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Patients and methods : A prospective registration of patients with colorectal cancer and a colonoscopy within the last 10 years. We tried to classify these post-colonoscopy colorectal cancers (PCCRCs) by most reasonable explanation and into subcategories suggested by the World Endoscopy Organization (WEO) and calculated the unadjusted PCCRC rate. Results : 47 PCCRCs were identified. The average age at diagnosis of PCCRC was 73 years. PCCRCs were more located in the right colon with a higher percentage of MSI-positive and B-RAF mutated tumours. The average period between index colonoscopy and diagnosis of PCCRC was 4.2 years. Sixty-eight % of all PCCRCs could be explained by procedural factors. The mean PCCRC-3y of our department was 2.46%. Conclusions : The data of our centre are in line with the data of the literature from which can be concluded that most post-colonoscopy colorectal cancers are preventable. The PCCRC-3y is an important quality measure for screening colonoscopy. Ideally all centres involved in the population screening should measure the PCCRC-3 y annually, with cooperation of the cancer registry and reimbursement data provided by the Intermutualistic Agency (IMA).

3610 Background: Although being the standard-of-care for stage III colon cancer, no biomarkers can identify patients (pts) who benefit from adjuvant chemotherapy. In metastatic pts, the lack of metabolic response (mR) in FDG-PET/CT after 1 chemotherapy cycle predicts the absence of treatment benefit. The PePiTA study aims to evaluate if the absence of mR after 1 cycle of pre-operative chemotherapy is predictive of recurrence in non-metastatic colon cancer pts. Herein, we report a preliminary analysis on surgical outcomes, adverse events and mR assessment after 1 cycle of pre-operative chemotherapy after completing the study accrual objective. Methods: Colon cancer pts eligible for curative resection and ECOG ≤1 received 1 cycle of mFOLFOX followed by surgery in this prospective, multicentre, non-randomized trial. FDG-PET/CT was performed at baseline and after 1 cycle of mFOLFOX. Adjuvant mFOLFOX was administered for up to 12 cycles for stage III pts, whereas for stage II pts the decision to pursue adjuvant chemotherapy was at investigator’s discretion. A decrease ≥15% in SUVmax after 1 cycle of chemotherapy was defined as mR (EORTC criteria) at central review. Results: mR was assessable on the primary tumor in 204/240 pts (85%). In 11 pts (4.6%), staging was modified by the baseline FDG-PET/CT, which detected metastatic disease or other tumors. Pre-operative mFOLFOX was administered to 218 pts, of which 14 (6%) had a grade ≥3 adverse event. Surgery was performed in 218 pts, with a median delay of 20 days (6 to 59) after chemotherapy. Surgical complications occurred in 28 (13%) pts, however no deaths occurred. The median SUVmax decrease between baseline and 2nd FDG-PET/CT was 24%. A mR was observed in 65.2% of the pts, whereas 34.8% showed no mR, including 3% who had progressive disease. Conclusions: One cycle of pre-operative mFOLFOX followed by a mR assessment has shown to be a feasible and safe strategy, raising interest on the potential of neoadjuvant chemotherapy in colon cancer. The early mR assessment identified pts that may not benefit from chemotherapy and might have a worse prognosis. The substantiation of this hypothesis is expected with the study’s long-term results. Clinical trial information: NCT00994864.

3532Background: BL-cfDNA combined with plasmatic changes in tumor-specific mutations after 14 days of therapy are explored as independent determinants of outcome in pts with aCRC. Methods: Archival...

Several studies have established symptomatic and mechanistic benefits of the somatostatin analogue octreotide in patients with dumping syndrome, but clinical use is hampered by the requirement for subcutaneous administration 3 times daily. We compared the efficacy of subcutaneous octreotide with that of the long-acting repeatable (LAR) octreotide formulation, which is administered monthly, in patients with dumping syndrome.The study included 30 consecutive patients with postoperative dumping, evidenced by oral glucose tolerance test (OGTT) results and insufficient response to dietary measures. OGTT, dumping severity score (summary of scores 0-3 for 8 early and 6 late dumping symptoms), and quality-of-life data were evaluated at baseline, after 3 days of subcutaneous administration of octreotide (0.5 mg), and then after 3 monthly intramuscular injections of octreotide LAR (20 mg).Both formulations of octreotide significantly reduced total dumping severity scores (21.7 +/- 1.6 at baseline, 11.2 +/- 1.2 for subcutaneous and 14.0 +/- 1.8 for LAR formulations; P.05). This reduction was associated with significant improvements in the increase in pulse rate (13.8 +/- 5.8 at baseline vs -0.3 +/- 2.2 and 1.9 +/- 1.7; P.05) as well as the increase in hematocrit level (4.0 +/- 1.4 at baseline vs 0.3 +/- 0.9. and 0.4 +/- 1.0; P.05), and the lowest glycemia level in the OGTT (54.1 +/- 6.7 at baseline vs 98.9 +/- 7.1 and 67.8 +/- 5.9; P.05). LAR octreotide administration significantly improved patients' quality of life. Patients' evaluations of their overall treatment efficacy was higher on LAR compared with the subcutaneous formulation (83% vs 52%; P = .01). Gallbladder stones occurred in 4 patients.Monthly administration of LAR octreotide improves OGTT results, symptoms, and quality of life in patients with postoperative dumping.

A new method for automatic analysis of resting lower esophageal sphincter pressure and postdeglutitive motor activity of esophageal body and lower esophageal sphincter (LES) is validated by comparing the results obtained with automatic and manual analysis of 11,700 esophageal body pressure peaks, 390 resting LES pressure measurements, and 3900 LES relaxations. The automatic analysis is based on the on-line transformation of pressure recordings into a mathematical formula using B-spline functions, which allows one to use the same parameters as those generally applied in manual analysis of esophageal manometric recordings. Statistical evaluation of the results indicates that this method provides a faithful analysis of the pressure tracings. The difference between manual and automatic analysis (mean ± SD) was only + 1.49 ± 4.26 mm Hg for wave amplitude, -0.15 ± 0.61 seconds for wave duration, +0.37 ± 1.05 cm/second for progression velocity, +0.95 ± 1.38 mm Hg for resting LES pressure, and -2.0 ± 1.67 mm Hg for residual LES pressure after deglutition. Wave form was correctly recognized in 95.3% of the waves. Pressure recordings were obtained from a study on the effect of the PGE1 analogue rioprostil (600 and 300 μg), administered orally on esophageal motor function in 10 normal volunteers. The drug increased both the resting LES pressure and the amplitude of esophageal body contractions and decreased the completeness of LES relaxation after swallowing.

