Gordon V. Ohning

Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial

Motilin‐receptor agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the motilin agonist ABT‐229 in functional dyspepsia patients with and without delayed gastric emptying.

Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

Childhood Trauma Is Associated With Hypothalamic-Pituitary-Adrenal Axis Responsiveness in Irritable Bowel Syndrome

BACKGROUND & AIMS A history of early adverse life events (EALs) is associated with a poorer outcome and higher levels of distress in adult patients with functional gastrointestinal disorders. An EAL is thought to predispose individuals to develop a range of chronic illnesses by inducing persistent changes in the central stress response systems, including the hypothalamic-pituitary-adrenal (HPA) axis. We sought to determine if EALs affect the HPA axis response to a visceral stressor in irritable bowel syndrome (IBS) patients and healthy controls, and to determine if this is affected by sex or related to symptoms or quality of life. METHODS Forty-four IBS patients (25 women, 19 men) and 39 healthy controls (21 women, 18 men) were assessed for gastrointestinal and psychological symptoms and EALs by validated questionnaires and interview. All subjects underwent a visceral stressor (sigmoidoscopy). Salivary cortisol was collected at baseline and serially for 1 hour poststressor. RESULTS Twenty-one IBS patients and 18 controls had EALs. In subjects with and without IBS, an EAL was associated with higher mean (+/-SD) cortisol levels (0.32 +/- 0.2 vs 0.20 +/- 0.1 microg/dL; P = .003) and higher area under the curve (28.1 +/- 17 vs 18.6 +/- 13 microg x min/dL; P = .005) after the stressor compared with subjects without EALs. In IBS, a faster resolution of cortisol to basal values corresponded to lower symptom severity (r = -0.36, P < .05) and better disease-specific quality of life (r = 0.33, P < .05). CONCLUSIONS HPA axis hyperresponsiveness to a visceral stressor is related more to a history of EALs than to the presence of IBS. However, HPA axis reactivity has a moderating effect on IBS symptoms.

PACAP type I receptor activation regulates ECL cells and gastric acid secretion

Pituitary adenylate cyclase activating polypeptide (PACAP) is present in gastric nerves, and PACAP receptors (PAC1) are found on gastric enterochromaffin-like (ECL) cells. Expression of PAC1 splice variants in purified ECL cells was determined by RT-PCR. PACAP effects on ECL cells were analyzed by video imaging of [Ca(2+)](i) and histamine release; its effects on gastric glands were examined by confocal microscopy of [Ca(2+)](i) in ECL and parietal cells. PACAP action on D cells was measured by [Ca(2+)](i) and radioimmunoassay. PACAP effects on acid secretion were determined in fistula rats with or without neutralizing anti-somatostatin antibodies. All splice variants of PAC1 were found, but vasoactive intestinal polypeptide (VIP) receptor (VPAC) products were absent. PACAP-27 and -38 dose-dependently raise [Ca(2+)](i) in ECL cells, and stimulated histamine release. VIP had a much lower affinity, which demonstrates the presence of PAC1 but not VPAC. PACAP elevated [Ca(2+)](i) in ECL and parietal cells of superfused gastric glands, but only the parietal cell signal was inhibited by ranitidine, showing the absence of PAC1 on parietal cells, and demonstrating functional coupling between the cell types. PACAP and VIP stimulated calcium signaling and somatostatin release from D cells with almost equal efficacy. Acid secretion was stimulated after intravenous injection of PACAP into rats treated with somatostatin antibody. PACAP is a candidate as a mediator of neural regulation of acid secretion.

Differential profile of CRF receptor distribution in the rat stomach and duodenum assessed by newly developed CRF receptor antibodies

Peripheral corticotropin‐releasing factor (CRF) receptor ligands inhibit gastric acid secretion and emptying while stimulating gastric mucosal blood flow in rats. Endogenous CRF ligands are expressed in the upper gastrointestinal (GI) tissues pointing to local expression of CRF receptors. We mapped the distribution of CRF receptor type 1 (CRF1) and 2 (CRF2) in the rat upper GI. Polyclonal antisera directed against the C‐terminus of the CRF receptor protein were generated in rabbits and characterized by western blotting and immunofluorescence using CRF1‐ and CRF2‐transfected cell lines and in primary cultured neurons from rat brain cortex. A selective anti‐CRF1 antiserum (4467a‐CRF1) was identified and used in parallel with another antiserum recognizing both CRF1 and CRF2 (4392a‐CRF1&2) to immunostain gastric tissue sections. Antiserum 4467a‐CRF1 demonstrated specific immunostaining in a narrow zone in the upper oxyntic gland within the stomach corpus. Conversely, 4392a‐CRF1&2 labeled cells throughout the oxyntic gland and submucosal blood vessels. Pre‐absorption with the specific antigen peptide blocked immunostaining in all experiments. Doublestaining showed co‐localization of 4392a‐CRF1&2 but not 4467a‐CRF1 immunoreactivity with H/K‐ATPase and somatostatin immunostaining in parietal and endocrine cells of the oxyntic gland. No specific staining was observed in the antrum with either antisera, whereas only antiserum 4392a‐CRF1&2 showed modest immunoreactivity in the duodenal mucosa. Finally, co‐localization of CRF2 and urocortin immunoreactivity was found in the gastric glands. These results indicate that both CRF receptor subtypes are expressed in the rat upper GI tissues with a distinct pattern and regional differences suggesting differential function.

