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Blueberries beneficially modulate physiologic mechanisms relevant to the pathogenesis of functional gastrointestinal disorders (FGID). Forty-three patients with FGID received freeze-dried blueberries (equivalent to 180 g fresh blueberries) or sugar and energy-matched placebo in a double-blind, randomized, cross-over study. After 6 weeks of treatment, the differences in Gastrointestinal Clinical Rating Scale (GSRS) scores and abdominal symptom relief were compared as primary outcome measures. The quality of life and life functioning ratings (OQ45.2 questionnaire), Bristol stool scales, and fructose breath test results constituted secondary outcome measures. Blueberry treatment resulted in more patients with relevant abdominal symptom relief compared to placebo (53% vs. 30%, p = 0.03). Total and pain GSRS scores improved insignificantly (mean treatment differences [95% CI]: -3.4 [-7.4 to 0.6] ( p = 0.09) and -1.0 [-2.2 to 0.1] ( p = 0.08), respectively). OQ45.2 scores improved during blueberry treatment compared to placebo (treatment difference -3.2 [95% CI: -5.6 to -0], p = 0.01). Treatment effect differences for the further measures did not reach statistical significance. Blueberries relieved abdominal symptoms and improved general markers of well-being, quality of life, and life functioning more than placebo in patients with FGID. Consequently, the polyphenol and fiber components of blueberries exert broad beneficial effects separate from the sugars present in both treatments.

Introduction: Patients with functional gastrointestinal disorders (FGIDs) are classified based on their gastrointestinal (GI) symptoms, without considering their frequent extra-GI symptoms. This study defined subgroups of patients using both GI and extra-GI symptoms and examined underlying mechanisms with fructose and lactose breath tests., Methods: Latent class analysis defined distinct clusters of patients with FGID based on their long-term GI and extra-GI symptoms. Sensory and breath gas responses after fructose and lactose ingestion were compared across symptom clusters to investigate differences in sensory function and fermentation by intestinal microbiota., Results: Six symptom clusters were identified in 2,083 patients with FGID. Clusters were characterized mainly by GI fermentation-type (cluster 1), allergy-like (cluster 2), intense pain-accentuated GI symptoms (cluster 3), central nervous system (cluster 4), musculoskeletal (cluster 5), and generalized extra-GI (cluster 6) symptoms. In the 68% of patients with complete breath tests, the areas under the curve of GI and central nervous system symptoms after fructose and lactose ingestion differed across the clusters (P < 0.001). The clusters with extensive long-term extra-GI symptoms had greater symptoms after the sugars and were predominantly women, with family or childhood allergy histories. Importantly, the areas under the curves of hydrogen and methane breath concentrations were similar (P > 0.05) across all symptom clusters. Rome III criteria did not distinguish between the symptom clusters., Discussion: Patients with FGID fall into clusters defined extensively by extra-GI symptoms. Greater extra-GI symptoms are associated with evidence of generalized sensory hypersensitivity to sugar ingestion, unrelated to intestinal gas production. Possible underlying mechanisms include metabolites originating from the intestinal microbiota and somatization.

Objectives: Mast cell involvement is evident in functional gastrointestinal disorders (FGID). FGID and mast cell activation syndrome (MCAS) are associated with multi-organ symptoms. An overlap has not been assessed. Methods: MCAS symptoms were determined by questionnaires in 2083 FGID patients. Results: The median number of MCAS symptoms ([IQR] (range 0-16)) was 6 [4-8] in all FGID, and in functional dyspepsia (FD) patients, 7 [5-9] in overlapping irritable bowel syndrome and FD (IBS+FD), 5 [3-8] in IBS and 5 [3-6] in non-IBS/non-FD ( p  < .001 vs. FD and IBS + FD) patients. MCAS symptoms in ≥2 organ-systems existed in 1773 (85%) of all patients. Conclusions: MCAS symptoms are common in FGID warranting further mechanistic investigation.

Background: Breath tests are used as measures of sugar intolerance or malabsorption in patients with functional gastrointestinal disorders (FGID), although the repeatability or anticipatory bias have not been adequately studied. We examined the repeatability and anticipatory bias during fructose breath testing using a nocebo-controlled, randomized, cross-over, and double-blind study design., Methods: Gastrointestinal symptoms and breath concentrations of hydrogen and methane were documented during breath tests with fructose (given open twice and blinded once), water (blind neutral nocebo) and a cyclamate/saccharine sweetener (blind sweet nocebo) on 5 days in patients with FGID. Repeatability of fructose breath tests (16 patients) and differences between open and blinded substrate groups (31 patients) was assessed using thresholds for intolerance and malabsorption, and areas-under-the-curve (AUC) of symptoms and breath gas concentrations., Key Results: Fructose breath tests showed moderate repeatability for intolerance status (absolute agreement 87%, kappa 0.72), but limited repeatability for malabsorber status (absolute agreement 53%, kappa 0.05). Repeatability of AUCs of GI symptoms, hydrogen and methane breath concentrations was moderate (intraclass correlation coefficients 0.70, 0.57, and 0.57, respectively). There were no significant differences between open and blinded fructose breath tests in intolerance or malabsorber status, or in AUCs of GI symptoms, hydrogen and methane concentrations., Conclusions & Inferences: Fructose breath tests showed moderate repeatability for intolerance status and for AUCs of symptoms and gas concentrations, lying within the range of accepted gastrointestinal sensory and transit tests. Repeatability for malabsorption status was inadequate and requires revisiting. The fructose breath test can be used unblinded in FGID., (© 2018 John Wiley & Sons Ltd.)