A subset of functional dyspepsia (FD) patients report meal-related symptoms, possibly representing a pathophysiologically homogeneous subgroup. The aim of the present study was to establish the time-course of symptoms in relation to meal ingestion, and to assess the relationship between self-reported meal-related symptoms and pathophysiological mechanisms in FD.218 FD patients (149 women, mean (SEM) age 39 (1) years) filled out a symptom questionnaire, including meal-induced aggravation. All patients underwent a gastric emptying breath test with severity (0-4) scoring of six symptoms (pain, fullness, bloating, nausea, burning and belching) at each sampling (15 min interval for 4 h). In 129 patients, gastric sensitivity and accommodation were assessed by barostat.The intensity of each FD symptom was significantly increased 15 min after the meal, compared with the premeal score, and remained elevated until the end of the measurement period (all p0.05). The time-course of individual symptoms varied, with early peaks for fullness and bloating, intermediate peaks for nausea and belching, and late peaks for pain and burning. Meal-induced aggravation was reported by 79% of patients, and in these patients postprandial fullness, which peaked early, was the most intense symptom. In patients without self-reported meal-induced aggravation, epigastric pain, which had a delayed peak, was the most intense symptom and they had a lower prevalence of gastric hypersensitivity (27.5% vs 7.7%).Meal ingestion aggravates FD symptoms in the vast majority of patients, with symptom-specific time-courses. Postprandial fullness is the most severe symptom in patients reporting aggravation by a meal, while it is pain in those not reporting meal-related symptoms.

Impaired accommodation to a meal has been recognized as a pathophysiological mechanism in functional dyspepsia (FD). Based on observations in tertiary care patients, the drinking test has been proposed as a non-invasive tool to estimate accommodation. Our aim was to assess the reproducibility of the drinking test and its correlation with demographic, symptomatic and pathophysiological parameters in secondary care FD patients and healthy controls. Thirty-four healthy controls and 78 FD patients completed a drinking test (3 respectively 2 times), a gastric emptying study and an FD symptom questionnaire. Factors influencing maximal volume and gastric emptying were determined, and the reproducibility of the drinking test was investigated. The maximal satiety was reached at a lower volume in patients (489 ± 276 and 503 ± 248 mL for first and second test respectively vs 937 ± 428 and 1048 ± 421 mL, P

Several studies have demonstrated that radiofrequency energy delivery at the gastroesophageal junction (the Stretta procedure) induces symptom relief in gastroesophageal reflux disease (GERD), although improvement of acid exposure on pH monitoring was usually limited. A role for decreased esophageal sensitivity has been suggested. Our aim was to evaluate the influence of Stretta on symptoms, acid exposure, and sensitivity to esophageal acid perfusion in GERD. Thirteen patients with established proton pump inhibitor (PPI)-dependent GERD (three males; mean age, 51+/-10 years) participated in the study. Before and 6 months after the procedure symptom score, pH monitoring and Bernstein acid perfusion test were performed. The latter was done by infusing HCl (pH 0.1) at a rate of 6 ml/min 15 cm proximal to the gastroesophageal junction for a maximum of 30 min or until the patients experienced heartburn. Results were compared by Student's t-test. Stretta procedure time was 51+/-4 min and no complications occurred. After 6 months, the symptom score was significantly improved (12.5+/-2.0 to 7.5+/-2.1; P

Sumatriptan, a 5-hydroxytryptamine(1D) (5-HT(1D))-receptor agonist used in the treatment in migraine, inhibits gastric motility via the enteric nervous system. As no studies have reported enteric neuronal 5-HT(1D) receptors, we used conventional intracellular recordings to characterize the actions of sumatriptan on 145 guinea-pig antral myenteric neurones. In 24 of 29 neurones with a 5-HT(1P) receptor-mediated depolarizing response to 5-HT, application of sumatriptan caused a dose-dependent depolarization, accompanied by increased membrane resistance and enhanced excitability. Depolarizing responses to sumatriptan occurred both in cholinergic and in nitrergic neurones. Sumatriptan did not mimic the 5-HT(3) receptor-mediated fast-depolarizing responses or 5-HT(1A) receptor-mediated inhibitory responses to 5-HT. Sumatriptan had no effect on neurones not responding to 5-HT. The depolarizing response to sumatriptan was inhibited by renzapride, but not by 5-HT(1-7) receptor antagonists. We conclude that sumatriptan behaves as an agonist at the 5-HT(1P) receptor on myenteric neurones in the guinea-pig gastric antrum. The actions of sumatriptan on gastric motility seem to be attributable to a direct action on enteric neurones.

In a subset of functional dyspepsia patients, we have recently described the association between unsuppressed postprandial phasic contractions of the proximal stomach and a specific symptom pattern. To better elucidate the role of phasic contractility of the proximal stomach in symptom generation, we aimed at inducing this motility pattern in healthy volunteers and we carefully monitored symptom onset.Eleven healthy volunteers underwent gastric barostat on two separate days. Gastric tone and phasic contractility were evaluated for a 90-minute period. In particular, after 30 min of basal recording, a caloric liquid meal and neostigmine 0.5 mg IV or saline in a double-blind, randomized, crossover protocol were administered. During the measurement, severity of 9 dyspeptic symptoms was evaluated on a visual analog scale. Computer-aided baseline reconstruction allowed us to quantify phasic contractions as a motility index (MI), reflecting the area between signal and baseline normalized over time. Perception of contractions after placebo or neostigmine was evaluated. Moreover, we tested for influence of gastric tone and phasic contractility on symptoms.After neostigmine, gastric accommodation was not different than after placebo (225 +/- 36 vs 206 +/- 76 mL, P= NS). During the first 30-min postprandial period, the MI was significantly higher after neostigmine than after placebo (26.4 +/- 3 vs 21.4 +/- 3, P0.001), confirming the induction of unsuppressed postprandial phasic contractions. The postprandial total symptom score was significantly higher after neostigmine compared to saline; several individual postprandial symptom scores were also significantly higher after neostigmine-compared placebo. After neostigmine, a higher percentage of postprandial contractions was perceived compared to placebo.Unsuppressed postprandial phasic contractility of the proximal stomach is a mechanism potentially involved in the pathogenesis of dyspeptic symptoms.

