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Background: Efficient fat digestion requires fat processing within the stomach and fat sensing in the intestine. Both processes also control gastric emptying and gastrointestinal secretions. Objective: We aimed to visualize the influence of the intragastric stability of fat emulsions on their dynamics of gastric processing and structuring and assess the effect this has on gastrointestinal motor and secretory functions. Design: Eighteen healthy subjects with normal body mass index (BMI) were studied on 4 separate occasions in a double-blind, randomized, crossover design. Magnetic resonance imaging (MRI) data of the gastrointestinal tract and blood triglycerides were recorded before and for 240 min after the consumption of the following 4 different fat emulsions: lipid emulsion 1 (LE1; acid stable, 0.33 mm), lipid emulsion 2 (LE2; acid stable, 52 mm), lipid emulsion 3 (LE3; acid unstable, solid fat, 0.32 mm), and lipid emulsion 4 (LE4; acid unstable, liquid fat, 0.38 mm). Results: The intragastric emulsion instability was associated with a change in gastric emptying. Acid-unstable emulsions exhibited biphasic and faster emptying profiles than did the 2 acid-stable emulsions (P # 0.0001). When combined with solid fat (LE3), different dynamics of postprandial gallbladder volume were induced (P # 0.001). For acidstable emulsions, a reduction of droplet size by 2 orders of magnitude [LE1 (0.33 mm) compared with LE2 (52 mm)] delayed gastric emptying by 38 min. Although acid-stable (LE1 and LE2) and redispersible (LE4) emulsions caused a constant increase in blood triglycerides, no increase was detectable for LE3 (P , 0.0001). For LE3, MRI confirmed the generation of large fat particles during gastric processing, which emptied into and progressed through the small intestine. Conclusions: MRI allows the detailed characterization of the in vivo fate of lipid emulsions. The acute effects of lipid emulsions on gastric emptying, gallbladder volume, and triglyceride absorption are dependent on microstructural changes undergone during consumption. Gastric peristalsis and secretion were effective at redispersing pools of liquid fat in the stomach. This trial was registered at clinicaltrials.gov as NCT01253005. Am J Clin Nutr doi: 10.3945/ajcn.114.100263.

Background: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular “Nottingham test meal” (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. Methods: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar-beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. Key Results: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45±20). The NTM produced normal postprandial fullness (VAS ≥30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS ≥30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. Conclusions and Inferences: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

The gastric accumulation of enteral formulas in tube-fed patients leads to an increased risk of vomiting and regurgitation. Gastric secretion-induced coagulation of proteins in enteral formulas might lead to gastric accumulation of solid protein particles that further increase the risk of upper digestive intolerance. This study used magnetic resonance imaging to noninvasively assess the half-emptying time (t50) of enteral formulas differing in protein composition.Three isocaloric (450 kcal) and isovolumetric (300 mL) enteral formulas, 1 with a noncoagulating P4 protein blend and 2 with coagulating casein-dominant protein blends, were compared in a double-blind, randomized, 3-way crossover study in 21 healthy volunteers. Gastric content emptying curves were fitted with the LinExp model to compute t50 and the parameter κ with κ1 reflecting the accumulation of gastric secretion. t50 and κ were compared between all 3 enteral formulas. The formula that emptied fastest was identified by an ordinal mixed model using the ranks of t50.As indicated by values for κ1, all enteral formulas induced gastric secretion. No differences were detected for t50. However, the noncoagulating formula emptied fastest in 74% of all participants (P = .004).This study demonstrates that a noncoagulating enteral formula can empty faster from the stomach compared with coagulating formulas in a large cohort of healthy volunteers. Investigations on the efficiency of the noncoagulating P4 protein blend in patients requiring tube feeding will further elucidate its potential for reducing upper digestive intolerance during enteral nutrition. Trial NTR2979.

Background: Limited information exists on the relation between fat emulsion structure and its effect on the release of gastrointestinal hormones and feelings of satiation.Objective: We investigated the impact of fat emulsion droplet size, gravitational and acid stability, and redispersibility on gastrointestinal responses and sought to deduce the relative importance of the hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and peptide YY (PYY) in controlling fat emptying and related satiation.Methods: Within a randomized, double-blind, 4-armed crossover study, an extensive data set was generated by MRI of gastric function, analysis of hormone profiles, and ratings of satiation in healthy participants [10 women and 7 men with a mean ± SD age of 25 ± 7 y and body mass index (in kg/m2) of 22 ± 1] after intake of 4 different fat emulsions. Iterative Bayesian model averaging variable selection was used to investigate the influence of hormone profiles in controlling fat emulsion emptying and satiation.Results: The emulsion structure had a distinct effect on the gastric emptying (primary outcome), gastrointestinal hormone profiles, and ratings of satiation (secondary outcomes). Gravitational and acid stability were stronger modulators of fat emptying and hormone profiles than were emulsion droplet size or redispersibility. Cholecystokinin and PYY were most strongly affected by fat emulsion instability and droplet size. Although both hormones were relevant predictors of gastric emptying, only PYY was identified as a relevant predictor of satiation.Conclusions: This work indicates that evenly dispersed, stable, small-emulsion droplets within the stomach lead to prolonged gastric distension, longer ghrelin suppression, and accelerated fat sensing (cholecystokinin and PPY), triggering prolonged feelings of satiation. It suggests that the effects of emulsion instability and droplet size on energy consumption are best studied by assessing changes in gastric emptying and ratings of satiation rather than changes in venous hormone profiles. This trial was registered at clinicaltrials.gov as NCT01253005.

