulcers. Current evidence suggests that application of human recombinant EGF in addition to standard treatment is able to achieve both partial and complete healing and to prevent foot amputations. Its efficacy has been tested at various concentrations and by various administration routes (topical application and intralesional injection). Intralesional injection has better availability on the deep wound layers, but pain at the injection site is a common complaint. Generally, adverse events have been minor to mild. Finally, numerous issues need to be further clarified before widespread use of EGF becomes possible in everyday practice. Such issues include optimal dosage and administration route, characteristics of the ulcers most likely to heal (severity and ischemic/neuropathic or both), and cost-effectiveness.

The role of hyperbaric oxygen in the treatment of diabetic foot ulcers.

Diabetic foot ulcers are still extremely difficult to heal. Therefore, therapeutic options to improve healing rates are continuously being explored. Hyperbaric oxygen (HBO) has been used in addition to standard treatment of the diabetic foot for more than 20 years. Evidence suggests that HBO reduces amputation rates and increases the likelihood of healing in infected diabetic foot ulcers, in association with improved tissue oxygenation, resulting in better quality of life. Nonetheless, HBO represents an expensive modality, which is only available in few centers. Moreover, adverse events necessitate a closer investigation of its safety. Finally, it is not entirely clear which patients stand to benefit from HBO and how these should be selected. In conclusion, HBO appears promising, but more experience is needed before its broad implementation in the routine care of the diabetic foot.

The implication of adiponectin and resistin in gastrointestinal diseases.

Adiponectin and resistin, members of the adipokine family, are multi-task hormones involved in several disorders, including those of the alimentary tract. In the present review, eligible studies focusing on the role of adiponectin and resistin in gastrointestinal diseases are manifested together and classified according to anatomic criteria. In addition, similarities and common patterns have been recognized, ultimately revealing an inverse association: the down-regulation of adiponectin and up-regulation of resistin - both in vitro and in vivo - in gastrointestinal disorders, irrespective of their diverse nature - inflammatory, autoimmune or malignant - or anatomic position - esophageal, gastric, of the small intestine, colonic. Finally, a potential role for both adipokines in alimentary tract-related carcinogenesis has been identified, possibly representing a missing link between obesity and cancer.

Calprotectin, calgranulin C, and other members of the s100 protein family in inflammatory bowel disease.

BACKGROUND: Since their discovery, S100 proteins have been associated with diverse diseases of inflammatory, degenerative, or malignant nature. Due to their participation in inflammation, they have also been studied with regard to inflammatory bowel disease (IBD). METHOD: To provide a review of available literature, a PubMed, MEDLINE, and Embase-based literature search was performed, using all available nomenclature for each member of the S100 protein family, along with the terms inflammatory bowel disease, ulcerative colitis, Crohn's disease, or indeterminate colitis. RESULT: S100A8/A9, also known as calprotectin, S100A12, or calgranulin C and in a lesser extent S100P, are involved in the pathogenesis, activity, diagnosis, and therapeutic management of IBD. The majority of available literature is focused primarily on S100A8/9, although there is growing evidence on the significance of S100A12. Most studies emphasize the potential merit of S100A8/A9 and S100A12, as markers for differential diagnosis, monitoring of activity, or disease relapse, in IBD. Limitations, regarding the diagnostic utility of these markers, seem to exist and are mainly related to the publication of conflicting results, i.e., for IBD activity, and to the fact that S100A8/A9 and S100A12 are not disease-specific. CONCLUSIONS: Although the existing data link specific S100 proteins with IBD, there are still several drawbacks in the use of these markers for diagnostic purposes. Thus, it seems that further research is mandatory in order to eliminate the impact of confounding factors but also to detect additional associations between S100 proteins and IBD or novel S100 proteins with a closer correlation with IBD.

The role of nerve growth factor in the prophylaxis and treatment of diabetic foot ulcers.