Corticotropin-releasing factor (CRF) is a 41-amino acid peptide with distinct effects on gastrointestinal motility involving both CRF-1 and CRF-2 receptor-mediated mechanisms that are generally claimed to be centrally mediated. Evidence for a direct peripheral effect is rather limited. Electrophysiological studies showed a cAMP-dependent prolonged depolarization of guinea pig myenteric neurons on application of CRF. The current study aimed to test the direct effect of CRF on myenteric neurons and to identify the receptor subtype and the possible mechanisms involved. Longitudinal muscle myenteric plexus preparations and myenteric neuron cultures of guinea pig small intestine were incubated with the calcium indicator Fluo-4. Confocal Ca2+ imaging was used to visualize activation of neurons on application of CRF. All in situ experiments were performed in the presence of nicardipine 10−6 M to reduce tissue movement. Images were analyzed using Scion image and a specifically developed macro to correct for residual minimal movements. A 75 mM K+-Krebs solution identified 1,076 neurons in 46 myenteric ganglia (16 animals). Administration of CRF 10−6 M and CRF 10−7 M during 30 s induced a Ca2+ response in 22.4% of the myenteric neurons ( n = 303). Responses were completely abolished in the presence of the nonselective CRF antagonist astressin ( n = 55). The selective CRF-1 receptor antagonist CP 154,526 ( n = 187) reduced the response significantly to 2.1%. Stresscopin, a CRF-2 receptor agonist, could not activate neurons at 10−7 M, and its effect at 10−6 M (15.3%, n = 59) was completely blocked by CP 154,526. TTX 10−6 M ( n = 70) could not block the CRF-induced Ca2+ transients but reduced the amplitude of the signals significantly. Removal of extracellular Ca2+ blocked all responses to CRF ( n = 47). L-type channels did not contribute to the CRF-induced Ca2+ transients. Blocking N- or P/Q-type Ca2+ channels did not reduce the responses significantly. Combined L- and R-type Ca2+ channel blocking (SNX-482 10−8 M, n = 64) abolished nearly all responses in situ. Combined L-, N-, and P/Q-type channel blocking also significantly reduced the response to 8.6%. Immunohistochemical staining for CRF-1 receptors clearly labeled individual cell bodies in the ganglia, whereas the CRF-2 receptor staining was barely above background. CRF induces Ca2+ transients in myenteric neurons via a CRF-1 receptor-dependent mechanism. These Ca2+ transients highly depend on somatic calcium influx through voltage-operated Ca2+ channels, in particular R-type channels. Action potential firing through voltage-sensitive sodium channels increases the amplitude of the Ca2+ signals. Besides centrally mediated effects, CRF is likely to modulate gastrointestinal motility on the myenteric neuronal level.

Previously, we demonstrated that intestinal inflammation leads to a postinflammatory loss of nitric oxide synthase (NOS)-expressing myenteric neurones and motility disturbances. Here, we investigated whether high NO concentrations could be responsible for the decrease in NOS neurones. Myenteric neurone cultures, prepared from guinea-pig small intestine, were incubated with NO donors [sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1)]. After fixation, NOS neurones were identified by NADPH diaphorase staining and neurone-specific enolase (NSE)-positive neuronal content was assessed with an enzyme-linked immunosorbent assay (ELISA)-based method. Twenty-four hours incubation with SIN-1 (10−3 mol L−1) or SNP (10−4 mol L−1 or higher) reduced the number of NADPH diaphorase-positive neurones. SNP incubation did not affect the NSE-positive neuronal content. Shorter incubations (SNP: 4 and 12 h) had no significant effect. The SNP-induced reduction was reversed by glutathione (GSH), but not by NO- or O-scavengers, whereas GSH depletion enhanced the decrease. The NO-dependent guanylate cyclase-blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) did not affect the SNP effect. This reduction can be explained by either specific apoptosis of NOS neurones or downregulation of NOS activity. However, TdT-mediated X-dUTP nick end labelling (TUNEL®) stainings argue in favour of the latter. In conclusion, the NO donor SNP decreases the number of NOS-expressing myenteric neurones time and concentration dependently, without affecting the amount of neuronal material. Glutathione plays an important protective role.

Summary Background Tricyclic antidepressants, which have multiple pharmacological influences, have a therapeutic effect in non-cardiac chest pain, but selective serotonin reuptake inhibitors have a single pharmacological effect. Aim To evaluate the acute effect of citalopram on oesophageal hypersensitivity. Methods On two separate occasions, 10 healthy subjects (seven men, mean age 25 years) with established oesophageal hypersensitivity, underwent oesophageal manometry with evaluation of mechanical and chemical sensitivity. Subjects received placebo or citalopram 20 mg i.v. in a randomized, crossover, double-blind fashion. Results Citalopram did not alter oesophageal motility. Citalopram significantly increased the threshold inducing first perception (4.6 ± 0.3 vs. 6.7 ± 0.4 mL, P

Aim: A subset of functional dyspepsia patients respond to acid suppressive therapy, but the prevalence of non-erosive reflux disease in functional dyspepsia and its relevance to symptoms have never been established. The aim of the present study was to study 24 hour pH monitoring in consecutive functional dyspepsia patients. Methods: A total of 247 patients with dyspeptic symptoms (166 women, mean age 44 (SEM 1) year), with a negative upper gastrointestinal endoscopy and without dominant symptoms of heartburn participated in the study. In all patients, the severity of dyspeptic symptoms and the presence of heartburn was assessed by a questionnaire and a 24 hour oesophageal pH monitoring study was performed. All patients underwent a gastric emptying breath test and in 113 a gastric barostat study was performed. Results: Abnormal pH monitoring (acid exposure >5% of time) was found in 58 patients (23%). Of 21 patients with a positive heartburn questionnaire, 76% had pathological pH monitoring, while this was the case in only 18.5% of patients with a negative heartburn questionnaire. Demographic characteristics and the prevalence of other pathophysiological mechanisms did not differ between heartburn negative patients with normal or abnormal acid exposure. Pathological acid exposure in heartburn negative patients was associated with the presence of epigastric pain (65 v 84%, p v 69%, p = 0.005). Conclusion: Pathological oesophageal acid exposure is only present in a subset of heartburn negative functional dyspepsia patients, which are characterised by a higher prevalence of epigastric pain.

OBJECTIVES: Proximal extent of gastroesophageal reflux (PER) is relevant for symptoms in GERD patients. It has been suggested that PER is determined by the volume of the refluxate that, in turn, might depend on the degree of gastric fullness. Abdominal straining, during ambulation, increases the likelihood of gastroesophageal reflux. We assessed the influence of gastric fullness and ambulation on proximal extent of reflux. METHODS: PER was assessed in 37 patients with GERD undergoing ambulatory pH impedance monitoring. In 14 controls and 19 GERD patients, esophageal pH impedance and gastric emptying were also studied simultaneously in stationary conditions. We compared PER during fasting, early postprandial (before half emptying), and late postprandial periods in ambulatory and stationary conditions. RESULTS: More reflux episodes reached the proximal esophagus in the postprandial period compared to fasting (60% ± 4 vs 29% ± 3, p < 0.05). In stationary conditions, early postprandial reflux reached higher proximal extent than late postprandial reflux (15 ± 3% vs 8 ± 4%, p < 0.05). The proportion of reflux events reaching the proximal esophagus was significantly higher in ambulatory than in stationary conditions (29 ± 5% vs 15 ± 3%, p < 0.05). CONCLUSION: Compared to fasting, reflux episodes occurring after the meals are more likely to reach higher proximal extent, particularly so during the early postprandial period. The highest proportion of postprandial proximal reflux occurred in ambulatory condition. These findings suggest that reducing meal volumes and early postprandial physical activity might contribute to decrease proximal extent of reflux and postprandial GERD symptoms.