Purpose: The purpose of this work was to evaluate the potential of substituting autogenous bone (AB) by bone marrow aspirate concentrate (BMAC). Both AB and BMAC were tested in combination with a bovine bone mineral (BBM) for their ability of new bone formation (NBF) in a multicentric, randomized, controlled, clinical and histological noninferiority trial.Materials and Methods: Forty-five severely atrophied maxillary sinus from 26 patients were evaluated in a partial cross-over design. As test arm, 34 sinus of 25 patients were augmented with BBM and BMAC containing mesenchymal stem cells. Eleven control sinus from 11 patients were augmented with a mixture of 70% BBM and 30% AB. Biopsies were obtained after a 3-4-month healing period at time of implant placement and histomorphometrically analyzed for NBF.Results: NBF was 14.3%+/- 1.8% for the control and nonsignificantly lower (12.6%+/- 1.7%) for the test (90% confidence interval: -4.6 to 1.2). Values for BBM (31.3%+/- 2.7%) were significantly higher for the test compared with control (19.3%+/- 2.5%) (p Conclusions: NBF after 3-4 months is equivalent in sinus, augmented with BMAC and BBM or a mixture of AB and BBM. This technique could be an alternative for using autografts to stimulate bone formation.

Background Magnetic resonance (MR) imaging provides direct, non-invasive measurements of gastric function and emptying. The inter-observer variability (IOV) of MR volume measurements and the most appropriate analysis of MR data have not been established. To assess IOV of total gastric volume (TGV) and gastric content volume (GCV) measurements from MR images and the ability of standard power exponential (PowExp), and a novel linear exponential (LinExp) model to describe MR data. Methods Ten healthy volunteers received three different volumes of a liquid nutrient test meal (200–800 mL) on 3 days in a randomized order. Magnetic resonance scans were acquired using a 1.5T system every 1–5 min for 60 min. Total gastric volume and GCV were measured independently by three observers. Volume data were fitted by PowExp and LinExp models to assess postprandial volume change and gastric emptying half time (T50). Key Results An initial rise in GCV and TGV was often observed after meal ingestion, thereafter GCV and TGV decreased in an approximately linear fashion. Inter-observer variability decreased with greater volumes from 12% at 200 mL to 6% at 600 and 800 mL. Inter-observer variability for T50 was

Aim To assess whether differences occur in bone formation after maxillary sinus floor elevation surgery with bovine bone mineral (BioOss (R)) mixed with autogenous bone or autogenous stem cells. The primary endpoint was the percentage of new bone three months after the elevation procedure. Material and methods In a randomized, controlled split-mouth design, in 12 consecutive patients (age 60.8 +/- 5.9 years, range 48-69 years) needing reconstruction of their atrophic maxilla, a bilateral sinus floor augmentation procedure was performed. Randomly, on one side the augmentation procedure was performed with bovine bone mineral (BioOss (R)) seeded with mononuclear stem cells harvested from the posterior iliac crest (test group) while BioOss (R) mixed with autogenous bone (harvested from the retromolar area) was applied on the contra-lateral side (control group). On 14.8 +/- 0.7 weeks after the sinus floor elevation, biopsies from the reconstructed areas were taken at the spots where subsequently the endosseous implants were placed. The biopsies were histomorphometrically analyzed. Results Significantly more bone formation was observed in the test group (17.7 +/- 7.3%) when compared with the control group (12.0% +/- 6.6; P=0.026). In both the test and control group, all implants could be placed with primary stability. In one patient, not all biopsies contained BioOss (R). This patient was excluded from analysis. Conclusion Mesenchymal stem cells seeded on BioOss (R) particles can induce the formation of a sufficient volume of new bone to enable the reliable placement of implants within a time frame comparable with that of applying either solely autogenous bone or a mixture of autogenous bone and BioOss (R). This technique could be an alternative to using autografts. To cite this article: Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM. Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial.Clin. Oral Impl. Res. 22, 2011; 251-258.doi: 10.1111/j.1600-0501.2010.01981.x.

Summary Background Gastro-oesophageal reflux disease (GERD) is an important problem in systemic sclerosis due to impaired salivation and oesophageal function. Aim To determine the efficacy of adding ranitidine at bedtime to control nocturnal acid breakthrough (NAB) and GERD in patients with systemic sclerosis already prescribed high-dose omeprazole. Methods Patients with systemic sclerosis and GERD symptoms (n = 14) were treated with omeprazole 20 mg b.d. and either placebo or ranitidine 300 mg at bedtime for 6 weeks in a randomized, cross-over, placebo controlled study. At the end of each period a 24 h pH-study with intragastric and oesophageal pH measurement was performed. Results Pathological acid reflux occurred in eight patients with omeprazole/placebo and in seven with omeprazole/ranitidine (P = ns) with technically adequate oesophageal pH-studies (n = 13). NAB was present in eight patients with omeprazole/placebo and six with omeprazole/ranitidine (P = ns) in whom technically adequate gastric pH-studies were obtained (n = 10). The addition of ranitidine had no consistent effect on patient symptoms or quality of life. Conclusion Many patients with systemic sclerosis experienced NAB and pathological oesophageal acid exposure despite high-dose acid suppression with omeprazole b.d. Adding ranitidine at bedtime did not improve NAB, GERD or quality of life in this population.