Diabetic foot ulcers are still particularly difficult to heal. Therefore, preventing and therapeutic adjuncts are increasingly being explored. Nerve growth factor (NGF) is a promising agent exhibiting beneficial actions on both diabetic peripheral neuropathy, one of the main causes of foot ulcers, and on ulcer healing. Indeed, preclinical research in animal models of diabetes has revealed the trophic effect of NGF on small C-fibres, while phase 2 human trials have provided evidence for a favourable effect on sensory neuropathy. However, the results of a phase 3 trial were moderate and, therefore, not enough to encourage widespread use of NGF in the treatment of diabetic neuropathy. Available literature on the role of NGF on diabetic wound healing is sparse but encouraging. Exogenous supplementation of NGF or the use of alternative techniques to increase its endogenous expression could emerge as a protective and therapeutic modality for diabetic foot ulcers in addition to standard treatment and other growth factors. The present review provides an outlook on the role of NGF in the prophylaxis and treatment of diabetic foot ulcers.

Angiogenin, angiopoietin-1, angiopoietin-2, and endostatin serum levels in inflammatory bowel disease.

BACKGROUND: Angiogenesis is a complex process, involving a great number of mediators. It is implicated in the pathogenesis of numerous diseases, holding a critical role in inflammatory bowel disease (IBD). The objective of this study was to assess serum levels of angiogenin, angiopoietin-1, angiopoietin-2, and endostatin in IBD patients. METHODS: Measurement of all angiogenesis mediators was performed with a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. The values were analyzed with regard to disease and patients characteristics. RESULTS: Angiogenin levels were significantly higher in IBD patients compared to HC (P < 0.001) and in UC and CD smoker patients compared to nonsmokers (P = 0.0121 and P = 0.005, respectively). Angiogenin levels were lower in UC patients receiving 5-aminosalicylate (5-ASA) alone, compared to those receiving combined therapy (P = 0.0478). Angiopoietin-1 levels were significantly lower in IBD patients compared to HC (P < 0.0001) and increased in smokers compared to nonsmoker UC patients (P = 0.0085). IBD patients demonstrated increased angiopoietin-2 levels compared to HC (P = 0.0131), while CD patients with disease restricted to the colon had significantly lower levels compared to other disease locations (P < 0.0001). Higher endostatin levels were recorded in UC patients with extensive colitis. CONCLUSIONS: Elevated serum angiogenin and angiopoietin-2 levels and lower serum angiopoietin-1 levels were shown in IBD patients, as well as a different pattern of angiogenic factor alterations related to location, treatment, smoking habits and gender.

Unraveling the link between leptin, ghrelin and different types of colitis.

Leptin and ghrelin are hormones with a tight inverse functional connection. Their inverse association is observed not only in the modulation of metabolism but also in the interaction with the immune system. A large number of studies have been launched regarding their association with various disorders, including different types of colitis. The majority of the available literature, however, focuses on inflammatory bowel disease. The role of leptin and ghrelin appears to be aggravating in most of these studies. Concerning intestinal infections, their levels seem to depend on the presence of certain species of micro-biota. As for models of ischemic and miscellaneous colitis, both hormones seem to act protectively, although evidence deriving from human studies is needed before any safe conclusions can be made. Conclusively, it seems that available data, from in vitro, animal and human studies, suggest of a multifarious role for leptin and ghrelin, in the face of different triggers, which in turn cause diverse types of colitis. Bearing this in mind, gaps and loose ends are detected in the associated literature to encourage further research through which the association of leptin and ghrelin with intestinal inflammation could be clarified and expanded so that other types of colitis could also be included.

Moderate performance of serum S100A12, in distinguishing inflammatory bowel disease from irritable bowel syndrome.

