Optimal Omeprazole Dosing and Symptom Control: A Randomized Controlled Trial (OSCAR Trial).

BACKGROUND: 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. METHODS: Patients with persistent heartburn symptoms ≥ 3 times per week treated with omeprazole 20 mg daily were enrolled and randomized to commonly recommended dosing or continued suboptimal dosing of omeprazole. The primary outcomes were changes in symptom, frequency, and severity, as determined using the Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS) 4 weeks after the intervention was administered. In secondary analysis, an alternative measure of symptom load was used to infer potential costs. RESULTS: Sixty-four patients were enrolled. GSAS symptom, frequency, and severity scores were significantly better when dosing was optimized for overall and heartburn-specific symptoms (P < 0.01 for all parameters). Cost savings resulting from reduced medical care and workplace absenteeism were estimated to be $159.60 per treated patient, with cost savings potentially exceeding $4 billion annually in the USA. DISCUSSION: Low-cost efforts to promote commonly recommended PPI dosing can dramatically reduce GERD symptoms and related economic costs. ClinicalTrials.gov, number: NCT02623816.

Gastric inhibitory polypeptide immunoneutralization attenuates development of obesity in mice.

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.

Consumer use of over-the-counter proton pump inhibitors in patients with gastroesophageal reflux disease.

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.

Obesity and the gastrointestinal tract: you are what you eat.

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.

Glucose-dependent insulinotropic polypeptide monoclonal antibodies prevent and treat obesity in wild-type and hyperphagic mice.

OBJECTIVE: This study aimed to investigate whether a glucose-dependent insulinotropic polypeptide (GIP) monoclonal antibody (mAb) will promote weight loss in wild-type mice and to determine effects of this mAb in preventing weight gain in ob/ob mice. METHODS: Phosphate-buffered saline (PBS) or GIP mAb was injected intraperitoneally to wild-type mice fed a 60% high-fat diet (HFD). After 12 weeks, mice that received PBS were divided into two groups and were fed a 37% HFD for 5 weeks; one group received PBS, and one group received GIP mAb. In a separate study, PBS or GIP mAb was injected intraperitoneally to ob/ob mice fed normal mouse chow for 8 weeks. RESULTS: PBS-treated mice gained significantly more than those treated with GIP mAb, with no difference in food consumption detected. Obese mice fed a 37% HFD and PBS continued to gain weight (+2.1% ± 0.9%), whereas mice administered GIP mAb lost 4.1% ± 1.4% body weight (p < 0.01). Leptin-deficient mice consumed similar amounts of chow, and, after 8 weeks, the PBS- and GIP mAb-treated mice gained 250.4% ± 9.1% and 192.4% ± 7.3%, respectively (p < 0.01). CONCLUSIONS: These studies support the hypothesis that a reduction in GIP signaling appears to affect body weight without suppressing food intake and might provide a novel, useful method for the treatment and prevention of obesity.

Effects of gastric inhibitory polypeptide (GIP) immunoneutralization on mouse motor coordination and memory.

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.

False-positive secretin stimulation test for gastrinoma associated with the use of proton pump inhibitor therapy.

We report the case of a 22-year-old woman who was referred for evaluation of possible Zollinger-Ellison syndrome because of hypergastrinemia and a positive secretin stimulation test. She was being treated with proton pump inhibitors (PPIs) for severe gastroesophageal reflux disease during her initial evaluation. At cessation of PPI therapy, her fasting serum gastrin levels normalized, as did her response to secretin injection. Previous reports describing false-positive secretin tests have been limited to cases of hypergastrinemia in the setting of chronic atrophic gastritis, presumably a result of achlorhydria. This case represents a clearly documented instance of PPI-related hypergastrinemia with a false-positive secretin test, with subsequent normalization of serum gastrin and a negative secretin test after withdrawal of PPI therapy. The current case emphasizes the need to assess the acid secretory status of individuals with hypergastrinemia and to discontinue the use of potent antisecretory agents, principally PPIs, to avoid the erroneous diagnosis of gastrinoma and before embarking on expensive and potentially invasive evaluations for the purpose of tumor localization.

Expression of glucose-dependent insulinotropic polypeptide in the zebrafish.

