BACKGROUND:

Measurements of CFTR function in rectal biopsies ex vivo have been used for diagnosis and prognosis of Cystic Fibrosis (CF) disease. Here, we aimed to evaluate this procedure regarding: i) viability of the rectal specimens obtained by biopsy forceps for ex vivo bioelectrical and biochemical laboratory analyses; and ii) overall assessment (comfort, invasiveness, pain, sedation requirement, etc.) of the rectal forceps biopsy procedure from the patients perspective to assess its feasibility as an outcome measure in clinical trials.

METHODS:

We compared three bowel preparation solutions (NaCl 0.9%, glycerol 12%, mannitol), and two biopsy forceps (standard and jumbo) in 580 rectal specimens from 132 individuals (CF and non-CF). Assessment of the overall rectal biopsy procedure (obtained by biopsy forceps) by patients was carried out by telephone surveys to 75 individuals who underwent the sigmoidoscopy procedure.

RESULTS:

Integrity and friability of the tissue specimens correlate with their transepithelial resistance (r = -0.438 and -0.305, respectively) and are influenced by the bowel preparation solution and biopsy forceps used, being NaCl and jumbo forceps the most compatible methods with the electrophysiological analysis. The great majority of the individuals (76%) did not report major discomfort due to the short procedure time (max 15 min) and considered it relatively painless (79%). Importantly, most (88%) accept repeating it at least for one more time and 53% for more than 4 times.

CONCLUSIONS:

Obtaining rectal biopsies with a flexible endoscope and jumbo forceps after bowel preparation with NaCl solution is a safe procedure that can be adopted for both adults and children of any age, yielding viable specimens for CFTR bioelectrical/biochemical analyses. The procedure is well tolerated by patients, demonstrating its feasibility as an outcome measure in clinical trials.

BACKGROUND:

Enhanced EGF receptor (EGFR) signaling is a hallmark of many human cancers, though the role of enhanced EGFR signaling within the surrounding tumor stroma has not been well studied. The myofibroblast is an important stromal cell that demonstrates enhanced EGFR expression in the setting of inflammation, though the functional relevance is not known. We recently reported that TNF-alpha and the G protein-coupled receptor (GPCR) agonist lysophosphatidic acid (LPA) lead to synergistic cyclo-oxygenase-2 (COX-2) expression, an enzyme strongly associated with the development of colitis-associated cancer. Here, we investigate whether EGFR signaling plays a role in the synergistic COX-2 expression induced by LPA and TNF-alpha.

METHODS:

18Co cells, a model of human colonic myofibroblasts, were grown to confluence on 35 x 10mm cell culture dishes and were used from passages 10--14. 18Co cells were treated with TNF-alpha (8.3 ng/ml) and LPA (10 muM). EGFR and COX-2 protein expression, Y1068 phosphorylation, and p42/44 MAPK phosphorylation were assessed by Western Blot, in the presence and absence of various inhibitors.

RESULTS:

Exposure of 18Co cells to either TNF-alpha or LPA alone had no effect on EGFR autophosphorylation at Y1068. However, chronic exposure to TNF-alpha led to upregulation of EGFR in association with sustained LPA-mediated EGFR phosphorylation at Y1068. TNF-alpha and LPA also led to sustained p42/44 MAPK phosphorylation and synergistic COX-2 expression, effects that were partially inhibited by the EGFR tyrosine kinase inhibitor AG1478. p42/44 MAPK phosphorylation and COX-2 expression were inhibited to the same degree by the MMP inhibitors GM6001 and BB-94, suggesting that LPA-mediated EGFR transactivation involved MMP-mediated release of EGFR ligands from the cell surface. The Src inhibitor SU6556 inhibited TNF-alpha/LPA-mediated EGFR phosphorylation at Y1068, p42/44 MAPK phosphorylation, and COX-2 expression in a dose-dependent fashion, suggesting an upstream role of Src in the transactivation of EGFR.

CONCLUSION:

Synergistic COX-2 expression induced by TNF-alpha and LPA involves Src/MMP-mediated transactivation of EGFR and downstream p42/44 MAPK activation in human colonic myofibroblasts. Enhanced EGFR expression induced by TNF-alpha promotes GPCR-mediated EGFR transactivation in colonic myofibroblasts, providing an important mechanism for stromal COX-2 over-expression that may predispose to the development of colitis-associated cancer.

BACKGROUND:

Case reports and case series studies suggest a positive association between intussusception and celiac disease (CD).

METHODS:

We contacted Sweden's 28 pathology departments and obtained data on 29,096 patients with biopsy-verified CD (equal to Marsh stage 3) through biopsy reports. Patients with CD were matched for age, sex, calendar period and county of residence with up to five reference individuals from the general population (n = 144,522). Cases of intussusception were identified from nationwide inpatient, hospital-based outpatient and day-surgery data from the Swedish Patient Register.Odds ratios (ORs) for future CD in patients with intussusception were estimated using conditional logistic regression.