Background & Aims: Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans. Methods: Positron emission tomography of the brain was performed in 11 healthy volunteers during 4 conditions: (1) no distention and isobaric distention to the individual thresholds for (2) first, (3) marked, and (4) unpleasant sensation. Data were analyzed using statistical parametric mapping. Results: During maximal distention relative to baseline, significant (Pcorrected < .05) regional brain activation occurred in the left and right gyrus postcentralis (Brodmann area [BA] 43), the left gyrus temporalis superior (BA 38), the right gyrus frontalis inferior (BA 47, orbitofrontal cortex), the right midanterior cingulate gyrus (BA 24), the right anterior insula, and the left cerebellar hemisphere. These areas showed a progressive increase in activation with increasing intensity of the distending stimulus. Conclusions: We found evidence for a neuronal network processing distention stimuli of the proximal stomach that is overall consistent with the “visceral stimulation network” described in the literature. In addition, we found activation of the orbitofrontal cortex, confirming its role as a convergence zone for processing of food-related stimuli and regulation of hunger, appetite, satiety, and food intake. We found no evidence for a functional neuroanatomic divergence in the processing of noxious and innocuous gastric stimuli.

In a subset of patients with gastroesophageal reflux disease (GERD), symptoms persist in spite of proton pump inhibitor (PPI) therapy. Endoscopic gastroplication (EG) was reported to provide a novel therapeutic option in GERD. To evaluate symptomatic and objective outcome of EG in PPI refractory GERD, consecutive GERD patients with persisting reflux symptoms during at least 2 months double dose PPI were recruited for EG (Endocinch). Exclusion criteria were high-grade esophagitis, Barrett's esophagus, and hiatal hernia > 3 cm. Symptoms and PPI use were evaluated before and 1, 3, and 12 months after the EG; 24-hr pH monitoring off PPI was performed before and after 3 and 12 months. All data are given as mean +/- SD and were analyzed by Student's t test. Twenty patients (10 females; mean age, 45 +/- 11 years) were recruited. Under conscious sedation with midazolam (6 +/- 2 mg) and pethidine (53 +/- 5 mg), a mean of 2.0 +/- 0.2 sutures was applied during a procedure time of 33 +/- 6 min. Throat ache and mild epigastric pain for up to 3 days after the procedure were the only adverse events. At 3 and 12 months symptom score (11.6 +/- 6 vs. 6.4 +/- 3.7 [P < 0.01] and 7.1 +/- 4.5 [P < 0.05]) as well as pH monitoring (% time pH < 4: 17.0 +/- 11.1 vs. 8.1 +/- 5.7% [P < 0.01] and 9.8 +/- 4.1% [P < 0.01]) significantly improved. Ph monitoring was normalized (< 4% of time) in seven patients after 3 months. PPIs could be stopped in 13 patients, with 2 patients still using H2-blockers and 1 using cisapride after 3 months. After 12 months only six patients were free of PPI use and pH monitoring was normalized in six patients. We conclude that EG provides short- and medium-term symptomatic and objective relief to a subset of GERD patients refractory to high-dose PPI.

Background: It is not known which region of the stomach is responsible for symptom generation or whether symptoms induced by gastric distension are region specific. Also, it is unclear whether low level gastric distension has a modulatory role on gastric tone and mechanosensitivity. Aims: To define differences in the sensorimotor response to distension between proximal and distal gastric distension, and to determine the effects of low level gastric distension on gastric tone and mechanosensitivity. Methods: In 14 healthy volunteers, a double barostat assembly incorporating a distal (antral) and proximal (fundic) bag was introduced into the stomach. Pressure sensitivity tests with either bag were performed with and without simultaneous background distension of the other bag in a randomised manner. Proximal gastric accommodation to a meal was measured with and without simultaneous distal gastric distension. Results: The distal stomach was less compliant than the proximal stomach to low level distension. Thresholds for first perception and discomfort, and symptom profiles did not differ between distal and proximal gastric distension. Simultaneously applied low level gastric distension of one segment did not affect gastric mechanosensitivity of the other segment. Both the proximal and distal stomach relax after ingestion of a meal. Simultaneous low level antral distension decreases proximal gastric accommodation to a meal. Conclusions: Compared with the proximal stomach, the distal stomach is less compliant but its mechanosensitivity is not different. Symptoms induced by gastric distension are not region specific and no spatial summation occurred. Meal induced relaxation occurs both in the proximal and distal stomach.

Summary Background : Intraduodenal administration of lipids, through lipid digestion and release of cholecystokinin (CCK), induces viscero-visceral reflexes that affect gastric tone and sensitivity. It is unclear whether the same mechanisms control gastric function after an orally ingested meal. Aim : To evaluate the effect of orlistat, a selective lipase inhibitor, on gastric response to an orally administered meal. Methods : Eighteen healthy volunteers participated in this study. They were treated for 5 days with orlistat (120 mg) or placebo t.d.s. in a double-blind randomized crossover design. During treatment, all subjects underwent a gastric barostat study, measurement of plasma CCK levels and a satiety drinking test. Results : Although CCK plasma levels were significantly decreased, pre-treatment with orlistat failed to affect gastric compliance (72 ± 6 mL/mm Hg and 64 ± 6 mL/mm Hg, NS), gastric sensitivity (discomfort threshold 12.2 ± 0.6 mm Hg vs. 10.9 ± 0.6 mm Hg above minimal distending pressure, NS) or gastric accommodation (172 ± 41 mL vs. 206 ± 49 mL, NS) to an orally ingested meal. Furthermore, orlistat pre-treatment had no significant effect on the amount of calories ingested during a satiety drinking test (1329 ± 88 kcal vs. 1217 ± 115 kcal, NS). Conclusion : Administration of a lipase inhibitor does not affect gastric compliance, sensitivity to distension and accommodation to an orally ingested meal, and does not influence meal-induced satiety.

Decreased acid clearance and increased exposure to acid of the duodenum have been reported in a subset of functional dyspepsia patients. However, the mechanism by which increased duodenal acid exposure may affect symptoms is unclear. The aim of the present study was to investigate the effects of duodenal acidification on proximal gastric tone and mechanosensitivity in humans. An infusion tube with a pH electrode attached was positioned in the second part of the duodenum, and a barostat bag was located in the gastric fundus. In 12 healthy subjects, fundic tone and sensitivity to distensions were assessed before and during duodenal infusion of 0.1 N hydrochloric acid or saline in a randomized, double-blind design. In 10 healthy subjects, meal-induced accommodation was measured during duodenal infusion of acid or saline. Acid infusion in the duodenum significantly increased fundic compliance and decreased fasting fundic tone. This was accompanied by a significant decrease in the pressures and the corresponding wall tensions at the thresholds for discomfort. During infusion of acid, significantly higher perception and symptom scores were obtained for the same distending pressures. The meal-induced fundic relaxation was significantly smaller during acid infusion compared with saline infusion. In conclusion, duodenal acidification induces proximal gastric relaxation, increases sensitivity to gastric distension, and inhibits gastric accommodation to a meal. Through these mechanisms, increased duodenal acid exposure may be involved in the pathogenesis of dyspeptic symptoms.