Background & Aims: Functional gastrointestinal disorders (FGID) are defined by broad phenotypic descriptions and exclusion of recognizable disease. FGIDs cause multi-organ symptoms and abnormal results in a wide range of laboratory tests, indicating broad mechanisms of pathogenesis. Many patients with FGID develop symptoms following ingestion of fermentable sugars; we investigated the associations between symptoms and intestinal gas production following sugar provocation tests to elucidate mechanisms of FGID., Methods: We performed fructose and lactose breath tests in 2042 patients with a diagnosis of FGID (based on Rome III criteria), referred to a gastroenterology practice from January 2008 through December 2011. Medical and diet histories were collected from all subjects. Breath samples were collected before and each hour after, for 5 hours, subjects ingested fructose (35 g) and lactose (50 g) dissolved in 300 mL water. Hydrogen and methane gas concentrations were measured and GI and non-GI symptoms were registered for 5 hours following sugar ingestion. Symptom and gas time profiles were compared, treelet transforms were used to derive data-related symptom clusters, and the symptom severity of the clusters were analyzed for their association with breath gas characteristics., Results: We identified 11 GI and central nervous system (CNS) symptom profiles and hydrogen and methane breath concentrations that changed significantly with time following sugar ingestion. Treelet transform analysis identified 2 distinct clusters, based on GI and CNS symptoms. The severity scores for the GI and CNS symptoms correlated following ingestion of sugars (all, P < .0001). However, only the GI symptoms associated with hydrogen and methane gas production (all, P < .0001)., Conclusions: In an analysis of breath test results from more than 2000 patients with FGIDs, we identified clusters of GI and CNS symptoms in response to fructose of lactose ingestion. The association between specific symptoms and breath gas concentrations indicate distinct mechanisms of FGID pathogenesis, such as changes in the microbiome or mechanical and chemical sensitization. ClinicalTrials.gov ID: NCT02085889., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is associated with changes in the intestinal microbiome and methane-producing archaea may be involved in energy homeostasis., Objective: The objective of this article is to investigate the associations between intestinal methane production, waist circumference and body mass index (BMI) as biomarkers for obesity., Methods: Breath methane and hydrogen concentrations were measured over five hours following fructose or lactose ingestion in 1647 patients with functional gastrointestinal disorders. The relationships between gas concentrations and measures of obesity were investigated by stratifying gas concentration-time profiles by BMI and waist circumference, and, conversely, BMI and waist circumference by peak breath hydrogen and methane concentrations., Results: Following fructose ingestion, patients with lower BMI and lesser waist circumference had greater breath methane concentrations (all p  < 0.003). Conversely, patients with increased methane concentrations had lower BMI ( p  < 0.001) and waist circumference ( p  = 0.02). After lactose ingestion, BMI and waist circumference were not associated with significant differences in methane. However, greater methane concentrations were associated with a lower BMI ( p  < 0.002), but not with waist circumference., Conclusion: In this large group of patients mainly negative associations between breath methane concentrations and anthropometric biomarkers of obesity were evident. Studies investigating microbial methane production and energy homoeostasis in different populations are of substantial interest to distinguish epiphenomena from true causality.A follow-up study was registered at Clinical trials.gov NCT02085889.

Background: Approximately 60% of patients presenting to dentists with erosive tooth wear have significant gastroesophageal reflux (GERD), despite minor reflux symptoms. No longitudinal studies of reflux-associated erosive tooth wear and of reflux characteristics have been reported to date. The aim of this study was to characterize the longitudinal course of GERD and of associated erosive tooth wear, as well as factors predictive of its progression, in a large group of patients., Methods: Seventy-two patients presenting to dentists with clinically significant erosive tooth wear and increased esophageal acid exposure by 24-h multichannel intraluminal pH-impedance measurement (MII-pH) were re-assessed clinically and by MII-pH after 1 year treatment with esomeprazole 20 mg twice-daily. Predictive factors for erosive tooth wear were assessed by logistic regression., Results: At follow-up, no further progression in erosive tooth wear was observed in 53 (74%) of patients. The percentage of time with a pH < 4, the number of acid reflux episodes and the percentage of proximal esophageal reflux off-PPI did not change significantly after one year, but the number of weakly acidic reflux episodes decreased significantly in the large subgroup without progression. None of the baseline demographic, clinical, endoscopic or esophageal acid exposure characteristics were significantly associated with progression of erosive tooth wear at follow-up., Conclusions: In this longitudinal study in patients with erosive tooth wear and oligosymptomatic GERD receiving esomeprazole for one year, erosive tooth wear did not progress further in the majority of patients. Background acidic esophageal reflux exposure appeared stable over time, whereas weakly acidic exposure decreased significantly in patients without erosion progression. MII-pH measurements on-PPI and with healthy controls will be useful in the further elucidation of the causal role of reflux in erosive tooth wear., Trial Registration: ClinicalTrials.gov , retrospectively registered: NCT02087345 .

Background: Diets low in fermentable sugars (low-FODMAP diets) are increasingly adopted by patients with functional gastrointestinal disorders (FGID), but outcome predictors are unclear., Aim: To identify factors predictive of an efficacious response to a low-FODMAP diet in FGID patients with fructose or lactose intolerance thereby gaining insights into underlying mechanisms., Methods: Fructose and lactose breath tests were performed in FGID patients to determine intolerance (positive symptom score) and malabsorption (increased hydrogen or methane concentrations). Patients with fructose or lactose intolerance consumed a low-FODMAP diet and global adequate symptom relief was assessed after 6-8 weeks and correlated with pre-diet clinical symptoms and breath test results., Results: A total of 81% of 584 patients completing the low-FODMAP diet achieved adequate relief, without significant differences between FGID subgroups or types of intolerance. Univariate analysis yielded predictive factors in fructose intolerance (chronic diarrhoea and pruritus, peak methane concentrations and fullness during breath tests) and lactose intolerance (peak hydrogen and methane concentrations and flatulence during breath tests). Using multivariate analysis, symptom relief was independently and positively predicted in fructose intolerance by chronic diarrhoea [odds ratio (95% confidence intervals): 2.62 (1.31-5.27), P = 0.007] and peak breath methane concentrations [1.53 (1.02-2.29), P = 0.042], and negatively predicted by chronic nausea [0.33 (0.16-0.67), P = 0.002]. No independent predictive factors emerged for lactose intolerance., Conclusions: Adequate global symptom relief was achieved with a low-FODMAP diet in a large majority of functional gastrointestinal disorders patients with fructose or lactose intolerance. Independent predictors of a satisfactory dietary outcome were only seen in fructose intolerant patients, and were indicative of changes in intestinal host or microbiome metabolism., (© 2017 John Wiley & Sons Ltd.)

Background: The MRI scanner environment induces marked psychological effects, but specific effects on pain perception and processing are unknown and relevant to all brain imaging studies., Objectives and Methods: We performed visceral and somatic quantitative sensory and pain testing and studied endogenous pain modulation by heterotopic stimulation outside and inside the functional MRI scanner in 11 healthy controls and 13 patients with irritable bowel syndrome., Results: Rectal pain intensity (VAS 0-100) during identical distension pressures increased from 39 (95% confidence interval: 35-42) outside the scanner to 53 (43-63) inside the scanner in irritable bowel syndrome, and from 42 (31-52) to 49 (39-58), respectively, in controls (ANOVA for scanner effect: p = 0.006, group effect: p = 0.92). The difference in rectal pain outside versus inside correlated significantly with stress (r = -0.76, p = 0.006), anxiety (r = -0.68, p = 0.02) and depression scores (r = -0.67, p = 0.02) in controls, but not in irritable bowel syndrome patients, who a priori had significantly higher stress and anxiety scores. ANOVA analysis showed trends for effect of the scanner environment and subject group on endogenous pain modulation (p = 0.09 and p = 0.1, respectively), but not on somatic pain (p > 0.3)., Conclusion: The scanner environment significantly increased visceral, but not somatic, pain perception in irritable bowel syndrome patients and healthy controls in a protocol specifically aimed at investigating visceral pain. Psychological factors, including anxiety and stress, are the likely underlying causes, whereas classic endogenous pain modulation pathways activated by heterotopic stimulation play a lesser role. These results are highly relevant to a wide range of imaging applications and need to be taken into account in future pain research. Further controlled studies are indicated to clarify these findings.

Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress-induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies.

Background: Dental erosion is a complication of gastro-oesophageal reflux disease (GORD) according to the Montreal consensus statement. However, GORD has not been comprehensively characterized in patients with dental erosions and pH-impedance measures have not been reported., Objectives: Characterize GORD in patients with dental erosions using 24-h multichannel intraluminal pH-impedance measurements (pH-MII) and endoscopy., Methods: This single-centre study investigated reflux in successive patients presenting to dentists with dental erosion using pH-MII and endoscopy., Results: Of the 374 patients, 298 (80%) reported GORD symptoms <2 per week, 72 (19%) had oesophagitis and 59 (16%) had a hiatal hernia. In the 349 with pH-MII the mean percentage time with a pH <4 (95% CI) was 11.0 (9.3-12.7), and 34.4% (31.9-36.9) for a pH <5.5, a critical threshold for dental tissue. The mean numbers of total, acidic and weakly acidic reflux episodes were 71 (63-79), 43 (38-49) and 31 (26-35), respectively. Of the reflux episodes, 19% (17-21) reached the proximal oesophagus. In 241 (69%) patients reflux was abnormal using published normal values for acid exposure time and reflux episodes. No significant associations between the severity of dental erosions and any reflux variables were found. The presence of GORD symptoms and of oesophagitis or a hiatal hernia was associated with greater reflux, but not with increased dental erosion scores., Conclusions: Significant oligosymptomatic gastro-oesophageal reflux occurs in the majority of patients with dental erosion. The degree of dental erosion did not correlate with any of the accepted quantitative reflux indicators. Definition of clinically relevant reflux parameters by pH-MII for dental erosion and of treatment guidelines are outstanding. Gastroenterologists and dentists need to be aware of the widely prevalent association between dental erosion and atypical GORD.

Background: Endogenous pain modulation (EPM) is central to the processing of sensory information. Visceral and somatic EPM are abnormal in irritable bowel syndrome, but have not been studied in functional dyspepsia (FD)., Methods: Visceral EPM was assessed in 34 FD patients and 42 healthy controls. Gastric pain was induced with oral capsaicin and EPM was studied by adding heterotopic thermal foot stimulation or distraction by STROOP test. Somatic EPM was assessed using foot heat stimulation with heterotopic hand electrical stimulation., Key Results: Endogenous pain modulation by distraction reduced mean gastric pain by 11.9 on the 0-100 visual analog scale (95% CI: 3.8-20.1) in controls (p = 0.006) and by 2.0 (-6.18 to 10.44) in FD (p = 0.6), with greater EPM in controls than in FD (difference -13.3 [-26.1 to -0.5]; p = 0.04). Endogenous pain modulation by heterotopic foot stimulation reduced gastric pain by 6.5 (-0.7 to 13.6) in controls (p = 0.07) and by 7.1 (-2.29 to 16.47) in FD (p = 0.1), with no significant difference in EPM between controls and FD (-2.0 [-14.5 to 10.5]; p = 0.75). In patients with prominent FD pain, greater pain correlated with decreased visceral EPM by distraction (r = 0.51, p = 0.04). Somatic EPM by heterotopic stimulation significantly decreased foot pain in controls (p = 0.004), but not in FD (p = 0.80)., Conclusions & Inferences: In FD, visceral pain modulation by distraction was dysfunctional compared to controls. Somatic pain modulation was also decreased in FD. These data and the correlation of abnormal pain modulation by distraction with clinical pain in pain-predominant FD suggest a potential pathophysiological significance of abnormal pain modulation in FD., (© 2013 John Wiley & Sons Ltd.)

Background: Gastrointestinal symptoms and malabsorption following fructose ingestion (fructose intolerance) are common in functional gastrointestinal disorders (FGID). The underlying mechanism is unclear, but is hypothesized to be related an abnormality of intestinal fructose transporter proteins., Objective: To assess the expression of the main intestinal fructose transporter proteins, glucose transport protein 5 (GLUT5) and 2 (GLUT2), in FGID., Methods: The expression of GLUT5 and GLUT2 protein and mRNA in small intestinal biopsy tissue was investigated using real-time reverse-transcription PCR and Western immunoblotting in 11 adults with FGID and fructose intolerance ascertained by breath testing and in 15 controls., Results: Median expression levels of GLUT5 mRNA normalized to beta-actin were 0.18 (interquartile range, IQR, 0.13-0.21) in patients and 0.17 (IQR 0.12-0.19) in controls (p > 0.05). Respective levels of GLUT2 mRNA were 0.26 (IQR 0.20-0.31) and 0.26 (IQR 0.19-0.31) (p > 0.05). Median expression levels of GLUT5 protein normalized to alpha-tubulin were 0.95 (IQR 0.52-1.68) in patients and 0.95 (IQR 0.59-1.15) in controls (p > 0.05). Respective protein expression levels for GLUT2 were 1.56 (IQR 1.06-2.14) and 1.35 (IQR 0.96-1.79) (p > 0.05)., Conclusions: Human fructose intolerance may not be associated with marked changes in GLUT5 and GLUT2 expression. Replication of these results in a larger subject group, including measures of transporter activation and membrane and subcellular localization, is warranted.

Background: Experimental data suggest stress-related cognitive dysfunction may be associated with increased blood-brain-barrier (BBB) permeability secondary to immune activation., Methods: We investigated the relationship between prolonged and intense physical and psychological combat-training stress, immune activation and blood-brain-barrier permeability in 37 healthy male army medical rapid response troops., Results: Soldiers during intense combat training showed greater self-reported stress, anxiety and depression levels than at rest, as assessed by specific questionnaires. S100B, a marker of BBB permeability, as well as serum cortisol, IL-6 and TNF-α concentrations, were significantly increased in soldiers during combat training compared to rest (all p<0.05). Serum S100B correlated negatively with morning serum cortisol in soldiers during combat training, but not during the rest period (r=-0.387, p<0.05)., Conclusion: We conclude that combat training inducing significant levels of stress, depression and anxiety is accompanied by evidence of increased blood-brain barrier permeability and by increases in systemic pro-inflammatory mediators.

Background: The association of fructose and lactose intolerance and malabsorption with the symptoms of different functional gastrointestinal disorders (FGID) remains unclear., Aim: To investigate the prevalence of fructose and lactose intolerance (symptom induction) and malabsorption and their association with clinical gastrointestinal (GI) as well as non-GI symptoms in FGID and the outcome of dietary intervention., Methods: Fructose and lactose intolerance (defined by positive symptom index) and malabsorption (defined by increased hydrogen/methane) were determined in 1372 FGID patients in a single centre using breath testing. Results were correlated with clinical symptoms in different FGID Rome III subgroups. The effectiveness of a targeted saccharide-reduced diet was assessed after 6-8 weeks., Results: Intolerance prevalence across all FGIDs was 60% to fructose, 51% to lactose and 33% to both. Malabsorption occurred in 45%, 32% and 16% respectively. There were no differences in intolerance or malabsorption prevalence between FGID subgroups. FGID symptoms correlated with symptoms evoked during testing (r = 0.35-0.61. P < 0.0001), but not with malabsorption. Non-GI symptoms occurred more commonly in patients with intolerances. Methane breath levels were not associated with constipation using several cut-off thresholds. Adequate symptom relief was achieved in >80% of intolerant patients, irrespective of malabsorption., Conclusions: Fructose and lactose intolerances are common in FGID and associated with increased non-GI symptoms, but not with specific FGID subtypes. Symptoms experienced during breath testing, but not malabsorption, correlate with FGID symptoms. Effective symptom relief with dietary adaptation is not associated with malabsorption. Mechanisms relating to the generation of GI and non-GI symptoms due to lactose and fructose in FGID need to be explored further., (© 2013 Blackwell Publishing Ltd.)