Background 13C-acetate breath testing (BT) is applied to assess and compare gastric emptying of liquid meals. Gastric half-emptying times (t50) from BT show offsets compared to t50 values from γ-scintigraphy and ultrasonography. Linear transformations have been proposed to correct these offsets. This investigation critically validates the BT for the assessment of liquid gastric emptying by using simultaneously recorded meal and total gastric content volume emptying data from magnetic resonance imaging (MRI). Methods Data were collected during a recently published double-blind, randomized, cross-over MRI gastric emptying study of three 13C-labeled enteral formulas differing in protein sources (PMID: 24699556). Breath testing-derived t50 was computed with the analysis methods commonly applied in gastric emptying research, i.e., the exponential-beta function and the Wagner–Nelson (WN) method, respectively. Key Results Breath testing t50 values from exponential-beta function and WN method showed a positive and negative offset to MRI data, respectively. Linear regression detected low concordance between MRI and both BT methods revealing meal specific and emptying rate-dependent offsets. The WN method showed worse agreement and correlation with MRI emptying data. Breath testing rather reflected meal volume than total gastric content volume emptying. Conclusions & Inferences This validation study indicates that the 13C-acetate breath test may not be applied to compare gastric emptying of arbitrary liquid meals without prior validation by imaging methods. t50 values from BT are biased by (i) the properties of the meal and (ii) the selected method used for 13CO2 exhalation analysis. No linear transformation common for all meals was applicable to correct the offsets between BT and MRI.

Summary Background Tegaserod is a partial 5-hydroxytryptamine 4 receptor agonist with prokinetic effects on the gastrointestinal tract, its effects on oesophageal function are unknown. Aim A randomized, placebo controlled, double-blind trial assessed the effect of tegaserod on the oesophagus in healthy, asymptomatic subjects. Method A 7-day course of tegaserod 6 mg b.d. vs. placebo was prescribed (n = 17/21 completed both phases of study). High-resolution manometry and pH measurements were performed before and after a test meal. Bolus transport of liquids and solids was studied by high-resolution manometry and videofluoroscopy. Results Tegaserod had no effect on lower oesophageal sphincter pressure compared with placebo, peristaltic velocity increased (P

To quantify healthy postprandial: 1) propagation, periodicity, geometry, and percentage occlusion by distal antral contraction waves (ACWs); and 2) changes in ACW activity in relationship to gastric emptying (GE).Using 1.5-T MR scanner, nine healthy fasted volunteers were examined in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) with 500 microM Gd-DOTA. Total gastric (TGV) and meal volumes (MV) were assessed every five minutes for 90 minutes, in and interspersed with dynamic scan sequences (duration: 2.78 minutes) providing detailed images of distal ACWs.TGV increased by 738+/-38 mL after ingestion (t0), subsequently decreasing in parallel to GE. The mean GE rate and half-emptying time were 24+/-3 mL/5 minutes and 71+/-6 minutes, respectively. Accompanying ACWs reached a periodicity of 23+/-2 seconds at t35 and propagated at an unvarying speed of 0.27+/-0.01 cm/second. Their amplitude of 0.70+/-0.08 cm was constant, but the width decreased along the antral wall by 6+/-2%/cm (P=0.003). ACWs were nonocclusive (percentage occlusion 58.1+/-5.9%, t0 at the pylorus) with a reduction in occlusion away from the pylorus (P0.001). No propagation and geometry characteristics of ACWs correlated with the changes of MV (mL/5 minutes; R20.05).Our results indicate that ACWs are not imperative for emptying of liquids. This study provides a detailed quantitative reference for MRI inquiries into pharmacologically- and pathologically-altered gastric motility.

Continence problems during treatment with orlistat (a lipase inhibitor) are caused when susceptible patients are exposed to increased volumes of loose, fatty stool. Aim: To investigate the dose-response effects of loperamide on continence and anorectal function in subjects susceptible to continence problems on orlistat. Method: Ten obese subjects enterred a randomized controlled, double-blind study of loperamide at placebo, 2, 4, and 6 mg/day in a factorial design. Continence problems during orlistat treatment were self-assessed by patient diary. Anorectal function and continence were assessed by barostat, manometry, and retention testing. Results: Loperamide increased stool consistency with dose (p = 0.07) and this effect reduced continence problems during orlistat treatment (p < 0.05). A bell-shaped dose-response relationship was present with anal sphincter function (p < 0.01) and anorectal sensitivity (p < 0.01). Conclusion: Loperamide has beneficial effects on stool consistency and continence in obese subjects taking orlistat. The effect on stool consistency appeared more important than effects on anorectal function.