Summary Background : Tegaserod, a 5-hydroxytryptamine-4 receptor agonist, enhances gastric emptying, but its effects on proximal stomach function have not been studied. Aim : To study the effect of tegaserod on gastric compliance, accommodation and perception of distension in humans. Methods : Nineteen healthy volunteers (10 females; mean age, 23.9 years) were studied on three separate occasions after 7 days of treatment with placebo, tegaserod 2 mg b.d. or tegaserod 6 mg b.d. in a double-blind, randomized, three-way cross-over design. After the introduction of a barostat bag, stepwise distensions were performed to determine gastric compliance and sensitivity, and a mixed liquid meal was administered in isobaric mode to assess accommodation. Results : Tegaserod had no effect on the pressures or volumes inducing first perception or discomfort. Tegaserod 6 mg b.d. enhanced fasting gastric compliance compared with placebo. Pre-prandial and post-prandial intra-balloon volumes were significantly higher after 6 mg b.d. than after placebo. Both tegaserod 2 and 6 mg b.d. shortened the time to maximum post-prandial intra-balloon volume. The amplitude of meal-induced gastric relaxation (post-prandial minus pre-prandial volumes) did not differ between the treatment arms. Conclusion : In humans, tegaserod allows for larger intra-balloon volumes both before and after a meal. These findings warrant the investigation of the therapeutic potential of tegaserod in dyspeptic patients with impaired accommodation.

Phasic fundic contractions induce transient increases in gastric wall tension and can be perceived in patients with functional dyspepsia. It is unclear whether phasic contractile activity contributes to postprandial symptoms. The aim of the study was to examine postprandial phasic contractility in functional dyspepsia in relation to pathophysiological, clinical, and demographic variables.A gastric barostat study was performed in 180 patients with functional dyspepsia and in 53 healthy control subjects. Sensitivity to distensions and the motor response to a standardized liquid meal were assessed. Phasic contractility in the proximal stomach was quantified using a motility index during three 30-min periods, namely, the preprandial period and the first and second postprandial periods. Unsuppressed phasic contractility after the meal was defined as motility index greater than mean + 2 SD in control subjects in at least one of the two postprandial periods. Relationships between unsuppressed phasic contractility and impaired accommodation, hypersensitivity, delayed gastric emptying, Helicobacter pylori (H. pylori) infection, symptom severity, and demographic factors were assessed.Patients demonstrated a higher motility index than did control subjects during the first (22.8 +/- 10.1 vs 20.3 +/- 6.8 ml/s; p = 0.04) but not the second (19.9 +/- 9.1 vs 18.7 +/- 6.9 ml/s; ns) postprandial 30-min period. The motility index before the meal was similar in patients and controls. Unsuppressed phasic contractility postprandially was observed in 15% of the patients. H. pylori infection (p = 0.01), relevant or severe bloating (p = 0.004), and absence of nausea (p = 0.004) were found to be independently associated with unsuppressed phasic contractility after a meal.Unsuppressed postprandial phasic contractility in the proximal stomach is present in a small subset of patients with functional dyspepsia. It is associated with relevant and severe bloating and H. pylori infection but also with the absence of nausea.

Duodenal acid has been suggested to be of importance for dyspeptic symptoms. We investigated the effects of acid on duodenal mechanosensitivity and antroduodenal motility in 10 healthy subjects before and during duodenal infusion of acid (0.1 N HCl) or water by using a combined barostat-manometry assembly. During acid infusion, increased sensitivity to balloon distension was seen, with reduced perception ( P = 0.04) and discomfort thresholds ( P = 0.06) and higher intensity of discomfort ( P = 0.02) compared with water. Higher balloon volumes were seen during acid infusion, indicating decreased tone ( P = 0.05). Large volume waves were more prevalent during acid than water infusion ( P = 0.009). The acid infusion suppressed antral contractions ( P = 0.04) and increased the number of contractions in the proximal duodenum ( P = 0.02) compared with before the infusion. In conclusion, duodenal acid enhances mechanical sensitivity in the duodenum, affects gastroduodenal motor function, and might be of importance for dyspeptic symptoms.

Summary Background: The γ-aminobutyric acid receptor type B agonist, baclofen, inhibits transient lower oesophageal sphincter relaxations by influencing a vagal pathway. Although post-prandial proximal gastric function, which is vagally mediated, is important in the occurrence of transient lower oesophageal sphincter relaxations, the effects of baclofen on post-prandial proximal gastric motility in humans remains undetermined. Aim: To determine the effects of baclofen on post-prandial lower oesophageal sphincter function and proximal gastric motility in healthy subjects. Methods: In 11 healthy volunteers, a barostat bag and an oesophageal manometric catheter with a sleeve were simultaneously positioned; 40 mg of oral baclofen or placebo was then given in a randomized, double-blind manner. Subsequently, the intragastric bag volume, oesophageal and lower oesophageal sphincter pressure and oesophageal pH were recorded during the 90 min before and 120 min after a meal. Results: During the post-prandial period, unlike the fasting period, baclofen decreased the rate of transient lower oesophageal sphincter relaxations and increased the basal lower oesophageal sphincter pressure compared with placebo. However, the meal-induced decrease in the tone and phasic contractility of the fundus was not affected by baclofen. Conclusion: The γ-aminobutyric acid receptor type B agonist, baclofen, has a potent effect on post-prandial lower oesophageal sphincter motility without altering post-prandial proximal gastric motility, suggesting differential effects of baclofen on different signals of gastrointestinal vagal afferents.

The myenteric plexus plays a key role in the control of gastrointestinal motility. We used confocal calcium imaging to study responses to electrical train stimulation (ETS) of interganglionic fiber tracts in entire myenteric ganglia of the guinea pig small intestine. ETS induced calcium transients in a subset of neurons: 52.2% responded to oral ETS, 65.4% to aboral ETS, and 71.7% to simultaneous oral and aboral ETS. A total of 41.3% of the neurons displayed convergence of oral and aboral ETS-induced responses. Responses could be reversibly blocked with TTX (10− 6 M), demonstrating involvement of neuronal conduction, and by removal of extracellular calcium. ω-Conotoxin (5 × 10−7 M) blocked the majority of responses and reduced the amplitude of residual responses by 45%, indicating the involvement of N-type calcium channels. Staining for calbindin and calretinin did not reveal different response patterns in these immunohistochemically identified neurons. We conclude that, at least for ETS close to a ganglion, confocal calcium imaging reveals complex oral and aboral input to individual myenteric neurons rather than a polarization in spread of activity.