Background: Gastrointestinal (GI) symptoms are common in soldiers in combat or high-pressure operational situations and often lead to compromised performance. Underlying mechanisms are unclear, but neuroendocrine dysregulation, immune activation and increased intestinal permeability may be involved in stress-related GI dysfunction., Aim: To study the effects of prolonged, intense, mixed psychological and physical stress on intestinal permeability, systemic inflammatory and stress markers in soldiers during high-intensity combat-training., Methods: In 37 male army medical rapid response troops, GI symptoms, stress markers, segmental intestinal permeability using the 4-sugar test (sucrose, lactulose, mannitol and sucralose) and immune activation were assessed during the 4th week of an intense combat-training and a rest period., Results: Combat-training elicited higher stress, anxiety and depression scores (all P < 0.01) as well as greater incidence and severity of GI symptoms [irritable bowel syndrome symptom severity score (IBS-SSS), P < 0.05] compared with rest. The IBS-SSS correlated with depression (r = 0.41, P < 0.01) and stress (r = 0.40, P < 0.01) ratings. Serum levels of cortisol, interleukin-6, and tumour necrosis factor-α, and segmental GI permeability increased during combat-training compared with rest (all P < 0.05). The lactulose:mannitol ratio was higher in soldiers with GI symptoms (IBS-SSS ≥75) during combat-training than those without (IBS-SSS <75) (P < 0.05)., Conclusions: Prolonged combat-training not only induces the expected increases in stress, anxiety and depression, but also GI symptoms, pro-inflammatory immune activation and increased intestinal permeability. Identification of subgroups of individuals at high-risk of GI compromise and of long-term deleterious effects of operational stress as well as the development of protective measures will be the focus of future studies., (© 2013 Blackwell Publishing Ltd.)

Background: Visceral hypersensitivity is one of the proposed underlying mechanisms in functional dyspepsia (FD). It is not clear whether visceral hypersensitivity in FD is a manifestation of a central sensitization also encompassing somatic sensitization. Transient receptor potential vanilloid-1 (TRPV(1)) pathways are involved in gastric mechanosensory physiology and the TRPV(1) receptor agonist, capsaicin, has been used as a chemical stimulant., Methods: In this double-blind, randomized study we evaluated both visceral and somatic sensory function in 34 FD patients and 42 healthy controls using quantitative sensory testing. Visceral pain sensitivity was assessed using a validated gastric pain model with oral capsaicin capsule titration and somatic pain sensitivity was determined by foot heat and hand electric stimulation., Key Results: The median capsaicin dose required to attain moderate pain was 0.5mg in FD and 1mg in controls (P = 0.03). At these doses, mean pain intensities on a 0-100 visual analog scale were greater for FD than controls [56.9 (95% confidence intervals, 52.2-61.5) vs 45.1 (41.6-48.6), resp.] (P = 0.005). Overall, mean somatic sensory and pain thresholds were similar in FD and control groups, but in a subgroup of FD pain hypersensitivity was seen on the hand and on the foot at different stimulation thresholds., Conclusions & Inferences: A majority of patients with FD have visceral chemo-hypersensitivity involving TRPV(1) pathways. A substantial subgroup also has somatic hypersensitivity as evidence of central sensitization., (© 2012 Blackwell Publishing Ltd.)

Objective: The aim of this study was to investigate whether patients with diagnosed erosive gastroesophageal reflux disease (ERD) have an increased probability of halitosis and tongue coating compared to patients with nonerosive gastroesophageal reflux disease (NERD)., Materials and Methods: Sixty-six patients (33 males and 33 females) were recruited for the study and received an upper gastrointestinal endoscopy. The presence of ERD (n = 31) and NERD (n = 35) was classified based on the Los Angeles classification for erosive changes in the esophagus. Additionally, the patients filled in a questionnaire regarding their subjective assessment of halitosis, and an organoleptic assessment of halitosis, a measurement of oral volatile sulfur compounds (VSC) with the Halimeter, and a tongue coating index were performed. ERD and NERD subjects were compared with regard to Halitosis-related clinical and anamnestic findings., Results: No statistically significant difference could be found between ERD and NERD patients regarding tongue coating index, organoleptic scores, and VSC values as well as self-perceived bad taste, tongue coating, and bad breath., Conclusions: These data suggest that halitosis is not typically associated with erosive gastroesophageal reflux disease and the presence of esophageal mucosal damage (ERD patients)., Clinical Relevance: The data of this investigation support the findings of interdisciplinary bad breath clinics that gastroesophageal reflux disease is not a leading cause for halitosis.

Functional gastrointestinal disorders (FGIDs) are characterised by visceral pain or discomfort with an unknown cause. There is increasing evidence for abnormal processing of sensory input in FGIDs. Modulation of sensory input occurs at all levels of the nervous system, with a dynamic balance between facilitation and inhibition and close integration with the body's wider homoeostatic control. Cognitive, emotional, autonomic and spinal reflex pathways effectively orchestrate supraspinal and spinal pain modulation, as demonstrated in neurophysiological and brain imaging studies. Endogenous pain modulation has been studied in visceral pain conditions and abnormal regulation has been shown in irritable bowel syndrome (IBS) and functional dyspepsia, as well as other chronic pain syndromes. A majority of patients with IBS have diminished pain inhibition or even pain facilitation compared with healthy controls. Brain imaging during specific activation of endogenous pain modulation demonstrates a fairly consistent functional hub of mainly frontal, limbic and brainstem modulatory regions in healthy humans. Patients with IBS have a different pattern of activation and a correlation between the imaging and sensory changes. Because the modulatory balance of inhibition and facilitation appears to be distributed within the same functional network, future imaging studies of modulation mechanisms should include conditions allowing quantification of inhibitory and facilitatory components. An altered modulatory balance may well be a unifying pathophysiological mechanism in FGID as it can be driven by both top-down (ie, CNS pathology) and bottom-up (ie, peripheral immune activation) influences, but further validation in diverse FGID groups over time is required. Therapeutic manipulation of the modulatory system is possible by both pharmacological and non-pharmacological means.