Rapid and long-term alterations of hippocampal GABAB receptors in a mouse model of temporal lobe epilepsy

Alterations of γ‐aminobutyric acid (GABA)B receptor expression have been reported in human temporal lobe epilepsy (TLE). Here, changes in regional and cellular expression of the GABAB receptor subunits R1 (GBR1) and R2 (GBR2) were investigated in a mouse model that replicates major functional and histopathological features of TLE. Adult mice received a single, unilateral injection of kainic acid (KA) into the dorsal hippocampus, and GABAB receptor immunoreactivity was analysed between 1 day and 3 months thereafter. In control mice, GBR1 and GBR2 were distributed uniformly across the dendritic layers of CA1–CA3 and dentate gyrus. In addition, some interneurons were labelled selectively for GBR1. At 1 day post‐KA, staining for both GBR1 and GBR2 was profoundly reduced in CA1, CA3c and the hilus, and no interneurons were visible anymore. At later stages, the loss of GABAB receptors persisted in CA1 and CA3, whereas staining increased gradually in dentate gyrus granule cells, which become dispersed in this model. Most strikingly, a subpopulation of strongly labelled interneurons reappeared, mainly in the hilus and CA3 starting at 1 week post‐KA. In double‐staining experiments, these cells were selectively labelled for neuropeptide Y. The number of GBR1‐positive interneurons also increased contralaterally in the hilus. The rapid KA‐induced loss of GABAB receptors might contribute to epileptogenesis because of a reduction in both presynaptic control of transmitter release and postsynaptic inhibition. In turn, the long‐term increase in GABAB receptors in granule cells and specific subtypes of interneurons may represent a compensatory response to recurrent seizures.

Adenoma detection rate is necessary but insufficient for distinguishing high versus low endoscopist performance

BACKGROUND Endoscopist quality is benchmarked by the adenoma detection rate (ADR)-the proportion of cases with 1 or more adenomas removed. However, the ADR rewards the same credit for 1 versus more than 1 adenoma. OBJECTIVE We evaluated whether 2 endoscopist groups could have a similar ADR but detect significantly different total adenomas. DESIGN We retrospectively measured the ADR and multiple measures of total adenoma yield, including a metric called ADR-Plus, the mean number of incremental adenomas after the first. We plotted ADR versus ADR-Plus to create 4 adenoma detection patterns: (1) optimal (↑ADR/↑ADR-Plus); (2) one and done (↑ADR/↓ADR-Plus); (3) all or none (↓ADR/↑ADR-Plus); (4) none and done (↓ADR/↓ADR-Plus). SETTING Tertiary-care teaching hospital and 3 nonteaching facilities servicing the same patient pool. PATIENTS A total of 3318 VA patients who underwent screening between 2005 and 2009. MAIN OUTCOME MEASUREMENTS ADR, mean total adenomas detected, advanced adenomas detected, ADR-Plus. RESULTS The ADR was 28.8% and 25.7% in the teaching (n = 1218) and nonteaching groups (n = 2100), respectively (P = .052). Although ADRs were relatively similar, the teaching site achieved 23.5%, 28.7%, and 29.5% higher mean total adenomas, advanced adenomas, and ADR-Plus versus nonteaching sites (P < .001). By coupling ADR with ADR-Plus, we identified more teaching endoscopists as optimal (57.1% vs 8.3%; P = .02), and more nonteaching endoscopists in the none and done category (42% vs 0%; P = .047). LIMITATIONS External generalizability, nonrandomized study. CONCLUSION We found minimal ADR differences between the 2 endoscopist groups, but substantial differences in total adenomas; the ADR missed this difference. Coupling the ADR with other total adenoma metrics (eg, ADR-Plus) provides a more comprehensive assessment of adenoma clearance; implementing both would better distinguish high- from low-performing endoscopists.

Raphe pallidus stimulation increases gastric contractility via TRH projections to the dorsal vagal complex in rats

The role of thyrotropin releasing hormone (TRH) in the dorsal vagal complex (DVC) in mediating the enhanced gastric contractility induced by glutamate (100 pmol) microinjected into the raphe pallidus (Rpa) was investigated in urethane-anesthetized rats acutely implanted with miniature strain gauge force transducers on the corpus of the stomach. Glutamate-induced stimulation of gastric contractility was dose-dependently inhibited by bilateral microinjection into the DVC of TRH antibody (0.17, 0.85 or 1.7 micrograms/100 nl/site) but not by vehicle. TRH antibody microinjected into the dorsal medullary reticular field had no effect. These data indicate that activation of Rpa neurons by glutamate increases gastric motor function through TRH release in the DVC.

Anti-hyperalgesic effect of octreotide in patients with irritable bowel syndrome.

Background : Octreotide has been found to be beneficial in the treatment of chronic pain, although the mechanisms underlying its therapeutic effect are incompletely understood.

Prospective randomized comparative study of bipolar electrocoagulation versus heater probe for treatment of chronically bleeding internal hemorrhoids

BACKGROUND Our purpose was to compare the efficacy, complications, failure rates, and crossovers of heater and bipolar probe treatments of chronically bleeding internal hemorrhoids. METHODS Eighty-one patients (31 female, 50 male) with mean age of 53 years had large (grade 2 to 3) internal hemorrhoids with bleeding for a mean of 12 years, had failed medical management, and were randomized in a prospective study of anoscopic treatments to heater versus bipolar probes. Failure was defined as a major complication or failure to reduce the size of all internal hemorrhoids with three or more treatments. RESULTS With similar background variables and no difference in treatment times, rectal bleeding and other symptoms were controlled in a shorter time with the heater probe than with the bipolar probe (77 versus 121 days). Five complications (fissures, bleeding, or rectal spasm) occurred with the bipolar probe, and two occurred with the heater probe. The heater probe caused more pain during treatments but had significantly fewer failures and crossovers. CONCLUSIONS For patients who had failed medical management of chronically bleeding internal hemorrhoids, the techniques and complications of heater and bipolar probes were similar, but pain was more common, failures and crossovers were less frequent, and the time to symptom relief was shorter with the heater probe than with the bipolar probe.