The intermittent loss of oil or stool (“spotting”) is an adverse effect that occurs in patients taking orlistat; the pathophysiology is unknown. This study was designed to investigate the local effects of orlistat, free fatty acids, and the effects of the physical properties of rectal contents on anorectal function and continence. Anorectal physiology and continence function were assessed in ten healthy patients after the application of four test enemas: 1) high-viscosity stool substitute, 2) stool substitute with free fatty acid, 3) low-viscosity oil with placebo, 4) oil with orlistat. Rectal function and capacity were assessed by barostat techniques. Anal resting pressure, squeeze pressure, and squeeze duration were assessed by manometry. A retention test was performed using the same enemas as a quantitative assessment of continence. Orlistat and free fatty acid had no adverse effects on anorectal function or continence. For each enema, the maximum volume retained correlated with rectal capacity (r = 0.85; P < 0.01). Continence during rectal filling was better maintained for high-viscosity stool substitute than low-viscosity oil enemas (P < 0.03). Patients able to maintain effective squeeze pressure retained more of the low-viscosity enemas than those with short squeeze duration (P < 0.01); in contrast, the volume retained of high-viscosity enemas was unaffected by anal sphincter function. The physical properties of rectal contents, rectal capacity, and voluntary anal sphincter function have effects on continence function in healthy patients. The occurrence of spotting may depend on both intrinsic anorectal function and the effects of orlistat on the volume and physical properties of stool.

Summary Background : The intermittent loss of oil or liquid faeces (‘spotting’) is an adverse effect that occurs in obese patients during treatment with the lipase inhibitor orlistat; the pathophysiology is unknown. Aim : To investigate the effects of orlistat on anorectal sensorimotor function and continence. Methods : Obese subjects susceptible to spotting were identified by an unblind trial of orlistat. Obese spotters (n = 15) and non-spotters (n = 16) completed a randomized, double-blind, cross-over trial of orlistat and placebo. Anorectal function was assessed by rectal barostat and anal manometry, together with a novel stool substitute retention test, a quantitative measurement of faecal continence. Results : Orlistat increased stool volume and raised faecal fat and water. Treatment had no effect on anorectal motor function, but rectal sensation was reduced; on retention testing, the volume retained was increased. Subjects susceptible to spotting had lower rectal compliance, heightened rectal sensitivity and weaker resting sphincter pressure than non-spotters. On retention testing, gross continence was maintained; however, spotters lost small volumes of rectal contents during rectal filling. Conclusion : Treatment with orlistat has no direct adverse effects on anorectal function or continence. Spotting occurs during treatment with orlistat when patients with sub-clinical anorectal dysfunction are exposed to increased stool volume and altered stool composition.

Background Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment. Methods We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 microg/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel. Results At concentrations corresponding to two thirds of C(50 awake), motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (N(b) latency increased by 11%, amplitude P(a)N(b) did not change). In contrast, the postauricular reflex was suppressed by 77%. Conclusions The large effect of both anesthetics on all spinal motor responses, compared with the small effect on electroencephalography and middle-latency auditory evoked responses, assuming that they represent cortical modulation, may suggest that the suppression of motor responses to transcranial magnetic stimulation is largely due to submesencephalic effects.

Background A prevalent modality to increase the amount of available bone prior to implantation is grafting of the maxillary sinus. Multiple factors such as the surgical technique, moment of implant placement as well as grafting materials and membranes are known to affect implant survival. However, the role of different factor combinations and associated reciprocal effects remain unclear. Conventional statistical methods do not consider inconsistency of study designs and do not take covariables into account. Hence, a systematic research and meta-analysis was conducted to investigate the influence of various treatment modalities on implant survival in the grafted maxillary sinus. Materials and Methods A meta-analysis was conducted according to the PRISMA guidelines. Articles published from 1980 through January 2013 were electronically and manually searched in MEDLINE (Ovid), the Cochrane Register of Controlled Trials, the Database of Abstracts of Effects, and the Cochrane Database of Systematic Reviews. Clinical reports on single intervention sinus augmentation with root-form implants, a minimum of 10 patients and 6 months of loading were eligible for inclusion if implant survival was stated or calculable. Results were calculated by non-parametric univariate Kaplan-Meier analysis and Bayesian multivariate interval-censored Cox regression. Results A total of 122 publications on 16268 endosseous implants placed in grafted maxillary sinus were included. The treatment parameters surgical approach, grafting material and implant type showed no selective preference. However, application of membranes showed a significantly reduced hazard-ratio, independent of other co-factors. Conclusions The use of membranes is the most significant factor to achieve long-term implant survival in sinus augmentation procedures. More data exceeding 3 years follow-up are needed to address prospective confounding and improve clinical evidence.

This study applies concurrent magnetic resonance imaging (MRI) and high-resolution manometry (HRM) to test the hypothesis that structural factors involved in reflux protection, in particular, the acute insertion angle of the esophagus into the stomach, are impaired in gastroesophageal reflux disease (GERD) patients.A total of 24 healthy volunteers and 24 patients with mild-moderate GERD ingested a test meal. Three-dimensional models of the esophagogastric junction (EGJ) were reconstructed from MRI images. Measurements of the esophagogastric insertion angle, gastric orientation, and volume change were obtained. Esophageal function was assessed by HRM. Number of reflux events and EGJ opening during reflux events were assessed by HRM and cine-MRI. Statistical analysis applied mixed-effects modeling.The esophagogastric insertion angle was wider in GERD patients than in healthy subjects (+7° ± 3°; P=0.03). EGJ opening during reflux events was greater in GERD patients than in healthy subjects (19.3 mm vs. 16.8 mm; P=0.04). The position of insertion and gastric orientation within the abdomen were also altered (both P0.05). Median number of reflux events was 3 (95% CI: 2.5-4.6) in GERD and 2 (95% CI: 1.8-3.3) in healthy subjects (P=0.09). Lower esophageal sphincter (LES) pressure was lower (-11 ± 2 mm Hg; P0.0001) and intra-abdominal LES length was shorter (-1.0 ± 0.3 cm, P0.0006) in GERD patients.GERD patients have a wider esophagogastric insertion angle and have altered gastric morphology; structural changes that could compromise reflux protection by the "flap valve" mechanism. In addition, the EGJ opens wider during reflux in GERD patients than in healthy volunteers: an effect that facilitates volume reflux of gastric contents.