Background:   Sensory sensitization is one of the main pathophysiological hypotheses in functional gastrointestinal disorders (FGIDs). As sensitization may affect various sensory modalities, we aimed to develop a reproducible gastric pain model utilizing polymodal pathways for use in functional and other pain disorders., Methods: In this double-blind, cross-over study 42 healthy subjects swallowed one capsule containing either capsaicin 0.5mg or nocebo every 15min until moderate pain (intensity >30 on 100mm visual analogue scale) was attained for at least 5min. Pain was rated every minute. Capsaicin titration was repeated thrice for reliability calculation., Key Results: Moderate pain in the upper abdomen was successfully achieved in 38 of 42 subjects (90%) with capsaicin titration and in one of 42 (2%) with nocebo. The median dosage required to induce moderate pain for at least 5min was two capsules (interquartile range 1-3) and the median gastric pain intensity was 47 (41-53). The median duration of moderate pain was 8min (5-12). Moderate pain was successfully reproduced with capsaicin in all subjects on study days 2 and 3, with an excellent Cronbach reliability coefficient of >0.8., Conclusions & Inferences: Standardized gastric pain can be conveniently achieved in a majority of healthy subjects using a simple oral capsaicin titration, with minimal adverse events. The between-test reproducibility is high and nocebo responses are negligible. This technique stimulating a multimodal physiological pathway will be useful in the investigation of sensory changes in FGIDs, including functional dyspepsia., (© 2011 Blackwell Publishing Ltd.)

Objectives: Dental erosion, the chemical dissolution of enamel without bacterial involvement, is a rarely reported manifestation of gastroesophageal reflux disease (GERD), as well as of recurrent vomiting and dietary habits. It leads to loss of tooth substance, hypersensitivity, functional impairment, and even tooth fracture. To date, dental erosions have been assessed using only very basic visual methods, and no evidence-based guidelines or studies exist regarding the prevention or treatment of GERD-related dental erosions., Methods: In this randomized, double-blind study, we used optical coherence tomography (OCT) to quantify dental tissue demineralization and enamel loss before and after 3 weeks of acid-suppressive treatment with esomeprazole 20 mg b.i.d. or placebo in 30 patients presenting to the Berne University Dental Clinic with advanced dental erosions and abnormal acid exposure by 24-h esophageal pH manometry (defined as >4% of the 24-h period with pH<4). Enamel thickness, reflectivity, and absorbance as measures of demineralization were quantified by OCT before and after therapy at identical localizations on teeth with most severe visible erosions as well as several other predefined changes in teeth., Results: The mean+/-s.e.m. decrease of enamel thickness of all teeth before and after treatment at the site of maximum exposure was 7.2+/-0.16 black trianglem with esomeprazole and 15.25+/-0.17black trianglem with placebo (P=0.013), representing a loss of 0.3% and 0.8% of the total enamel thickness, respectively. The change in optical reflectivity to a depth of 25 black trianglem after treatment was-1.122 +/-0.769 dB with esomeprazole and +2.059+/-0.534 dB with placebo (P 0.012), with increased reflectivity signifying demineralization., Conclusions: OCT non-invasively detected and quantified significantly diminished progression of dental tissue demineralization and enamel loss after only 3 weeks of treatment with esomeprazole 20 mg b.i.d. vs. placebo. This suggests that esomeprazole may be useful in counteracting progression of GERD-related dental erosions. Further validation of preventative treatment regimens using this sensitive detection method is required, including longer follow-up and correlation with quantitative reflux measures.

All sensory input underlies modulation by endogenous central nervous system pathways. Dysfunctional endogenous pain modulation has been demonstrated in central sensitization and in several pain syndromes, including Irritable Bowel Syndrome (IBS) Activation of endogenous visceral pain modulation by heterotopic stimulation was compared using different methods. Rectal electrical or distension pain alone or with simultaneous (i.e. heterotopic) noxious hand or foot cold stimulation were investigated in randomized sequence in 14 male and 1 female healthy subjects. Mean pain intensities on a visual analogue scale of 0-100 (95% CI) during tonic rectal electrical and distension stimulation alone were 64 (52-76) and 55 (39-71), respectively. Rectal distension pain decreased by 36% (18-55) with simultaneous hand and by 45% (24-66) with simultaneous foot cold pain. Rectal electrical pain decreased by 45% (29-61) during hand and by 46% (28-64) during foot cold pain. Facilitation, i.e. increased rectal pain during heterotopic stimulation was observed in only 1 of 60 stimulation runs. Potent and consistent activation of endogenous visceral pain inhibition was achieved with heterotopic cold pain limb stimulation. Somato-visceral convergence did not affect the effectiveness of induction of endogenous visceral pain inhibition in healthy subjects, as hand and foot heterotopic stimulation resulted in similar pain inhibition. Pain facilitation, as shown earlier in IBS patients, was not evident in healthy controls.

Objective: Bacterial factors, including strain type, anatomic distribution and density, and host responses are important determinants in the pathogenesis of erosive and neoplastic changes linked to gastric Helicobacter pylori (H. pylori) infection. The purpose of this study was to investigate the potential use of photodiagnostics in mapping H. pylori infection. The relationship between fluorescence in individual gastric pits of H. pylori(+) and H. pylori(-) subjects versus that in larger field views of the gastric mucosa and the use of fluorescence to determine H. pylori status in different gastric areas were studied., Material and Methods: Antrum, corpus and fundus biopsies from 8 H. pylori(+) and 4 H. pylori(-) subjects taken during two gastroscopies were used for autofluorescence (535 nm excitation) and aminolevulinic acid (ALA)-induced protoporphyrin IX fluorescence (405 nm excitation) determinations., Results: In the antrum, corpus and fundus a close correlation between individual pit and full-field image (FFI) fluorescence was demonstrated for H. pylori status (R>0.85; R>0.75; R>0.80) and both excitation wavelengths (R>0.89; R>0.85; R>0.95), respectively. In the antrum, FFI in H. pylori(+) subjects exceeded that in H. pylori(-) subjects using 405 nm but not 535 nm excitation regardless of ALA treatment (pcorpus>antrum for both H. pylori(+) and H. pylori(-) subjects regardless of ALA treatment (p=0.03)., Conclusions: Fluorescence-based identification of areas of H. pylori-infected gastric mucosa using 405 nm excitation combined with ALA treatment is feasible and, using a ratio of 535 nm:405 nm-excited fluorescence, it is possible to distinguish H. pylori status and the different areas of the stomach even without ALA.

Aim: To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome (IBS). Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function., Methods: Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities (visual analogue scale, VAS 0-100) during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously (heterotopic stimulation) were recorded in 40 female patients with IBS and 20 female healthy controls., Results: Rectal hypersensitivity (defined by 95% CI of controls) was seen in 21 (53%), somatic hypersensitivity in 22 (55%) and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 (-11 to -1) in controls, but increased rectal pain by 2 (-3 to +6) in all IBS patients (P < 0.05) and by 8 (-2 to +19) in IBS patients with somatic and visceral hypersensitivity (P < 0.02)., Conclusion: A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.