Background & Aims: Categorization of functional dyspepsia into subgroups is based on expert opinion according to (dominant) symptoms or on underlying pathophysiological mechanisms. We used an evidence-based approach to the determination of subtypes of functional dyspepsia. Methods: Consecutive functional dyspepsia patients were recruited from a tertiary referral center. The following were performed: (1) exploratory (EFA) and confirmatory factor analysis (CFA) of symptom patterns in a large group of patients with functional dyspepsia; (2) external validation of these factors by the determination of their association pattern with physio- and psychopathological mechanisms, and with health-related quality of life and sickness behavior; and (3) cluster analysis of their distribution in this population. Results: Both EFA and CFA do not support the existence of functional dyspepsia as a homogeneous (unidimensional) condition. A 4-factor model is found to be valid, with differential distribution within the patient population according to cluster analysis. Factor 1 is characterized by nausea, vomiting, early satiety, and weight loss and factor 2 by postprandial fullness and bloating. Both factor 1 and 2 are associated with delayed emptying, but only factor 1 is associated with younger age, female sex, and sickness behavior. Factor 3 is characterized by pain symptoms and associated with gastric hypersensitivity and several psychosocial dimensions including medically unexplained symptoms and health-related quality of life dimensions. Factor 4, characterized by belching, is also associated with hypersensitivity, but is unrelated to psychosocial dimensions. Conclusions: In a tertiary care population, functional dyspepsia is a heterogeneous condition characterized by 4 major dimensions differentially associated with psychopathological and physiopathological mechanisms.

Summary Background : The role of 5-hydroxytryptamine in the control of gastric fundus tone in humans is still unknown. Selective 5-hydroxytryptamine re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically released 5-hydroxytryptamine. Aim : To study the influence of a selective 5-hydroxytryptamine re-uptake inhibitor, paroxetine, on gastric fundus tone, on the perception to gastric distension and on gastric accommodation to a meal. Methods : Sixteen healthy volunteers underwent a gastric barostat study on two occasions, after pre-treatment with placebo or paroxetine, 20 mg/day. Graded isobaric and isovolumetric distensions were performed and perception was scored by a questionnaire. Subsequently, the amplitude of the gastric accommodation to a mixed liquid meal was also measured. Results : Pre-treatment with paroxetine did not alter the thresholds for perception and discomfort during isobaric (4.7 ± 2.3 vs. 4.0 ± 2.0 mmHg and 13.3 ± 3.1 vs. 12.7 ± 2.3 mmHg above the minimum intragastric distending pressure, N.S.) and isovolumetric (307 ± 90 vs. 417 ± 114 mL and 772 ± 74 vs. 750 ± 76 mL, N.S.) distensions. Paroxetine significantly enhanced the amplitude of the meal-induced fundus relaxation (136 ± 51 vs. 255 ± 43 mL, P

To avoid food impaction artifacts during ambulatory bile reflux monitoring (Bilitec), some groups have allowed only a liquid diet, while others omitted the meal and postprandial periods from the analysis. Our aim was to study whether Bilitec monitoring requires the use of a liquid diet. In 40 healthy subjects and 211 consecutive patients evaluated for suspected gastroesophageal reflux disease, we performed ambulatory 24-hr esophageal pH and Bilitec monitoring. The subjects were randomized to either solid or liquid meals during the procedure. All patients underwent an upper gastrointestinal endoscopy. In healthy subjects, liquid and solid diets were followed by similar acid exposure of the distal esophagus. During bile reflux monitoring, major meal artifacts occurred in 19% of the patients using solid meals, but in none of the patients using liquid meals. With liquid meals, but not with solid meals, a progressive increase in duodenoesophageal reflux occurred with increasing severity of endoscopic lesions. With liquid meals, but not with solid meals, the prevalence of pathological exposure to duodenoesophageal reflux increased with increasing severity of endoscopic lesions. With liquid meals, the results of pH monitoring and bile reflux monitoring correlated better than with solid meals. Thus, ambulatory Bilitec monitoring requires the use of liquid meals, as the use of solid meals is associated with too many meal artifacts and a poorer correlation with acid reflux and severity of endoscopic lesions.

Recently, we developed a disposable acid exposure sensor whose in vitro response to acid below pH 4 is linearly determined by the duration of exposure and the degree of acidity. The aim of the present study was to compare the SR to simultaneous esophageal pH and duodenogastroesophageal reflux (DGER) monitoring (Bilitec) in patients investigated for presumed gastroesophageal reflux disease (GERD). Twenty-six patients (16 men, mean age 46 ± 2 years) with symptoms suggestive of GERD underwent 24-hr ambulatory pH monitoring and SR monitoring at 5 cm proximal to the LES. DGER monitoring was performed in 21 patients. Exposure of the esophagus to acid and to DGER were analyzed. These data were compared to SR. A significant correlation was found between the exposure of the distal esophagus to acid and SR (R = 0.85; P 5% of time were 91% and 93%, respectively conclusion, the response of the acid exposure sensor is strongly correlated with the results of simultaneous esophageal pH monitoring. The sensor seems able to reliably predict pathological esophageal acid exposure. These findings warrant larger studies of the clinical potential of the acid exposure sensor in the diagnosis and quantification of GERD.

Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors.Koek GH, Sifrim D, Lerut T, Janssens J, Tack J.Center for Gastroenterological Research, University Hospital Gasthuisberg, Leuven, Belgium.BACKGROUND AND AIMS: A subset of patients with gastro-oesophageal reflux disease (GORD) with refractory symptoms during therapy with proton pump inhibitors (PPIs), have persistent non-acid duodeno-gastro-oesophageal reflux (duodenal reflux). The aim of the present study was to investigate the effect of the GABA(B) receptor agonist baclofen, which was shown to inhibit the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) in patients with persistent non-acid duodenal reflux during PPI therapy. METHODS: Patients were eligible for the study if they had persistent reflux symptoms, normal pH monitoring, and pathological Bilitec monitoring during PPI treatment. Upper gastrointestinal endoscopy and reflux symptom score were performed at the beginning of the study. Baclofen 5 mg three times daily was associated with treatment, and was increased by 5 mg every fourth day until a maintenance dose of 20 mg three times daily was reached. A reflux symptom questionnaire, ambulatory pH monitoring, and Bilitec monitoring were repeated four days later while PPI and baclofen were continued. All data are given as mean (SEM) or median (interquartile range) and were compared using the Student's t test or the Mann-Whitney U test. RESULTS: Sixteen patients (11 women, mean age 46 (3) years) with persistent heartburn or regurgitation for at least three months, in spite of PPI therapy, were included in the study. Erosive oesophagitis was present in seven patients (five with grade 1, two with grade 2). Under PPI therapy alone, all patients had normal acid exposure (0.3 (0.05; 2.2)% of the time) but pathological duodenal reflux exposure (13.8 (11.8; 15.5)% of the time). After addition of baclofen 20 mg three times daily, acid exposure was similar (0.4 (0.15; 2.3)% of the time; NS) but duodenal reflux had significantly decreased (6.1 (0.8; 10.3)% of the time; p5 minutes) was decreased, respectively, from 23 (14.5; 34) to 12 (5; 21) (p = 0.06) and from 5 (3; 8) to 2 (0.5;4.5) (p