This study aimed to resolve controversy regarding the effects of Helicobacter pylori eradication therapy and H. pylori infection in gastro-oesophageal reflux disease.A randomized, double-blind, multicentre trial was performed in patients presenting with reflux symptoms. H. pylori-positive patients were randomized to receive either antibiotics or placebo for 7 days. H. pylori-negative patient controls received placebo. All received esomeprazole 20 mg b.d. for 7 days, followed by 40 mg o.d. to complete an 8-week course, and were followed up for 32 weeks by telephone.In this study, 198/589 (34%) patients were H. pylori-positive and 113 H. pylori-negative patients served as controls. Baseline endoscopy revealed 63% Los Angeles grade 0A and 37% Los Angeles grade BCD oesophagitis with no difference between patient groups. Symptom improvement on esomeprazole was seen in 89%. H. pylori eradication was successful in 82%. H. pylori eradication had no effect on symptomatic relapse (hazard ratio 1.15, 95% CI 0.74-1.8; p = 0.5). Overall, H. pylori-positive patients had a lower probability of relapse compared to H. pylori-negative controls (hazard ratio 0.6, 95% CI 0.43-0.85; p = 0.004). Relapse hazard was modulated also by oesophagitis grade (BCD vs. 0A, hazard ratio 2.1, 95% CI 1.5-3.0).Relapse of gastro-oesophageal reflux disease symptoms after a course of high dose acid suppression took longer for H. pylori-positive patients than H. pylori-negative controls; however eradication therapy had no effect on the risk of relapse; ClincialTrials.gov number, NCT00574925.

BACKGROUND A surgical knot is the key feature to assure appropriate wound support while combining tissue edges. Little evidence is available on the in vivo behavior of knots and the evaluation of knots in the living tissue. This study introduces a knot score model, which is defined by microscopic evaluation and the loop-holding capacity. MATERIALS In a double-blinded and comparative study, 3 surgeons placed 10 intramuscular single-loop sutures in the longissimus muscle group of the dorsolumbar region at each side parallel to the vertrebral column. For accomplishing the study, 72 rabbits and 3 calibers of a test and control suture were used. On the fourth day, the knot safety was assessed by microscopical and mechanical analyses for scoring and classifying the knots of the different suture materials into the defined categories for loop-holding capacity. The statistical evaluation was performed using Hodges-Lehmann rank score. A Wilcoxon test was used to estabilish a significant difference between the suture types. RESULTS When comparing Novosyn (Aesculap AG) with Vicryl (Johnson & Johnson Medical GmbH) a comparable knot safety was assessed based on a 95% confidence interval. CONCLUSIONS The new method compares the knot safety between 2 braided multifilament sutures in the living tissue. Results were discussed and examined for statistical significance.

Dynamic contrast enhanced (DCE-) MRI is commonly applied for the monitoring of antiangiogenic therapy in oncology. Established pharmacokinetic (PK) analysis methods of DCE-MRI data do not sufficiently reflect the complex anatomical and physiological constituents of the analyzed tissue. Hence, accepted endpoints such as Ktrans reflect an unknown multitude of local and global physiological effects often rendering an understanding of specific local drug effects impossible. In this work a novel multi-compartment PK model is presented, which for the first time allows the separation of local and systemic physiological effects. DCE-MRI data sets from multiple, simultaneously acquired tissues, i.e. spinal muscle, liver and tumor tissue, of hepatocellular carcinoma (HCC) bearing rats were applied for model development. The full Markov chain Monte Carlo (MCMC) Bayesian analysis method was applied for model parameter estimation and model selection was based on histological and anatomical considerations and numerical criteria. A population PK model (MTL3 model) consisting of 3 measured and 6 latent (unobserved) compartments was selected based on Bayesian chain plots, conditional weighted residuals, objective function values, standard errors of model parameters and the deviance information criterion. Covariate model building, which was based on the histology of tumor tissue, demonstrated that the MTL3 model was able to identify and separate tumor specific, i.e. local, and systemic, i.e. global, effects in the DCE-MRI data. The findings confirm the feasibility to develop physiology driven multi-compartment PK models from DCE-MRI data. The presented MTL3 model allowed the separation of a local, tumor specific therapy effect and thus has the potential for identification and specification of effectors of vascular and tissue physiology in antiangiogenic therapy monitoring., PLoS ONE, 6 (10), ISSN:1932-6203

Objective To compare the effects of drinking white wine or black tea with Swiss cheese fondue followed by a shot of cherry schnapps on gastric emptying, appetite, and abdominal symptoms. Design Randomised controlled crossover study. Participants 20 healthy adults (14 men) aged 23-58. Interventions Cheese fondue (3260 kJ, 32% fat) labelled with 150 mg sodium 13Carbon-octanoate was consumed with 300 ml of white wine (13%, 40 g alcohol) or black tea in randomised order, followed by 20 ml schnapps (40%, 8 g alcohol) or water in randomised order. Main outcome measures Cumulative percentage dose of 13C substrate recovered over four hours (higher values indicate faster gastric emptying) and appetite and dyspeptic symptoms (visual analogue scales). Results Gastric emptying was significantly faster when fondue was consumed with tea or water than with wine or schnapps (cumulative percentage dose of 13C recovered 18.1%, 95% confidence interval 15.2% to 20.9% v 7.4%, 4.6% to 10.3%; P