Visceral pain processing is abnormal in a majority of irritable bowel syndrome (IBS) patients. Aberrant endogenous nociceptive modulation and anticipation are possible underlying mechanisms investigated in the current study. Twelve IBS patients and 12 matched healthy controls underwent brain fMRI scanning during the following randomised stimuli: sham and painful rectal distensions by barostat without and with simultaneous activation of endogenous descending nociceptive inhibition using ice water immersion of the foot for heterotopic stimulation. Heterotopic stimulation decreased rectal pain scores from 3.7+/-0.2 to 3.1+/-0.3 (mean+/-SE, scale 0-5) in controls (p<0.01), but not significantly in IBS. Controls differed from IBS patients in showing significantly greater activation bilaterally in the anterior insula, SII and putamen during rectal stimulation alone compared to rectal plus heterotopic stimulation. Greater activation during rectal plus heterotopic versus rectal stimulation was seen bilaterally in SI and the right superior temporal gyrus in controls and in the right inferior lobule and bilaterally in the superior temporal gyrus in IBS. Rectal pain scores were similarly low during sham stimulation in both groups, but brain activation patterns differed. In conclusion, IBS patients showed dysfunctional endogenous inhibition of pain and concomitant aberrant activation of brain areas involved in pain processing and integration. Anticipation of rectal pain was associated with different brain activation patterns in IBS involving multiple interoceptive, homeostatic, associative and emotional areas, even though pain scores were similar during sham distension. The aberrant activation of endogenous pain inhibition appears to involve circuitry relating to anticipation as well as pain processing itself.

Objective: The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen., Material and Methods: Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily (n=25), AZD3582 375 mg twice daily versus 750 mg twice daily (n=25) and naproxen 250 mg twice daily versus 500 mg twice daily (n=25)., Results: Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily (mean number of erosions and ulcers+/-SD: 2.88+/-3.95 versus 3.08+/-2.80, respectively; p=0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.92+/-2.08 versus 2.71+/-4.75, respectively; p=0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily (2.88+/-3.95 versus 6.16+/-9.36; p<0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily (3.08+/-2.80 versus 6.68+/-6.97; p<0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B(2) inhibition., Conclusions: AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.

Reflux of acidic gastric secretions into the oral cavity may cause significant dental erosion. This gastro-oesophageal reflux has been shown to occur in children as well as in adults, and is often not accompanied by typical reflux symptoms. When symptoms are present the children may complain of heartburn, food regurgitation and epigastric pain. Current investigation involves ambulatory 24-hour oesophageal pH-measurements. In the case of exaggerated reflux, the main therapeutic option is medical acid suppression for several years. The pathogenesis, the diagnostic and therapeutic procedures as well as the importance of the cooperation between dentists and gastroenterologists are described and therapeutic advices are given.

Objectives: Two studies compared the effects of intravenous (i.v.) and oral esomeprazole (40 mg and 20 mg) on gastric acid suppression and pharmacokinetics after both single (day 1) and repeated (day 5) dosing., Methods: Two randomized, two-way, cross-over, comparative studies of similar design were performed in healthy male and female volunteers. In both studies, subjects received esomeprazole as a 30-min i.v. infusion or orally once-daily for 5 days, separated by a wash-out period of at least 13 days. In one study, which was double-blind (double dummy), subjects received 40 mg esomeprazole. In the other open study, subjects were given 20 mg esomeprazole., Results: In total, 40 and 24 subjects were randomized for treatment with 40 mg and 20 mg esomeprazole, respectively. No significant differences were found between i.v or oral administration of esomeprazole with respect to the amount of time with mean intragastric pH>4 throughout day 1 or day 5 of treatment in the 40 mg study (day 1, 10.1 h and 8.8 h versus day 5, 15.9 h and 15.3 h, respectively) and the 20 mg study (day 1, 7.3 h and 6.6 h versus day 5, 11.9 h and 12.3 h, respectively). The area under the plasma concentration-time curve values were higher following i.v. relative to oral administration on day 1 of dosing, with less pronounced differences after repeated (day 5) dosing. Both administration routes were similarly well tolerated., Conclusions: Esomeprazole, 40 mg and 20 mg i.v., provides similar levels of intragastric acid control on both day 1 and day 5 of treatment compared with oral administration.

Background: The objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer., Methods: Studies 1 and 3-5 recruited healthy male volunteers aged 18-65 years; study 2 recruited male or female patients aged>or=18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n=12)--intravenous infusion of 50 or 100 mg followed by a single oral dose of 250 mg; study 2 (bioavailability in cancer patients; n=19)--intravenous infusion of 50 mg followed by a single oral dose of 250 mg; study 3 (intrasubject variability; n=24)--two single oral doses of 250 mg; study 4 (dose-proportionality; n=15)--three single oral doses of 50-500 mg; study 5 (effect of food; n=26)--two single doses of 250 mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods., Results: Study 1: Oral bioavailability of a gefitinib 250 mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5-110 ng/mL) reached 5 hours following an oral dose of 250 mg. Study 2: Oral bioavailability of a gefitinib 250 mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7-324 ng/mL) typically reached 3 hours (range 1-8 hours) following an oral dose of 250 mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) and Cmax were variable--up to 15-fold between subjects and 2-fold within an individual. Study 4: AUCinfinity and Cmax increased with dose across the range of 50-500 mg, and increased dose-proportionally up to 250 mg. Study 5: Small, clinically insignificant increases in AUCinfinity and Cmax were seen in the presence of food (32% and 37%, respectively)., Conclusions: The gefitinib 250 mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.

Background: Oral esomeprazole 40 mg provides greater acid control than oral pantoprazole 40 mg., Aim: To compare the effects on intragastric acid control of esomeprazole 40 mg administered intravenously with pantoprazole 40 mg intravenously., Methods: Healthy Helicobacter pylori-negative male and female subjects were enrolled into this single-centre, open, randomized, two-way crossover study. Esomeprazole 40 mg intravenously and pantoprazole 40 mg intravenously were administered as 15-min infusions once daily at 09:00 hours for 5 days. Continuous 24-h intragastric pH monitoring was carried out at baseline and on days 1 and 5., Results: pH-data were available for all 25 subjects who completed the study. Esomeprazole 40 mg intravenously resulted in 8.3 and 13.9 h with an intragastric pH > 4 on days 1 and 5 compared with 5.3 and 9.0 h, respectively for pantoprazole 40 mg intravenously (day 1: P < 0.001, day 5: P < 0.0001). During the first 4 h of dosing on day 1 corresponding values were 1.7 and 0.6 h respectively (P < 0.0001). A mean median pH above 4 on day 5 was only attained with esomeprazole 40 mg intravenously., Conclusions: Once-daily dosing with esomeprazole 40 mg intravenously provides faster and more pronounced intragastric acid control than pantoprazole 40 mg intravenously.