In mammals, glucose-dependent insulinotropic polypeptide (GIP) is synthesized predominately in the small intestine and functions in conjunction with insulin to promote nutrient deposition. However, little is known regarding GIP expression and function in early vertebrates like the zebrafish, a model organism representing an early stage in the evolutionary development of the compound vertebrate pancreas. Analysis of GIP and insulin (insa) expression in zebrafish larvae by RT-PCR demonstrated that although insa was detected as early as 24 h postfertilization (hpf), GIP expression was not demonstrated until 72 hpf, shortly after the completion of endocrine pancreatic development but prior to the commencement of independent feeding. Furthermore, whole mount in situ hybridization of zebrafish larvae showed expression of GIP and insa in the same tissues, and in adult zebrafish, RT-PCR and immunohistochemistry demonstrated GIP expression in both the intestine and the pancreas. Receptor activation studies showed that zebrafish GIP was capable of activating the rat GIP receptor. Although previous studies have identified four receptors with glucagon receptor-like sequences in the zebrafish, one of which possesses the capacity to bind GIP, a functional analysis of these receptors has not been performed. This study demonstrates interactions between the latter receptor and zebrafish GIP, identifying it as a potential in vivo target for the ligand. Finally, food deprivation studies in larvae demonstrated an increase in GIP and proglucagon II mRNA levels in response to fasting. In conclusion, the results of these studies suggest that although the zebrafish appears to be a model of an early stage of evolutionary development of GIP expression, the peptide may not possess incretin properties in this species.

Glucose-dependent insulinotropic polypeptide enhances adipocyte development and glucose uptake in part through Akt activation.

BACKGROUND & AIMS: In addition to its role as the primary mediator of the enteroinsular axis, glucose-dependent insulinotropic polypeptide (GIP) may play a critical role in the development of obesity. The purpose of these studies was to characterize the effects of GIP and its receptor (GIPR) in adipocyte development and signaling. METHODS: Effects of GIP and GIPR on differentiated 3T3-L1 cells were analyzed using Western blot analysis, Oil-Red-O staining, cyclic adenosine monophosphate radioimmunoassay, immunofluorescence microscopy, and glucose uptake measurements. RESULTS: To determine whether GIP and GIPR are important components in adipocyte development, the expression profile of GIPR during differentiation was examined. GIPR protein expression was enhanced during the differentiation process, and coincubation with its ligand GIP augmented the expression of aP2, a fat cell marker. Conversely, the suppression of GIPR expression by a specific short hairpin RNA attenuated Oil-Red-O staining and aP2 expression, suggesting that the GIPR may play a critical role in adipocyte development. To investigate specific signaling components that may mediate the effects of GIP, we analyzed Akt, glucose transporter-4, and glucose uptake, all of which are modulated by insulin in fat cells. Like insulin, GIP induced the activation of Akt in a concentration-dependent manner, promoted membrane glucose transporter-4 accumulation, and enhanced [(3)H]-2-deoxyglucose uptake. CONCLUSIONS: These studies provide further evidence for an important physiologic role for GIP in lipid homeostasis and possibly in the pathogenesis of obesity. Furthermore, our data indicate that the GIPR might represent a suitable target for the treatment of obesity.

Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells.

Activation of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPARgamma in HCC, PPARgamma expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPARgamma activation and inhibition were compared. PPARgamma expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPARgamma inhibitors and PPARgamma small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPARgamma inhibitors had no effect on initial beta1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPARgamma inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPARgamma overexpression is present in HCC. Inhibition of PPARgamma function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPARgamma inhibitors represent a potential novel treatment approach to HCC.

Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer.

PURPOSE: To determine whether the nonselective and relatively inexpensive nonsteroidal anti-inflammatory drug ibuprofen would be effective in inhibiting colorectal cancer and might improve mortality in a mouse model. EXPERIMENTAL DESIGN: The effects of ibuprofen on tumor growth inhibition and animal survival have been examined in both mouse and human colorectal cancer tumor models. Angiogenesis was measured by in vitro endothelial cell tube formation and immunohistochemistry. RESULTS: Ibuprofen significantly inhibited cell proliferation in mouse (MC-26) and human (HT-29) colorectal cancer cell lines. In vitro angiogenesis assays also indicated that ibuprofen decreased both cell proliferation and tube formation. The administration of chow containing 1,360 ppm ibuprofen, which achieved an average plasma concentration of ibuprofen lower than the peak level achieved in humans at therapeutic doses, inhibited tumor growth by 40% to 82%. Fewer liver metastases were found in the ibuprofen group compared with the control group. In combination therapy with the standard antineoplastic agents, 5-fluorouracil, or irinotecan (CPT-11), tumor volumes in the groups with ibuprofen +/- CPT-11 or 5-fluorouracil were smaller than in the control group. Ibuprofen was similar to the cyclooxygenase-2 selective inhibitor rofecoxib in its ability to suppress tumor growth and improve overall survival. CONCLUSIONS: Ibuprofen, in part by modulating tumor angiogenesis, decreases both tumor growth and metastatic potential in mice. The ibuprofen doses were in the low range of therapeutic human plasma concentrations. Ibuprofen potentiates the antitumor properties of CPT-11 and improves survival of mice without increasing gastrointestinal toxicity.

Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice.

A large number of epidemiological studies have shown that regular use of aspirinor other nonsteroidal anti-inflammatory drugs (NSAIDs) results in a 40-50% reduced risk of colorectal cancer (CRC). Furthermore, NSAIDs cause the regression of preexisting adenomas in patients with familial adenomatous polyposis and significantly inhibit tumor growth in animal models of CRC. To establish a CRC liver metastasis model, we implanted mouse colon tumor MC-26 cells into the splenic subcapsule of BALB/c mice, after which mice were given either standard chow or chow containing the cyclooxygenase (COX)-2-specific inhibitor rofecoxib, alone or in combination with the standard antineoplastic agents, 5-fluoruracil or irinotecan. After 14 days, mice that were given rofecoxib or irinotecan, but not 5-fluoruracil, had significantly smaller primary tumors and fewer metastases. Rofecoxib, at clinical anti-inflammatory plasma concentrations, enhanced the effects of both antineoplastic agents when used in combination. Biochemical analyses of the primary splenic tumor in rofecoxib-treated mice showed no alteration in COX-1 expression, but significant decreases in the expression of the tumor-promoting proteins COX-2, cyclin D1, cytosolic beta-catenin, matrix metalloproteinases-2 and -9, and vascular endothelial cell- derived growth factor. Rofecoxib also decreased growth-enhancing prostaglandin E(2) and tumor-suppressive interleukin-10, whereas antineoplastic interleukin-12 was increased. Two separate survival studies were performed. When mice were fed chow containing 0.01% rofecoxib beginning on day 0 after tumor cell implantation, which achieved clinical anti-inflammatory plasma concentrations, survival time was significantly longer compared with mice given control chow. After 30 days, mortality in the control group was 90%, whereas only one mouse (5%) treated with rofecoxib had died after 30 days. In the second survival study, all of the mice were initially fed with regular chow after tumor cell implantation. On day 7, mice were randomly divided into three dietary groups: control chow, low-dose (0.01%) rofecoxib chow, and high-dose (0.025%) rofecoxib chow. After 28 days, mortality was 100%, 20%, and 10% in control, low-, and high-dose rofecoxib fed groups, respectively. These studies demonstrate that rofecoxib decreases the growth and metastatic potential of CRC in mice through multiple mechanisms. These studies in mice also provide important information that supports the benefit of COX-2 inhibition, not only in the prevention of CRC, but also potentially in the treatment of this common malignancy. Clinical trials will be necessary to assess the utility of COX-2 inhibitors as adjuvant therapy for early-stage disease and as potential agents, either alone or in combination, with more established drugs, for the treatment of refractory CRC.

Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells.

Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G(1)-specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steady-state levels of total and nonphospho beta-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of beta-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of beta-catenin and CREB pathways.

Cell-specific expression of glucose-dependent-insulinotropic polypeptide is regulated by the transcription factor PDX-1.

Glucose-dependent insulinotropic polypeptide (GIP) is a potent stimulator of insulin secretion and comprises an important component of the enteroinsular axis. GIP is synthesized in enteroendocrine K-cells located principally in the upper small intestine. The homeobox-containing gene PDX-1 is also expressed in the small intestine and plays a critical role in pancreatic development and in the expression of pancreatic-specific genes. Previous studies determined that the transcription factors GATA-4 and ISL-1 are important for GIP expression. In this study, we demonstrate that PDX-1 is also involved in regulating GIP expression in K-cells. Using immunohistochemistry, we verified the expression of PDX-1 protein in the nucleus of GIP-expressing mouse K-cells and evaluated the expression of PDX-1, serotonin, and GIP in wild-type and PDX-1(-/-) mice at 18.5 d after conception. Although we demonstrated a 97.8% reduction in the number of GIP-expressing cells in PDX-1(-/-) mice; there was no statistical difference in the number of serotonin-positive cells. Additionally, PDX-1 transcripts and protein were detected in a GIP-expressing neuroendocrine cell line, STC-1. Electromobility shift assays using STC-1 nuclear extracts demonstrated the specific binding of PDX-1 protein to a specific regulatory region in the GIP promoter. Using chromatin immunoprecipitation analysis, we demonstrated binding of PDX-1 to this same region of the GIP promoter in intact cells. Lastly, overexpression of PDX-1 in transient transfection assays led to a specific increase in the activity of GIP/Luc reporter constructs. The results of these studies indicate that the transcription factor PDX-1 plays a critical role in the cell-specific expression of the GIP gene.

Gastroprotection by coxibs: what do the Celecoxib Long-Term Arthritis Safety Study and the Vioxx Gastrointestinal Outcomes Research Trial tell us?