BACKGROUND: S100A12, a calcium-binding proinflammatory protein secreted by granulocytes, has been associated with different diseases of inflammatory origin, including inflammatory bowel disease (IBD). In this study, the utility of serum S100A12, in discriminating IBD from irritable bowel syndrome (IBS), was tested. METHODS: S100A12 serum levels were determined in 64 patients with ulcerative colitis (UC), 64 with Crohn's disease (CD) and 73 with IBS, by means of an enzyme-linked immunosorbent assay. S100A12 serum levels were evaluated with respect to the levels of known inflammatory markers and patients' characteristics. RESULTS: The median values of serum S100A12 levels were 68.2 ng/mL (range: 43.4-147.4) in UC, 70 ng/mL (41.4-169.8) in CD and 43.4 ng/mL (34.4-74.4) in IBS patients. UC and CD patients had significantly higher serum S100A12 levels compared to IBS patients (P = 0.001 for both comparisons). Moreover, a cut-off for serum S100A12 levels of 54.4 ng/mL could predict both UC and CD with a 66.7% sensitivity and a 64.4% specificity. The area under curve was estimated at 0.67 with a 95% confidence interval of 0.60-0.75 (P < 0.001). Considering standard activity indices, higher serum S100A12 levels in active compared to inactive IBD were observed, although the recorded difference did not reach statistical significance. C-reactive protein (CRP) and serum amyloid A (SAA) levels, showed a statistically significant positive correlation with S100A12 (r = 0.39, P = 0.001 and r = 0.23, P = 0.02 respectively). CONCLUSIONS: Increased levels of circulating S100A12 are found in IBD, compared to IBS. When used to distinguish IBD from IBS adult patients, serum S100A12 levels exhibit moderate performance. On the other hand, serum S100A12 may serve as an inflammatory marker in IBD, since it is well correlated with CRP and SAA.

Downregulation of serum epidermal growth factor in patients with inflammatory bowel disease. Is there a link with mucosal damage?

BACKGROUND: Epidermal growth factor (EGF) is a multipotent peptide which contributes to epithelial development, inhibition of gastric acid secretion, acceleration of wound healing, and promotion of angiogenesis. The aim of this study is to evaluate serum EGF concentrations in inflammatory bowel disease (IBD) patients, with regard to disease and patients' characteristics. METHODS: EGF determination was performed by a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. RESULTS: Mean ( ± SEM) serum EGF levels were 217.2 ( ± 30.40) pg/mL in UC patients, 324.6 ( ± 37.29) pg/mL in CD patients, and 453.1 ( ± 39.44) pg/mL in HC. Serum EGF levels were significantly lower in UC and CD patients compared to HC (P < 0.0001 and P = 0.0199, respectively). Lower serum EGF levels were observed in UC compared to CD patients (P = 0.0277). Extent of the disease was found to affect serum EGF levels in UC, demonstrating significant reduction in patients with left-sided colitis and pancolitis in comparison with those with proctitis (P = 0.0190 and P = 0.0024, respectively). EGF concentration was not influenced by other characteristics of patients and disease. CONCLUSIONS: Significantly, lower levels of serum EGF are observed in IBD patients compared to HC, while disease extent plays a key role in regulation of serum EGF in UC. Downregulation of serum EGF may be correlated with different patterns of bowel inflammation, epithelial development, and wound healing in IBD.

Hemobilia as the initial manifestation of cholangiocarcinoma in a hemophilia B patient.

Hemobilia is a rare manifestation of hemophilia and is usually iatrogenic following liver biopsy. There are only few reports of spontaneous hemobilia in hemophilia patients. Cholangiocarcinoma is a well-established cause of hemobilia. We describe a case of a 70-year-old male, with known haemophilia B and a past history of papillotomy, who presented with classical symptoms of hemobilia. The initial diagnostic work-up failed to demonstrate a potential cause of bleeding other than the coagulopathy. Three months later, he was readmitted to our hospital with a second episode of hemobilia. During the second work-up, a cholangiocarcinoma was diagnosed both by imaging studies and by a significant elevation of cancer antigen 19-9. Although hemobilia could be attributed to hemophilia, especially in a patient with previous papillotomy, an underlying malignancy of the biliary tree should be suspected.