Background and Aims: Many patients with irritable bowel syndrome (IBS) show intestinal hypersensitivity to distension and sensitisation after repeated intestinal distensions. Abnormalities in endogenous pain inhibitory mechanisms, such as diffuse noxious inhibitory controls (DNIC), may be implicated and were investigated during brain functional magnetic resonance imaging (fMRI)., Patients and Methods: fMRI was performed in 10 female patients with IBS (five constipated (IBS-C) and five with diarrhoea (IBS-D)) and 10 female healthy controls during rectal balloon distension alone or during activation of DNIC by painful heterotopic stimulation of the foot with ice water. Rectal pain was scored with and without heterotopic stimulation (0 = none, 10 = maximal)., Results: Heterotopic stimulation decreased median rectal pain scores significantly in healthy controls (-1.5 (interquartile range -2 to -1); p = 0.001) but not in IBS-C (-0.7 (-1 to 0.5)), IBS-D (-0.5 (-1.5 to 0.5)), or in all IBS patients (0 (-1.5 to 1.3)). Brain activation changes during heterotopic stimulation differed highly significantly between IBS-C, IBS-D, and controls. The main centres affected were the amygdala, anterior cingulate cortex, hippocampus, insula, periaqueductal gray, and prefrontal cortex, which form part of the matrix controlling emotional, autonomic, and descending modulatory responses to pain., Conclusions: IBS-C and IBS-D appear to have differing abnormal endogenous pain inhibitory mechanisms, involving DNIC and other supraspinal modulatory pathways.

Unlabelled: Combining different analgesic mechanisms can reduce postoperative pain. We investigated postoperative pain and sensory sensitization in a double-blinded, placebo-controlled, randomized, single-dose comparison of the monoaminergic and micro -opioid agonist tramadol, 100 mg, and diclofenac 75 mg given IM in combination or alone in 120 patients who had elective cesarean delivery. The time to first postoperative demand for rescue analgesia, pain, tramadol pharmacokinetics, and electrical sensory thresholds at or distant from the incision were studied. The median time to first rescue (interquartile range) was 197 min (70-1000 min) with tramadol plus diclofenac, 48 min (25-90 min) with tramadol plus placebo, 113 min (35-270 min) with diclofenac plus placebo, and 55 min (30-100 min) with double placebo (tramadol plus diclofenac versus all other groups, P < 0.05). Pain intensity decreased markedly over time in all groups, and time and drug effects were significant (analysis of variance; P < 0.00001). Side effects were similarly minimal with all treatments. Pain thresholds at or distant from the incision increased significantly after surgery only with tramadol plus diclofenac. Preoperative sensory thresholds correlated with postoperative sensory changes (r > 0.53; P < 0.0001). The pharmacokinetics of tramadol and O-desmethyltramadol were unchanged by diclofenac. The combination of tramadol and diclofenac resulted in improved analgesia compared with monotherapy. Only the analgesic combination prevented both primary and secondary hyperalgesia. Preoperative sensory thresholds may allow prediction of postoperative sensitization., Implications: The parenteral combination of tramadol and diclofenac resulted in more prolonged and pronounced postoperative analgesia and reduced sensory sensitization compared with the single drugs, with no increase in side effects.

Aim: To compare the effects of standard-dose esomeprazole with those of standard doses of lansoprazole and rabeprazole on intragastric pH during repeated daily oral dosing in healthy volunteers., Methods: In two standardized, randomized crossover studies, Helicobacter pylori negative healthy volunteers (study A: 19 males, 5 females; study B: 13 males, 10 females) received esomeprazole 40 mg and either lansoprazole 30 mg (study A) or rabeprazole 20 mg (study B) orally once daily in the morning for 5 days. Continuous 24-hour intragastric pH recording was performed on day 5., Results: The intragastric pH was maintained >4 for 65% (95% CI 59.5-71.3) of the 24-hour period with esomeprazole and for 53% of the time (95% CI 47.0-58.9) with lansoprazole in study A (p < 0.001). In study B, the proportion of time with pH >4 was 61% (95% CI 53.6-68.3) with esomeprazole versus 45% (95% CI 37.7-52.5) with rabeprazole (p = 0.005). The 24-hour median pH and the proportion of volunteers with intragastric pH >4 for > or =12 h and > or =16 h were significantly higher with esomeprazole than with either lansoprazole or rabeprazole., Conclusion: Esomeprazole 40 mg provides significantly more effective and more sustained gastric acid control than lansoprazole 30 mg or rabeprazole 20 mg in healthy volunteers., (Copyright 2003 S. Karger AG, Basel)

Objective: Inadequate morphometric characterization of the normal adult submucous plexus has precluded the diagnosis of colonic dysganglionoses associated with constipation, such as intestinal neuronal dysplasia type B (IND B). The internal submucous plexus (Meissner plexus) was morphometrically quantified in adult healthy volunteers., Design: Open, prospective morphometric study in balanced groups of female and male volunteers., Participants: Thirty-seven adult healthy male and female volunteers with normal bowel function and no history of gastrointestinal disease., Methods: Four jumbo rectal biopsies (3-5 mm3) were taken 5 and 10 cm above the pectinate line. Two expert gastrointestinal pathologists assessed biopsy sections after specific nerve cell staining for lactic dehydrogenase, nitric oxide synthase and acetylcholinesterase, mainly for characteristics of ganglia and nerve cells in the submucous plexus., Results: No healthy individual demonstrated over 20% of submucosal ganglia as giant ganglia or more than four giant ganglia per 30 sections (the morphometric criteria for IND B). Single submucosal nerve cells and ganglion numbers halved between 10 and 5 cm above the pectinate line, but there were no age or gender differences. The biological variability of nerve cell and ganglion density in the submucous plexus was large., Conclusions: Healthy adults show less than 20% of submucosal ganglia as giant ganglia and no more than four giant ganglia per 30 rectal biopsy sections. There is therefore no overlap with the histomorphological criteria of IND B. These data therefore support the specificity of the previously defined criteria for IND B in adults.

Background and Objectives: Helicobacter pylori (HP) is an endemic pathogenic bacterium causing gastritis and gastroduodenal ulceration in humans and is linked to the development of gastric malignancies. These first human in vivo studies investigated the photoeradication of HP using laser and white light., Study Design/materials and Methods: In 13 HP-positive volunteers, a zone of gastric antrum was irradiated with laser (410 nm, 50 J/cm(2)) or endoscopic white light (10 J/cm(2)) 45 minutes after oral 5-aminolevulinic acid (5-ALA) 20 mg/kg. HP-eradication was assessed by biopsy urease test and HP-culture from irradiated and control zones 5 minutes, 4 and 48 hours post-irradiation., Results: A maximum eradication effect was achieved at 4 hours post-irradiation when 85% of biopsies in the monochromatic and 66% in the white light exposed zones, and 58 and 33% in the respective control zones were HP-negative., Conclusions: HP numbers were greatly reduced following exposure to 5-ALA and either laser or white light in vivo. Photoeradication appears feasible, but further light dosimetry and the development of convenient application methods is required., (Copyright 2002 Wiley-Liss, Inc.)