Functional bowel disorders may follow acute intestinal infection. In animals, postinflammatory dysmotility is associated with nitrergic dysfunction. The aim of this study was to identify and characterize patients with presumed postinfectious dyspepsia (PD) compared with unspecified-onset dyspepsia (UD).A total of 400 consecutive dyspeptic patients filled out a questionnaire to assess whether their symptoms were of postinfectious origin. They underwent testing for Helicobacter pylori infection as well as gastric emptying and gastric barostat studies. Pharmacological studies of nitrergic gastric function were performed in controls, in patients with presumed PD, and in patients with UD using sumatriptan, an activator of nitrergic neurons, and amylnitrite, a nitric oxide donor.Presumed PD was present in 17% of the patients and associated with more prevalent early satiety, weight loss, nausea, and vomiting compared with UD. Both groups did not differ in H. pylori infection, gastric emptying, or gastric sensitivity. Impaired accommodation was significantly more prevalent in patients with presumed PD (67% vs. 30%; P0.05). Sumatriptan relaxed the stomach in controls and patients with UD but not in patients with presumed PD, whereas amyl nitrite relaxed the stomach in all subjects.A subset of dyspeptic patients has a history suggestive of postinfectious dyspepsia. These patients have a high prevalence of impaired accommodation attributable to a dysfunction at the level of gastric nitrergic neurons.

To characterize further the Ca2+ signalling mechanisms of myenteric neurones, we studied the effect of thapsigargin, a blocker of the Ca2+-store ATPase, and the mechanisms involved in restoring the intracellular Ca2+ concentration ([Ca2+]i) after activation. Thapsigargin (5 x 10(-6) mol L(-1)) induced an oscillatory [Ca2+]i response in 86.6% of the neurones (n=276), which was blocked by the removal of extracellular Ca2+ and by omega-conotoxin MVIIA (5 x 10(-7) mol L(-1)). The IP3-blocker, 2-aminoethyl-diphenyl-borate (75 x 10(-6) mol L(-1)), blocked or reduced the responses in 74.5% of the neurones. The oscillatory responses induced by the depletion of Ca2+ stores suggest that myenteric neurones might recruite N-type Ca2+ channels as a refill mechanism. Thapsigargin pretreatment increased the amplitude, the upstroke and duration of the K+-induced [Ca2+]i responses. Mitochondrial blockers (rotenone and antimycin/oligomycin) also prolonged the responses, but without affecting the amplitude. Furthermore, it was found that for high [Ca2+]i, the thapsigargin-sensitive Ca2+ uptake was crucial, while mitochondrial blockade affected the Ca2+ uptake over a wide range of concentrations. The Ca2+-sequestering components might also have been compensating for each other, as most drugs only delayed and not inhibited Ca2+ removal.

Background & Aims: Hypersensitivity to gastric distention has been reported in functional dyspepsia, but its characteristics and relevance to symptoms remain unclear. The aim of this study was to define hypersensitivity to gastric distention and its association to specific symptoms in functional dyspepsia. Methods: We used a gastric barostat to study sensitivity to gastric distention in 80 healthy subjects and in 160 functional dyspepsia patients. Demographic characteristics, gastric emptying, Helicobacter pylori status, gastric accommodation, and a dyspepsia symptom score were obtained from all patients and the relationship with visceral sensitivity was assessed using univariate and multivariate analysis. Results: The increase of intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain is the most appropriate expression of sensitivity to gastric distention because it yields a meaningful lower range of normal and it is independent from age and body mass index. Hypersensitivity to gastric distention was found in 34% of the patients, who did not differ from the other patients in demographic and other pathophysiological characteristics. Hypersensitivity to distention was associated with a higher prevalence of postprandial pain, belching, and weight loss. Conclusions: Hypersensitivity to gastric distention is present in a subset of functional dyspepsia patients. It is associated with symptoms of postprandial epigastric pain, belching, and weight loss.

OBJECTIVES: Gastric barostat studies are increasingly being performed, but their reproducibility and the most suitable study protocol have not been determined. The aim of this study was to verify the reproducibility of gastric sensitivity and accommodation testing in healthy and in dyspeptic subjects, and to compare stepwise and double random staircase distensions. METHODS: A total of 13 dyspeptic patients and 25 healthy control subjects underwent two successive studies. Sensory thresholds were assessed on a same-day/different-days protocol, using a stepwise (11/14 healthy subjects and 11/13 patients) or a double random staircase inflation (11/21 healthy subjects). In 10 healthy subjects, both methods were compared. Gastric accommodation was measured on different days in 13 patients and nine healthy subjects. Data (mean ± SEM) were compared using the paired t test, and individual variability was expressed as the percent coefficient of variation. RESULTS: In healthy subjects, the thresholds for first perception and for discomfort were highly reproducible (p > 0.05) and the pressure thresholds showed a lower degree of variability than the volumes. Pressure thresholds quantified by stepwise showed lower variability than double random staircase inflation. In the patients, the sensory thresholds were unchanged between the sessions on the same and on different days (p > 0.05). Gastric accommodation also showed excellent reproducibility for both dyspeptic patients and healthy control subjects (p > 0.05). CONCLUSIONS: Both in dyspeptic patients and in healthy control subjects, gastric sensitivity and accommodation quantified by isobaric distensions show excellent reproducibility. Pressure and volume thresholds both are well reproducible, but the former shows less variability. Finally, the simplest stepwise protocol is better than the double random staircase to assess the gastric sensitivity to distension.

Sumatriptan is able to improve symptoms of early satiety in dyspeptic patients by relaxing the gastric fundus. The aim of this study was to verify the efficacy of intranasal administration of sumatriptan on gastric sensory motor function, in order to provide a new pharmacotherapeutic approach to functional dyspepsia. Thirteen healthy subjects were investigated twice on separate days. A gastric barostat was used to study the effect of placebo and sumatriptan, 20 mg intranasally, on basal fundic tone. In addition, stepwise isobaric distensions were performed and perception was measured before and after administration of drugs. Placebo had no effect on gastric tone and on perception. Sumatriptan caused a small, but short-lasting gastric relaxation and had no significant effect on sensitivity to distension and gastric compliance. Unlike the subcutaneous formulation, the intranasal administration of sumatriptan had no effect on gastric sensory motor functions, and this probably reflects a low biovailability of intranasally administered sumatriptan.