This study assessed the effects of meal volume (MV) and calorie load (CL) on gastric function. MRI and a minimally invasive fiber-optic recording system (FORS) provided simultaneous measurement of gastric volume and pressure changes during gastric filling and emptying of a liquid nutrient meal in physiological conditions. The gastric response to 12 iso-osmolar MV-CL combinations of a multinutrient drink (MV: 200, 400, 600, 800 ml; CL: 200, 300, 400 kcal) was tested in 16 healthy subjects according to a factorial design. Total gastric volume (TGV) and gastric content volume (GCV = MV + secretion) were measured by MRI during nasogastric meal infusion and gastric emptying over 60 min. Intragastric pressure was assessed at 1 Hz by FORS. The dynamic change in postprandial gastric volumes was described by a validated three-component linear exponential model. The stomach expanded with MV, but the ratio of GCV:MV at t0 diminished with increasing MV ( P < 0.01). Postprandial changes in TGV followed those of GCV. Intragastric pressure increased with MV, and this effect was augmented further by CL ( P = 0.02); however, the absolute pressure rise was

Gastric emptying (GE) may be driven by tonic contraction of the stomach ('pressure pump') or antral contraction waves (ACW) ('peristaltic pump'). The mechanism underlying GE was studied by contrasting the effects of clonidine (alpha(2)-adrenergic agonist) and sumatriptan (5-HT(1) agonist) on gastric function. Magnetic resonance imaging provided non-invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min(-1) IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r(2 )=49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r2=15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the 'pressure pump' mechanism.

Specific carbohydrates, i.e. prebiotics such as fructo-oligosaccharide (FOS), are not digested in the small intestine but fermented in the colon. Besides beneficial health effects of an enhanced bifidobacteria population, intestinal gas production resulting from fermentation can induce abdominal symptoms. Partial replacement with slowly fermented acacia gum may attenuate side effects. The aim was to compare the effects of FOS with those of a prebiotic mixture (50 % FOS and 50 % acacia gum; BLEND) and a rapidly absorbed carbohydrate (maltodextrin) on general intestinal wellbeing, abdominal comfort and anorectal sensory function. Twenty volunteers (eight male and twelve female; age 20–37 years) completed this double-blind, randomised study with two cycles of a 2-week run-in phase (10 g maltodextrin) followed by 5 weeks of 10 g FOS or BLEND once daily, separated by a 4-week wash-out interval. Abdominal symptoms and general wellbeing were documented by telephone interview or Internet twice weekly. Rectal sensations were assessed by a visual analogue scale during a rectal barostat test after FOS and BLEND treatment. Both FOS and BLEND induced more side effects than maltodextrin. Belching was more pronounced under FOS compared with BLEND (P = 0·09 for females; P = 0·01 for males), and for self-reported general wellbeing strong sex differences were reported (P = 0·002). Urgency scores during rectal barostat were higher with FOS than BLEND (P = 0·01). Faced with a growing range of supplemented food products, consumers may benefit from prebiotic mixtures which cause fewer abdominal side effects. Sex differences must be taken in consideration when food supplements are used.

The effects of macronutrients on gastric volume changes, emptying, and gastrointestinal symptoms are incompletely understood. Three liquid meals of 500 ml (fat emulsion, 375 kcal; protein solution, 375 kcal; glucose solution, 400 kcal) were infused into the stomach of 12 healthy volunteers on three occasions. Studies were performed in seated body position using an open-configuration magnetic resonance imaging (MRI) system. MRI imaging sequences, assessing stomach and meal volumes, were performed prior to and at times t = 0, 3, 6, 9, 12, 15, 25, 35, 45, 60, 75, and 90 min after meal administration. Areas under the curve for the early emptying phase (0–15 and 0–45 min) were calculated, and characteristics of the volume curves were analyzed by a gastric emptying model. Gastrointestinal symptoms were assessed by a self-report scale. Initial ( t = 0 min) and early postprandial gastric volumes were highest for glucose because of lower initial emptying. However, in the early emptying phase the characteristics of the volume curves for stomach and meal were uniform for all macronutrients. Perceptions of fullness and satiety were linearly associated with postprandial gastric volumes, but not with macronutrient composition. Isovolumic macronutrient meals modulate gastric volume response by initial meal emptying patterns. Macronutrient specific accommodation responses, as shown in barostat studies, are not reflected as gastric volume responses under noninvasive conditions.