Opioids are increasingly used in the treatment of chronic non-malignant pain. The aim of this open-label, randomised, parallel group study was to compare analgesia and side-effects of two commonly used opioid analgesics, tramadol and dihydrocodeine, in long-acting formulations in 60 osteoarthritis patients with strong pain despite NSAID's. Dose titration based on effect was performed with the respective immediate release solutions given additionally to tramadol 100 mg bid and dihydrocodeine 60 mg bid during the first 4 days of the 1 month treatment. Electrical sensation and pain thresholds over the osteoarthritic joint and at a distant location and gastrointestinal transit times were performed before and during treatment. Thirty patients with pain controlled by NSAID's alone formed the comparator group. Pain intensities at rest and during movement decreased highly significantly with tramadol and dihydrocodeine from median pre-treatment verbal ratings of over 3 (0=none, 4=unbearable) to 1 and below from the second treatment day onwards (ANOVA P<0.0001). Pain at rest was significantly lower with tramadol (ANOVA P=0.04), but ratings were similar during movement. Mean (95% CI) daily doses on days 1 and 28 were 209 (198-220) mg and 203 (191-206) mg of tramadol, and 129 (122-136) mg and 130 (121-134) mg of dihydrocodeine, respectively. Minor side-effects were more common with tramadol (P=0.04). Changes in bowel functions and symptoms were minor with both treatments, but the frequency of defaecation was lower and stools were harder with dihydrocodeine. Orocaecal transit time remained unchanged and similar to controls with both analgesics. Colonic transit times only increased significantly during treatment with dihydrocodeine. Sensation and pain thresholds were lower pre-treatment in both groups than in controls and increased during treatment. These antinociceptive effects were more marked in the tramadol group and distant from the osteoarthritic joint. We conclude rapid pain relief was achieved with both long-acting tramadol and dihydrocodeine with NSAID's in strong osteoarthritis pain. Minimal dose titration was required and side-effects were minor. Tramadol interfered less with intestinal function and showed greater antinociceptive action.

Background/aims: Helicobacter pylori is considered to be the primary cause of most forms of gastritis, but its role as a causative agent in gastric erosions is unclear. The aim of this study was to estimate the prevalence of gastric erosions and H. pylori infection in asymptomatic volunteers., Methods: 175 asymptomatic subjects underwent upper gastrointestinal endoscopy. Antral biopsies were taken for bacterial cultures, histology and quick urease (CLO) test. A (13)C-urea breath test was performed after endoscopy. NSAID intake, alcohol consumption and smoking habits were also recorded in each subject., Results: 33 (19%) of 175 asymptomatic volunteers had macroscopic lesions on upper gastrointestinal endoscopy, 7 were H. pylori positive, 26 were H. pylori negative. Gastric erosions occurred in 8% (14 subjects) of all volunteers. 10 subjects were H. pylori negative and 4 H. pylori positive. In 11 volunteers, gastric erosions were restricted to the prepyloric antrum. Only 1 of 14 subjects had a history of NSAID intake and 6 subjects were alcohol abstainers., Conclusion: We conclude that gastric erosions occur in a considerable amount of asymptomatic volunteers. They are predominantly localized in the prepyloric antrum and are most likely not associated with H. pylori infection, NSAID intake, smoking or alcohol consumption., (Copyright 2000 S. Karger AG, Basel.)

The pharmacodynamics of morphine-6-glucuronide (M-6-G) i.v. were assessed in 12 healthy male volunteers in an open study. After a single bolus dose of M-6-G 5 mg i.v., we measured antinociceptive effects, using electrical and cold pain tests, and plasma concentrations of M-6-G, morphine-3-glucuronide (M-3-G) and morphine. Pain intensities during electrical stimulation (at 30, 60 and 90 min after injection) and ice water immersion (at 60 min) decreased significantly (P < 0.005) compared with baseline. Mean plasma peak concentrations of M-6-G were 139.3 (SD 38.9) ng ml-1, measured at 15 min. Our data demonstrate that M-6-G has significant analgesic activity.

Background: Chronic nociceptive input induces sensitization and changes in regulatory reflexes in animal models. In humans, postoperative somatic and visceral sensitization and the secondary effects on reflex gut motility are unclear., Methods: Somatic and visceral sensation and gastrointestinal motility were evaluated after abdominal hysterectomies in 50 patients who were randomized to receive double-blinded postoperative 48-h infusions of morphine or tramadol. Pain scores, rectal distension, skin electric sensation and pain tolerance thresholds, and gastrointestinal transit were assessed before and after operation, during and after analgesic infusions., Results: Pain intensity scores decreased similarly with morphine and tramadol infusions (total doses, 66.8+/-20 mg and 732.4+/-152 mg [mean +/- SD], respectively). Skin pain tolerance thresholds in the incisional dermatome remained similar with morphine and tramadol throughout the study. During morphine infusions, pain tolerance thresholds on the shoulder increased (P<0.05) and then decreased after discontinuation on day 4 (P<0.02) compared with before operation. Rectal distension pain tolerance pressure thresholds increased after operation during morphine infusions (P<0.05). Similar but nonsignificant trends occurred with tramadol. Orocecal and colonic transit times increased after operation with both morphine and tramadol (P<0.005), but gastric emptying was prolonged only with morphine (P = 0.03). AU motility and sensory parameters had returned to preoperative levels by 1 month after operation., Conclusions: Pain control was equally effective with morphine and tramadol infusions. No somatic or visceral sensitization was evident during morphine and tramadol infusions, but pain tolerance thresholds as markers of antinociception were increased more during morphine infusions. The significant sensitization seen only after morphine discontinuation may be due to convergent visceral input. Gut motility was prolonged significantly by visceral surgery itself and also by morphine.

Tramadol and morphine were compared for treatment of severe chronic pancreatitis pain and their interaction with gut motor function. Oral tramadol or morphine doses were titrated double-blinded and randomized for five days in 25 patients and pain, side effects, bowel function, orocecal and colonic transit, anal resting pressure, and rectal distension thresholds were measured. Pain intensities (mean+/-SD, 0 = none, 100 = unbearable) before treatment and on day 4 were 75+/-19 and 8+/-13 with tramadol (P < 0.001), and 65+/-21 and 5+/-6 with morphine (P < 0.001). On day 4, 67% of patients with tramadol and 20% with morphine rated their analgesia as excellent (P < 0.001) with mean respective doses of 840 mg (range: 80-1920) and 238 mg (20-1125). Orocecal transit was unchanged after five days of tramadol, but increased with morphine (P < 0.05). More patients had prolonged colonic transit times with morphine by day 5 (P < 0.05). Rectal distension threshold pressures increased only with tramadol (P < 0.01). It is concluded tramadol and morphine are potent analgesics in severe chronic pancreatitis pain when individually titrated. Tramadol interfered significantly less with gastrointestinal function and was more often rated as an excellent analgesic than morphine.