Proton pump inhibitors (PPIs) are potent inhibitors of acid secretion and are the mainstay of therapy for gastroesophageal reflux disease (GERD). Initially designed to be taken 30 min before the first daily meal, these agents are commonly used suboptimally, which adversely affects symptom relief. No study to date has assessed whether correcting dosing regimens would improve symptom control. The objective of this study was to determine whether patients with persistent GERD symptoms on suboptimal omeprazole dosing experience symptomatic improvement when randomized to commonly recommended dosing regimen and to evaluate the economic impact of suboptimal PPI dosing in GERD patients.

Gastric inhibitory polypeptide (GIP) is a regulatory peptide expressed in the mammalian upper small intestine, and both GIP and its receptor (GIPR) are expressed in the cortex and hippocampus regions of the brain as well. While learning and memory deficits have been observed in GIPR(-/-) mice, the effects of peripheral GIP immunoneutralization on motor-coordination, learning, and memory have not been examined. In the present study, adult GIPR(-/-) mice (KO) and age-matched wild-type C57BL/6 J mice (WT) received weekly vehicle PBS injections for 12 weeks, while a third group of wild-type mice were injected weekly for 12 weeks with 30 mg/kg body weight humanized GIP-mAb (AB) to assess the possibility of long-term effects of peripheral GIP antagonism on rodent memory and behavior. All mice groups then underwent a battery of tests that evaluated motor behavior, body coordination, and memory. Performance deficits in several memory studies after 12 weeks of treatment were demonstrated in KO, but not in AB or WT mice. Body coordination performance showed no significant differences among the 3 groups. A similar short-term study (3 injections over 9 days) was also conducted and the results were similar to those from the long-term study. Thus, short-term and long-term peripheral GIP antagonism by GIP-mAb did not appear to affect learning and memory in mice, consistent with the notion that the GIP-mAb does not cross the blood brain barrier. Furthermore, our studies indicate that GIP signaling in the brain appears to involve local neurocrine pathways.

Ulcerative colitis has various extraintestinal manifestations, including coagulation disorders, however the presence of disseminated intravascular coagulation (DIC) is rare. The current case depicts a patient in whom DIC arose secondary to damage of the endothelium of colonic blood vessels. A 19 year-old female was admitted with abdominal pain, nausea, emesis, and hematochezia. Abdominal CT scan suggested extensive colitis and colonoscopy confirmed Mayo grade 3 ulcerative pancolitis. The patient subsequently developed extensive thromboses, anemia, and purpura fulminans. Her laboratory evaluation was consistent with DIC. Because she failed to respond to corticosteroids and infliximab induction, total proctocolectomy with end-ileostomy was performed, which led to resolution of DIC. DIC involves mechanical and/or endothelial cell injury, and thus, intestinal vasculature may play a key role in thrombosis in IBD. IBD results in destructive inflammation of the GI tract, and chronic inflammation of endothelial cells and microvasculature of the GI tract precipitates physiologic and functional alterations in contrast to uninvolved intestine. The damaged microvasculature subsequently has decreased perfusion and stenosis, which may predispose patients to hypercoagulability [1]. In our patient, the underlying cause of coagulopathy was fulminant UC that was unresponsive to corticosteroid and biologic therapy. Ultimately, surgical intervention with total colectomy resulted in rapid improvement of DIC parameters. In conclusion, we report a rare case of an association of DIC and UC which can be managed with timely diagnosis and appropriate therapeutic management of the underlying condition.

INTRODUCTION:A long-term single-center trial showed that LES-EST significantly improves esophageal acid exposure

Objectives and study Achalasia is a rare chronic motility disorder with a big impact on Quality of Life (QoL), even in patients treated successfully.We aimed to prospectively assess current symptoms and QoL in patients diagnosed with achalasia in childhood (0-18yr).Methods: Dutch children diagnosed with achalasia between 1990-2013 were contacted either by telephone or by mail and were asked complete 4 questionnaires.Severity of achalasia symptoms was assessed using the Eckardt score (suggestive for achalasia when >3) and the Reflux Disease Questionnaire (RDQ, suggestive for gastro esophageal reflux disease (GERD) when ≥mild heartburn/regurgitation occurred ≥2 days a week).Disease specific QoL was assessed with the Achalasia DS-QoL (when <18yr at time of study, 0= worst 100=best) or HRQoL (≥18yr, 0= worst 100=best).General QoL was measured with the KIDSCREEN-52 (<18yr, T-values over 10 domains relative to healthy norm, higher value suggests better QoL) or the SF-36 (≥18yr, 8 domains, 0= worst 100=best QoL per domain) and compared to healthy population norms.Results Seventy-two of 87 (83%) patients were prospectively reached.Median (inter quartile range, IQR) time since last clinical follow up was 1.7 years (0.5-6.9 years).Twenty (32%) patients were <18yr.Median Eckardt score was 3 (IQR 2-5) with 32 patients (44.5%) having a positive score.Median RDQ score was 0.92 (0.10-1.65).GERD was reported relatively more frequent after initial treatment with Heller's myotomy compared to pneumodilation (PD, P=0.04) and median RDQ scores were higher when initially treated with HM(F) (1.58 (0.96 -2.71)) compared to ≥1x PD (0.58 (0 -1.58)), P=0.005.Eckardt and RDQ scores were similar for adult and paediatric patients (P=0.980 and P=0.454, respectively).Overall HR-QoL score was 61.3 (48.3-71.0).General QoL (SF-36) in adults (n=52) was lower compared to healthy population norms for 7/8 domains, with scores on 'bodily pain' and 'general health perceptions' domains (18-25 yr) significantly lower compared to age adjusted norm (P=0.018 and P<0.0001).SF-36 scores were similar for patients initially treated with PD or HM.Paediatric achalasia DS-QoL score was 17.5 (8-29).Self-reported QoL (KIDSCREEN-52, n=20) was similar to population norms.On 2 domains (School Environment, Financial Resources) achalasia patients even scored better (P=0.038 and P=0.049).Conclusion Almost half of patients with achalasia diagnosed <18yr still have symptoms suggestive of active disease.This observation stresses the need for regular clinical follow-up and good transition to the adult gastroenterologist.Disease specific and general quality of life is lower for adult patients compared to paediatric patients.This suggests that the impact of achalasia increases with duration of disease.