G A A b st ra ct s both transcriptional levels through stimulating its classical nuclear receptors: ER α and ERβ. On the other hand, a G protein coupled receptor, GPR30 responds to estrogen with rapid signaling. Whether estrogen has a direct physiologic role in the exacerbation of GI symptoms by altering GI motility or visceral sensation has not been sufficiently explored. We designed this study to see if: a) estrogen alters GI motility and pain sensation and b) its effects are mediated by GPR30. Methods: CD1 female mice (4-5 weeks old) were used in this study. The effects of cumulative concentrations (100 nM-3μM) of β-Estradiol and a potent and selective GPR30 agonist, G-1 on the contractility of the longitudinal colonic preparations induced by electrical field stimulation (EFS; 4Hz, 10Sec, 24V, 50Sec intervals) or, at the highest concentration (3μM), on the muscarinic agonist bethanechol (10μM) induced contractions were studied in vitro. Colonic propulsion of a glass bead after administration of β-Estradiol or G-1 was studied in vivo. The effects of either compound on visceral pain, induced by intracolonic mustard oil (MO) were characterized by recording spontaneous behaviors. Results: G-1 and β-Estradiol inhibited colonic EFS and bethanechol induced contractilities. G-15, a selective GPR30 antagonist, blocked the effects of G-1 but not βEstradiol on the colonic contractility. MPP dihydrochloride, a highly selective ERα antagonist partially reversed the effects of G-1 and β-Estradiol; however, PHTPP, an ERβ antagonist, did not alter the effects of either G-1 or β-Estradiol on the colonic contractility. In vivo, βEstradiol and G-1, both at the dose of 10-20 mg. i.v., prolonged colonic propulsion. The effects of β-Estradiol on colonic propulsion were significantly reversed by G-15 (5 mg, i.v.) or MPP dihydrochloride (5 mg, i.v.). The effects of G-1 were significantly reversed by G15 and partially by the ER antagonists. The number of MO induced pain related behaviors was decreased by G-1 or β-Estradiol (20 mg, i.v.). G-15 and MPP dihydrochloride, but not PHTPP (5 mg, i.v.) reversed the effects of G-1 on visceral pain. The antinociceptive effect of β-Estradiol was only blocked by G-15 and not by ER antagonists. Conclusion: GPR30 is involved in the regulation of GI motility and visceral sensation. Our data suggests that GPR30 may be a promising target for the treatment of functional GI disorders with impaired GI motility or visceral sensation.

Introduction Increasing duration of pH studies improves consistency of GERD diagnosis but clinical utility of the method is not established. Aim: (1) to identify measurements from prolonged pH studies that discriminate healthy volunteers (HVs) and GERD patients (2) to compare prediction of PPI response from prolonged and standard measurement. Methods HVs and patients with reflux symptoms entered a prospective trial. Quality of life (RAND-36) and symptom severity (Eraflux) was assessed on and off PPI and after 2 weeks ×2/day PPI. Endoscopy recorded mucosal disease. Wireless pH system (Bravo®, Given Imaging) measured acid reflux and symptoms up to 4 days. Receiver Operating Curve (ROC) assessed prediction of PPI response. For each prediction 80% of patients were randomly selected as training set, remaining 20% constituted test set. This was repeated 200 times producing average ROC with SEs. Area under Curve (AUC) quantified quality of prediction. Results Complete data were available from 25/33 HVs (18F, age 20–56) and 70/108 patients (31F, age 18–77), >320 days in total. Oesophagitis was present in 9 HVs (32%: Grade A) and 26 patients (33%: Grade A=19, B=2, C-D=5). Acid exposure time was elevated (AET >5.6%) in 3 (12%) HVs and 35 (50%) patients. Eraflux off-PPI was >25 (consistent with GERD) in 60/63 patients and fell by mean 7 (95% CI 5 to 10) on PPI, 46% reported positive response (>3 fall). Diagnosis: Endoscopy, AET and reflux-symptom association analysis (Symptom Index (SI)) did not discriminate health/disease; but reflux-associated symptoms/day (nRS/Day) covered different ranges for HV and patients. Logistic regression with bootstrap validation identified that ≥3 RS/day corresponded to ∼50% probability that participant was a patient. PPI response: Clinical parameters and AET did not predict outcome. SI (9.2 vs 30.2, p=0.0023) and nRS/Day (1 vs 2.6, p=0.012) were higher in responders. RAND-36 scores for poor physical role and pain were higher in non-responders (p∼0.1). SI ROC had an AUC of 0.73 (CI 0.51 to 0.92). SI >25 was the optimal cut-off for identifying PPI responders (Abstract PTU-197 figure 1). Prediction quality from 24 h studies was lower (AUC 0.69) and CIs for all parameters were wider with lower CI. Conclusion Diagnostic consistency for all parameters increases with study duration. A simple count of nRS/Day best discriminates HVs from patients on pH studies. SI >25 provides single best prediction of PPI response; but quality of predictions was modest in this population with low PPI response. Competing interests None declared.

Background The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. Methods A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. Key Results The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal–air interface, forming a ‘secretion layer’ in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. Conclusions & Inferences The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric ‘acid pocket’.