This work presents the design and implementation of a 2-V cellular transceiver front-end in a standard 0.25-/spl mu/m CMOS technology. The prototype integrates a low-IF receiver (low noise amplifier, I/Q mixers, and VGAs) and a direct-upconversion transmitter (I/Q mixers and pre-amplifier) on a single die together with a complete phase-locked loop, including a 64/79 prescaler, a fully integrated loop filter, and a quadrature voltage controlled oscillator with on-chip inductors. Design trade-offs have been made over the boundaries of the different building blocks to optimize the overall system performance. All building blocks feature circuit topologies that enable comfortable operation at low voltage. As a result, the IC operates from a power supply of only 2 V, while consuming 191 mW in receiver (RX) mode and 160 mW in transmitter (TX) mode. To build a complete transceiver system for 1,8-GHz cellular communication, only an antenna, an antenna filter, a power amplifier, and a digital baseband chip must be added to the analog front-end. This work shows the potential of achieving the analog performance required for the class I/II DCS-1800 cellular system in a standard 0.25-/spl mu/m CMOS technology, without tuning or trimming.

We studied the effect of excitatory neurotransmitters (10− 5 M) on the intracellular Ca2+ concentration ([Ca2+]i) of cultured myenteric neurons. ACh evoked a response in 48.6% of the neurons. This response consisted of a fast and a slow component, respectively mediated by nicotinic and muscarinic receptors, as revealed by specific agonists and antagonists. Substance P evoked a [Ca2+]i rise in 68.2% of the neurons, which was highly dependent on Ca2+ release from intracellular stores, since after thapsigargin (5 μM) pretreatment only 8% responded. The responses to serotonin, present in 90.7%, were completely blocked by ondansetron (10− 5M), a 5-HT3 receptor antagonist. Specific agonists of other serotonin receptors were not able to induce a [Ca2+]i rise. Removing extracellular Ca2+ abolished all serotonin and fast ACh responses, whereas substance P and slow ACh responses were more persistent. We conclude that ACh-induced signaling involves both nicotinic and muscarinic receptors responsible for a fast and a more delayed component, respectively. Substance P-induced signaling requires functional intracellular Ca2+ stores, and the 5-HT3 receptor mediates the serotonin-induced Ca2+ signaling in cultured myenteric neurons.

In patients with gastroesophageal reflux disease (GERD), transient lower esophageal sphincter relaxations (TLESRs) are more frequently accompanied by acid reflux than in normals. The role of esophageal tone during gastroesophageal reflux events is unknown. We studied the tonic motor activity in the body of the esophagus during TLESRs with and without acid reflux in 11 patients with erosive esophagitis and compared the results with those previously obtained in healthy subjects. Esophageal peristaltic contractions were recorded 13, 8, and 3 cm above a sleeve that measured LES pressure. An intraluminal balloon was inflated 8 cm above the sleeve to induce an esophageal tonic contraction [artificial high pressure zone (HPZ)]. The percentage of TLESRs with acid reflux was significantly higher in patients with esophagitis than in healthy controls (58.3% vs 37.3%, P < 0.05). TLESRs per se were not associated with an inhibition or increase in esophageal body contractility, which, however, changed substantially immediately after reflux. In patients with esophagitis the esophageal body tonic contractility was inhibited in 59.5% of TLESRs vs 36% in controls (P < 0.05). Esophageal contractions during TLESRs traveled down the esophagus in 77% of the instances in patients vs 96.5% in controls (P < 0.05). In conclusion, gastroesophageal reflux during TLESRs was more frequently associated with inhibition of esophageal body tonic contractility in patients with esophagitis than in normals. The different response of the esophageal body to reflux observed in GERD patients may partially contribute to the higher prevalence of reflux during TLESRs in these patients.

Some methodological in vitro observations concerning bile reflux monitoring (Bilitec) suggested that Bilitec monitoring is underestimating reflux in an acid environment. Moreover, other studies showed that the area above the cutoff level of bilirubin absorbance would provide an adequate quantitative marker for reflux of duodenal contents. Our aim was to study whether correction for intraesophageal acidity and the area above cutoff during Bilitec monitoring affects the results and the correlation with pH measurement and esophageal lesions. In 84 patients (46 men; mean age 46 +/- 2.7 years) evaluated for suspected gastroesophageal reflux disease, we performed ambulatory 24-hr esophageal pH and Bilitec monitoring after an upper gastrointestinal endoscopy. We obtained total area, percent total time, and correction by computer software. The correction factor for bilirubin absorbance was based on literature data for acidified bile (0.06 for pH < 3.6; 0.21 for pH < 2.6). Endoscopy revealed esophagitis grade 1-2 (E1-2) and 3-4 (E3-4) in 23 and 16 patients, respectively. A progressive increase of mixed (acid + bile) reflux occurred with increasing severity of endoscopic lesions (E3-4 vs no esophagitis, P < 0.05). A pathologic Bilitec monitoring result was present in the same 35 patients before and after correction and the correlation between the pH measurement and percent time of bile reflux was not improved by correction for intraesophageal pH (r = 0.386 and r = 0.391; P < 0.05). The total area of bilirubin absorbance above 0.14 (abs x min) was 7.8 +/- 2.2 in patients without esophagitis, and 11.7 +/- 4.4 and 17.0 +/- 4.2 in the E1-2 and E3-4 groups, respectively (E3-4 vs no esophagitis, P < 0.05). The correlation between the Bilitec monitoring and pH measurement regarding percent (r = 0.427, P < 0.01) or area of time below 4 (r = 0.280, P < 0.05) was not improved by considering the area of bilirubin absorbance above the cutoff level. Correction for intraesophageal pH has only a minor effect on the results of ambulatory Bilitec monitoring. Taking into account the surface rather than the percent of time above the cutoff level for bilirubin absorbance does not improve the correlation of Bilitec with acid reflux and with esophageal lesions.

This work describes the design and realization of a low voltage single-chip wireless transceiver front-end in a standard 0.25 μm CMOS technology. The presented prototype integrates the LNA, down-converters, VCO, quadrature generator, up-converter and pre-amplifier on a single die. A high level of integration is achieved by using a low-IF topology for reception, a direct quadrature up-conversion topology for transmission and an oscillator with on-chip integrated inductor. The final objective of this design is to develop a complete transceiver system for wireless communications at 1.8 GHz that can be built with a minimum of surrounding components: only an antenna, a duplexer, a power amplifier and a baseband signal processing chip. The presented circuit consumes 240 mW from a 2.5 V supply and occupies a die area of 8.6\,\hbox{mm}^{2}.