Previous reports have suggested that the abrogation of gastric inhibitory polypeptide (GIP) signaling could be exploited to prevent and treat obesity and obesity-related disorders in humans. This study was designed to determine whether immunoneutralization of GIP, using a newly developed specific monoclonal antibody (mAb), would prevent the development of obesity. Specific mAb directed against the carboxy terminus of mouse GIP was identified, and its effects on the insulin response to oral and to intraperitoneal (ip) glucose and on weight gain were evaluated. Administration of mAb (30 mg/kg body wt, BW) to mice attenuated the insulin response to oral glucose by 70% and completely eliminated the response to ip glucose coadministered with human GIP. Nine-week-old C57BL/6 mice injected with GIP mAbs (60 mg·kg BW(-1)·wk(-1)) for 17 wk gained 46.5% less weight than control mice fed an identical high-fat diet (P < 0.001). No significant differences in the quantity of food consumed were detected between the two treatment groups. Furthermore, magnetic resonance imaging demonstrated that subcutaneous, omental, and hepatic fat were 1.97-, 3.46-, and 2.15-fold, respectively, lower in mAb-treated animals than in controls. Moreover, serum insulin, leptin, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides were significantly reduced, whereas the high-density lipoprotein (HDL)/TC ratio was 1.25-fold higher in treated animals than in controls. These studies support the hypothesis that a reduction in GIP signaling using a GIP-neutralizing mAb might provide a useful method for the treatment and prevention of obesity and related disorders.

Obesity represents a complex multifactorial syndrome that develops from interactions among genetic and environmental factors and is a leading cause of illness and death. The prevalence of obesity in the United States has increased dramatically since 1975. Although often ignored, the gastrointestinal tract, and the gastrointestinal regulatory peptides in particular, constitutes an ideal starting point for defining and investigating obesity as it represents the route by which all nutrients are ingested, processed, and absorbed. Another important factor to consider when evaluating the etiology of obesity is the capacity for all animals to store nutrients. Insulin is the most potent anabolic hormone, and it appears to have evolved from the need to maximize energy efficiency, obviating the requirement to continuously forage for food. Organisms expressing this important peptide possessed a distinct survival advantage and flourished. During the course of evolution, insulin biosynthesis translocated from the intestine to pancreatic islets, which necessitated a messenger from the intestine to complete the “enteroinsular axis.” The eventual development of glucose-dependent insulinotropic polypeptide (GIP) and other incretins fulfilled this requirement. GIP appears to offer an additional survival benefit by not only stimulating intestinal glucose transport and maximally releasing insulin to facilitate nutrient storage but also by its insulin-mimetic properties, including enhanced uptake of glucose by adipocytes. This physiological redundancy offered by insulin and GIP ensured the survival of organisms during times when food was scarce. As food is no longer scarce, at least in the West, this survival advantage appears to have contributed to the current obesity epidemic.

OBJECTIVES:Optimal administration of proton pump inhibitor (PPI) for the treatment of gastroesophageal reflux disease (GERD) requires consideration of meal timing. Since becoming available over the counter (OTC), no studies have assessed treatment patterns and symptom control in OTC consumers. The objective of this study was to survey dosing patterns and symptom control in OTC and prescription PPI users. METHODS:Patients at five clinics were surveyed regarding diagnosis of GERD, use of OTC or prescription PPIs, information on time of day dosing, demographics, and Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS; 2001, Johnson & Johnson). RESULTS:Of the 1,959 patients surveyed, 610 (31%) used PPIs for GERD. Of these, 190 (31%) and 223 (37%) received prescriptions from gastroenterologists (GIs) and primary care physicians (PCPs), respectively; 197 (32%) purchased OTC PPIs. Of the patients prescribed PPIs by GIs, 71% were optimal users, whereas 47% of patients receiving prescriptions from PCPs and 39% of consumers used PPIs optimally (P<0.001 compared with GIs). GSAS symptom, frequency, and severity scores were significantly better in patients prescribed PPIs by GIs (all P<0.001, GI compared with PCP and consumer). GSAS symptom, frequency, and severity scores were also significantly better in patients using PPIs optimally (P<0.001 for all parameters) compared with those taking PPIs suboptimally or excessively. CONCLUSIONS:Patients receiving prescription PPI from a GI are more likely to be optimal users with better symptom control. Conversely, consumers are more likely to be suboptimal users with inadequate symptom control.