Introduction Previous studies suggest that prolonged ambulatory reflux monitoring can improve measurement consistency; however, previous reports were not analysed appropriately or adequately powered to determine the impact on key clinical parameters. The aim of this study was to assess measurement consistency for acid exposure time (AET) and symptom association with reflux events used to establish the diagnosis of GORD. Methods Acid reflux (pH) and symptom data were acquired by prolonged, 4 day, wireless pH recording (Bravo, Given Imaging). 163 consecutive patients presenting with predominantly typical reflux symptoms (heartburn, regurgitation) studied 2006–2009 with a record duration of >3.7 days were studied (636 days). Data were exported in XML format, redundant symptom markers were removed in one pass with reflux detection. A cross-validation procedure assessed measurement variability (standard deviation (SD)) and diagnostic consistency of AET, symptom index (SI) and symptom association probability (SAP). The 4-day records were divided into 1-day sections and re-assembled as all possible subsets. Index parameters were computed for all subsets and labelled with a sequence identifier in the database. Bias due to self-referential comparisons was excluded (i.e., day 1 was not compared with day 123) and, also, no comparisons with 4-day results are given. Standard diagnostic thresholds were applied. In addition, the effect of varying threshold pH value used for reflux detection on diagnostic consistency was assessed. Results Measurement variability: There was no change in AET or SI over time; however, SAP increased progressively with study duration. Standard deviation (SD) was higher for 1-day than 3-day records for AET (+50% (confidence interval (CI): 10%…120%)) and SI (+100% (CI 120%…270%)) with no important difference across the observed range. Results for 2 days were intermediate. Similar findings were present for SAP (1 day vs 3 days at 95% SAP (+100% (CI 10%…700%); however, for this parameter measurement variability increased exponentially as SAP approached 100%. Diagnosis: Consistency for GORD diagnosis increased with study duration (table 1) for all parameters studied. Conclusion Increasing the duration of reflux studies progressively improves diagnostic consistency for GORD based on both AET and reflux-symptom association analysis independent of diagnostic threshold applied.

Introduction The diagnosis of gastro-oesophageal reflux disease (GORD) by ambulatory reflux monitoring is based on oesophageal acid exposure time (AET) or temporal association of reflux events with patient symptoms. Several key issues required for reflux-symptom association, such as the most appropriate pH threshold and time window, have not been defined and current statistical analysis has important limitations: Symptom Index (SI) is a measure of an effect size, not of confidence. Symptom Association Probability (SAP) is a measure of confidence but not of size and applies the Fisher exact test inappropriately (dividing time into fixed intervals does not produce independent counts). This study presents a systematic assessment of symptom association in ambulatory gastro-oesophageal reflux monitoring data. Methods Acid reflux (pH) and symptom data were acquired by wireless pH recording (Bravo, Given Imaging). 163 consecutive patients presenting with predominantly typical reflux symptoms (heartburn, regurgitation) studied 2006–2009 with duration >3.7 days were studied (636 days). Data were exported in XML format, and analyzed by custom written program. A systematic analysis was performed. Results (1) Symptom markers A finite-state algorithm was developed to equalise patient responses, removing redundant markers in one pass with reflux detection. (2) pH threshold: Setting pH thresholds for reflux detection is not physiological and a weighted S-shaped (‘dose response9) curve could be more appropriate. This was assessed varying the centre and steepness of the curve to maximise association with SI and SAP. A steep S-curve almost indistinguishable to a threshold was found: maximum correlation SI pH threshold 4.5, correlation 0.55; SAP pH threshold 4.4, correlation 0.34. (3) time window: The frequency of reflux associated symptom markers was above baseline only during minute 1. The association in minute 2 was no higher than chance. (4) Over time (day 1–4) SI was stable; however SAP increased progressively. Both parameters increased with the frequency of reflux events. CI for SI were computed by assuming a binomial distribution (Agresti-Coull method). Conclusion A novel approach to symptom association of ambulatory reflux monitoring data is presented. Confounding due to redundant symptom markers is removed by a finite-state algorithm. Acid threshold of pH 4.5 and a time window of 1 min provided optimal correlation with SI. Computing SI with CI provides a statistically valid, single parameter that describes both size of effect and likelihood of association between reflux events and symptoms.

Transnasal, Ultrathin Endoscopy for the Placement of Nasoenteral Feeding Tubes in Critically Ill Patients: Does the Working Length of the Endoscope Matter? First Results Stephan Wildi, Christoph Gubler, Stephan Vavricka, Dieter Menne, Michael Fried, Peter Bauerfeind Background: Early enteral feeding may improve outcomes in critically ill patients. Transnasal endoscopy with an ultrathin endoscope has been shown to be helpful for the placement of nasoenteral feeding tubes in these patients. Success rates were limited by the short working length of the ultrathin endoscopes. Aim: To compare the success rate of a 133 cm-long, ultrathin video-endoscope with a standard 92.5 cm-long, ultrathin, fiberoptic endoscope for the transnasal placement of nasoenteral feeding tubes. Methods: Critically ill patients were randomly assigned to transnasal feeding tube placement with the standard 92.5 cm-long, ultrathin, fiberoptic endoscope (Olympus GIF-N30) or a new 133 cmlong, ultrathin, prototype video-endoscope (Olympus XGIF-N140Y). Patients characteristics, procedure time, technical difficulties, patient tolerance, and radiologic tube position were assessed. Results: To date, 89 patients (29 women; mean age 51.8, range 20-81) were analyzed. The two groups were similar with regard to patients characteristics, body length, technical difficulty and patient tolerance. So far, the 133 cm-long instrument tended to be superior with respect to successful placement of the nasoenteral feeding tube (90% vs. 76%). Procedure time tended to be longer with the 133 cm-long instrument (557sec vs. 462sec). Conclusions: This ongoing study demonstrates that placement of a nasoenteral feeding tube with a 133 cm-long, ultrathin video-endoscope is safe and tends to be more successful than with 92.5 cm-long, ultrathin, standard instrument. Abstracts