Current evidence suggests that PPIs might be effective in maintaining patients in remission during continued NSAID use and that the combination of omeprazole plus diclofenac is as effective as treatment with celecoxib in preventing recurrent bleeding. Larger outcome studies comparing the combination of a PPI with other nonselective NSAIDs and a selective COX-2 inhibitor (and the combination of a selective COX-2 inhibitor with a PPI or misoprostol) are required to determine whether or not any regimen will further decrease or eliminate the risk of ulcer complications in high-risk individuals.

Cell-specific expression of the glucose-dependent insulinotropic polypeptide gene functions through a GATA and an ISL-1 motif in a mouse neuroendocrine tumor cell line.

BACKGROUND/AIMS: Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that, in the presence of glucose, stimulates insulin secretion from beta-cells. GIP is expressed in gastrointestinal K-cells. Prior analysis of the GIP promoter demonstrated that 193 bases of the promoter are required to direct cell specific expression. Here we sought to identify and characterize the transcription factors involved. RESULTS: By mutational analysis of the GIP promoter in a neuroendocrine cell line (STC-1), we identified two regions located between bases -193 and -182 and bases -156 and -151 that, when independently altered, were responsible for a 90% and 85% reduction in transcription, respectively. When we compared these two regions with known motifs from transcription factor databases, we identified the cis elements as potential GATA and ISL-1 binding sites. With subsequent electrophoretic mobility shift analysis (EMSA) using STC-1 nuclear extracts, we demonstrated the ability of these regions to form specific DNA protein complexes. Furthermore, we utilized antisera to confirm the specific binding of GATA-4 to the upstream site and ISL-1 to the downstream element. CONCLUSION: These findings provide evidence for the involvement of the transcription factors GATA-4 and ISL-1 in the cell-specific expression of the GIP gene.

Gastrin stimulates receptor-mediated proliferation of human esophageal adenocarcinoma cells.

The prevalence of esophageal adenocarcinoma in the setting of Barrett's metaplasia continues to increase in Western nations at a rate greater than any other cancer. The trophic properties of gastrin have been documented in gastric, pancreatic and colon cancer cell lines, suggesting a potential role for this regulatory peptide in the growth of these malignancies. The aims of these studies were to identify and characterize the presence of functional cholecystokinin type-2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of cholecystokinin type-2 receptor transcripts in human esophageal adenocarcinoma cell lines. Competitive binding assays revealed specific binding of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by laser scanning confocal microscopy through internalization of rhodamine green labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent increase in proliferation of SEG-1 cells when compared to controls. This effect was abolished by co-incubation with L365,260, a CCK-2-specific receptor antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated protein kinases was demonstrated by Western blot analysis. In conclusion, the studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2 (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation in SEG-1 cells.

Gastric outlet obstruction as a consequence of a duodenal web masquerading as gastrinoma in an adult.

We present the case of a 24-year-old man with recurrent peptic ulcers and hypergastrinemia, in whom a multidisciplinary investigation for gastrinoma revealed a duodenal web. The affected duodenal segment was excised, and a gastroduodenostomy with highly selective vagotomy was performed. Postoperative serum gastrin levels returned to the normal range over the next 6 weeks. Congenital duodenal anomalies are unusual causes of gastric outlet obstruction in adults. Chronic gastric outlet obstruction secondary to an adult duodenal web can induce neurohumoral changes in gastric function, which enhance both acid output and gastrin secretion. This case reminds clinicians to consider congenital anomalies in adults presenting with recurrent peptic ulcers and hypergastrinemia.

Risk factors associated with the development of gastroduodenal ulcers due to the use of NSAIDs.

The risk of gastrointestinal mucosal injury with non-steroidal anti-inflammatory drugs (NSAIDs) is dose-dependent. Epidemiological studies have clearly demonstrated a rank order of risk of ulcer complications for commonly used NSAIDs, with ibuprofen consistently associated with the lowest risk and piroxicam with the highest. Antacids, H2 receptor antagonists and misoprostol all have drawbacks as prophylaxis. Of the cyclo-oxygenase (COX)-2 selective NSAIDs, rofecoxib is associated with a lower risk of gastrointestinal toxicity but there is uncertainty about the long-term risk associated with celecoxib. Rofecoxib has been associated with a significantly higher incidence of myocardial infarction than naproxen that may counteract the benefit of greater gastrointestinal safety. At over-the-counter doses, the short duration of use and the low dose reduce the risk of a serious adverse event compared with chronic use at prescribed doses. Intermittent therapy with low-dose NSAIDs has proved extremely safe and it has not been determined whether COX-2 selective agents offer a safety advantage compared with such treatment.