RESULTS:

34 (0.12%) individuals with CD had a diagnosis of intussusception vs. 143 (0.10%) reference individuals, suggesting that intussusception was not a risk factor for later CD (OR = 1.17; 95% confidence interval (CI) = 0.82-1.67). The OR for CD in patients with at least two records of intussusception was 0.40 (95% CI = 0.06-2.99).In contrast, a post-hoc analysis showed that CD was associated with a statistically significantly increased risk of intussusception after CD diagnosis (hazard ratio = 1.95; 95% CI = 1.01-3.77); however, this analysis was based on only 12 cases with both CD and intussusception.

CONCLUSION:

We found no association between intussusception and future CD; and a mostly modest increased risk of intussusception after a diagnosis of CD.

BACKGROUND:

Ligation-assisted endoscopic enucleation (EE-L) was developed for the pathological diagnosis and resection of small gastrointestinal tumors originating from the muscularis propria. The technique combines endoscopic band ligation and endoscopic enucleation. The aim of this study was to evaluate the efficacy and safety of EE-L in the diagnosis and resection of gastrointestinal tumors originating from the muscularis propria.

METHODS:

A total of 43 patients were eligible for inclusion in this study from June 2009 to June 2011. Endoscopic ligation was first performed to force the tumor to assume a polypoid form with a pseudostalk. EE-L was then performed until the tumor was completely enucleated from the muscularis propria. Wound closure was performed using clips and adhesive tissue.

RESULTS:

All 43 tumors were completely enucleated. The mean enucleation time was 7.2 minutes (range, 5--11 minutes). No perforation, massive hemorrhage, or peritonitis requiring further endoscopic or surgical intervention occurred. Histopathology, 19 lesions were identified as gastrointestinal stromal tumors and 24 lesions were identified as leiomyomas. The mean follow-up time was 20.4 months (range, 14--38 months). No recurrence has occurred during the follow-up period.

CONCLUSIONS:

EE-L appears to be a safe, effective, and relatively simple method for the histologic diagnosis and removal of small gastrointestinal tumors originating from the muscularis propria.

The study aimed to survey for FD in a primary care setting in a population known to have an extremely low prevalence of Helicobacter pylori (H. pylori) infection, with the hypothesis that in such a population, dyspepsia should have been relatively less common.The Rome III FD Diagnostic Questionnaire was translated into the Malay language and later tested for reliability. A prospective cross-sectional survey was then performed involving 160 Malay patients attending primary care clinic after informed consent. Patients positive for symptoms of FD were subjected to upper endoscopy and exclusion of H. pylori infection. Univariable and multivariable analyses were used to test for associated risk factors.The back-translated questionnaire was similar to the original English version and was reliable (Cronbach Alpha-coefficient 0.85). Of the 160 surveyed subjects, 19 of them (11.9%) had symptoms of FD. With exclusion of erosive diseases (3/160 or 1.9%) from endoscopy, 16 subjects or 10% had FD. None of the 19 subjects were positive for H. pylori infection. Epigastric pain syndrome was present in 11/16 (68.8%) and the rest, overlap with postprandial distress syndrome. With multivariable analysis, a married status (OR = 8.1; 95% CI 1.0-36.5) and positive psychosocial alarm symptoms (OR = 3.8; 95% CI 1.0-14.0) were associated with FD. Of those married subjects, females were more likely to have FD and psychosocial symptoms than men (6.3% vs. 1.9%), P = 0.04.FD was more common than one had expected among Malays attending primary care clinic in an area with low prevalence of H. pylori.

The detection of serum tumor marker becomes a common method for screening tumors. However, this method has not been widely used for routine gastric cancer screening. In this study we aimed to determine whether the combined use of tumor markers may increase the sensitivity for the diagnosis of gastric cancer.Serum AFP, CEA, CA125 and CA19-9 levels were measured in 149 patients with gastric cancer, 111 patients with benign gastric diseases and 124 healthy people, who visited the First Affiliated Hospital of Nanchang University from May 2011 to May 2012. Statistical analysis including receiver operating characteristic (ROC) curve, the area under the curve (AUC), and logistic regression analysis was performed to evaluate the diagnostic value of these markers on gastric cancer.Serum levels of CEA, CA125, and CA19-9 in gastric cancer group were higher than that in the benign gastric disease group and the healthy control group (P <0.005). The sensitivity of AFP, CEA, CA125 and CA19-9 in the diagnosis of gastric cancer was 4.7-20.8% individually, and increased to 40.3% in combination. By using optimal cut-off value, the sensitivity of CEA, CA125, and CA19-9 for the diagnosis of gastric cancer was improved. Especially, the sensitivity of CEA increased to 58.4% and the sensitivity of combined use of four markers increased to 69.1%. The age and gender had no effects on the diagnostic value of these markers.The determination and application of optimal cut-off values based on ROC curve and logistic regression analysis could improve the diagnosis of gastric cancer based on common tumor markers.

Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications.We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies.Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized.Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy.

Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects.Thirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment.There was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) and Group I (from 1.0 ± 0.0 to 6.0 ± 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031).Irsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole.This study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114).

Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF.In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6) groups. In a further pilot study, two animals were treated with the MARS-system. All animals received the same medical and surgical procedures. An intraparenchymal intracranial pressure was inserted. Hemodynamic monitoring and goal-directed fluid therapy using the PiCCO system was done. Animals underwent functional end-to-side portacaval shunt and ligation of hepatic arteries. Treatment with albumin dialysis was started after fall of cerebral perfusion pressure to 45 mmHg and continued for 8 h.All animals in the Hepa Wash group survived the 13-hour observation period, except for one that died after stopping treatment. Four of the control animals died within this period (p=0.03). Hepa Wash significantly reduced impairment of cerebral perfusion pressure (23±2 vs. 10±3 mmHg, p=0.006) and mean arterial pressure (37±1 vs. 24±2 mmHg, p=0.006) but had no effect on intracranial pressure (14±1 vs. 15±1 mmHg, p=0.72). Hepa Wash also enhanced cardiac index (4.94±0.32 vs. 3.36±0.25 l/min/m2, p=0.006) and renal function (urine production, 1850 ± 570 vs. 420 ± 180 ml, p=0.045) and eliminated water soluble (creatinine, 1.3±0.2 vs. 3.2±0.3 mg/dl, p=0.01; ammonia 562±124 vs. 1382±92 μg/dl, p=0.006) and protein-bound toxins (nitrate/nitrite 5.54±1.57 vs. 49.82±13.27 μmol/l, p=0.01). No adverse events that could be attributed to the Hepa Wash treatment were observed.Hepa Wash was a safe procedure and improved multiorgan system failure in pigs with ALF. The survival benefit could be the result of ameliorating different organ functions in association with the detoxification capacity of water soluble and protein-bound toxins.

BACKGROUND:

Prior studies suggest that obstructive sleep apnea may be associated with gastroesophageal reflux disease, a strong risk factor for Barrett's esophagus. The goals of this pilot case--control study were to determine whether Barrett's esophagus patients have an increased likelihood of obstructive sleep apnea and to determine whether nocturnal gastroesophageal reflux symptoms affect the relationship between Barrett's esophagus and obstructive sleep apnea risk.

METHODS:

Patients with Barrett's esophagus completed the Berlin Questionnaire, a validated survey instrument identifying subjects at high risk for obstructive sleep apnea. Two outpatient control groups were recruited: 1) EGD Group, subjects matched to Barrett's esophagus cases by age, race, and gender with esophagogastroduodenoscopy negative for Barrett's esophagus; and 2) Colonoscopy Group, patients getting colonoscopy. Rates of scoring at high risk for obstructive sleep apnea were compared. Respondents were also questioned regarding severity of their typical gastroesophageal reflux symptoms and presence of nocturnal gastroesophageal reflux symptoms.

RESULTS:

The study included 287 patients (54 Barrett's esophagus, 62 EGD, and 171 colonoscopy subjects). Barrett's esophagus patients were slightly older than colonoscopy patients and more obese. 56% (n = 30) of Barrett's esophagus subjects scored at high risk for obstructive sleep apnea, compared with 42% (n = 26) of EGD subjects (OR 1.73, 95% CI [0.83, 3.62]) and 37% (n = 64) of colonoscopy patients (OR 2.08, 95% CI [1.12, 3.88]). The association between Barrett's esophagus and scoring at high risk for obstructive sleep apnea compared with colonoscopy patients disappeared after adjusting for age. Barrett's esophagus patients reported more severe typical heartburn and regurgitation symptoms than either control group. Among all subjects, patients with nocturnal reflux symptoms were more likely to score at high risk for obstructive sleep apnea than patients without nocturnal reflux.

CONCLUSIONS:

In this pilot study, a high proportion of Barrett's esophagus subjects scored at high risk for obstructive sleep apnea. Having Barrett's esophagus was associated with more severe gastroesophageal reflux symptoms, and nocturnal reflux symptoms were associated with scoring at high risk for obstructive sleep apnea. The need for obstructive sleep apnea screening in Barrett's esophagus patients with nocturnal gastroesophageal reflux symptoms should be further evaluated.