Epidemiological characteristics of a population visiting a patient-centered informative website about irritable bowel syndrome.

Background and aims: Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain and an altered bowel habit. The aim of this study was to evaluate the characteristics of a population visiting a patient-centered informative website about IBS. Methods: Five digital surveys were used to assess the Rome IV criteria, red flag symptoms, healthcare use, psychological comorbidities, quality of life, symptom severity, diet, physical activity. Patients were divided into a Rome positive and negative population with the Rome positive population being further subtyped based on dominant stool pattern. Results: Red flag symptoms (42%) and comorbid psychological disorders (65% anxiety and 39% depression) were common. Despite consulting health care professionals and therapy, most patients (96%) still experienced moderate to severe symptoms with an average impact on quality of life. 73% performed regular physical exercise and 25% of the Rome positive population followed the FODMAP diet. Almost all participants consulted a health care professional at one point in time and used some form of therapy. 54% of the patients believed there is generally sufficient information available and 57% thinks that their physician takes IBS seriously. However, only 41% thinks that their physician has sufficient knowledge about IBS. Conclusions: This study underlines the importance of a thorough characterization of IBS patients. Furthermore, patients expressed an urgent need for high quality information and education for both health care professionals and patients.

Phenotypic and functional characterization of in vitro cultured human mast cells.

BACKGROUND: Mast cell progenitor cells, derived from CD34+ hematopoietic stem cells, enter the circulation and subsequently mucosal or connective tissues where they mature to mast cells. Upon activation, mast cells increase the expression of activation markers, e.g. CD63, and release histamine amongst other mediators. Traditionally, release of these mediators is quantified using assays measuring their extracellular concentration in the supernatant of stimulated cells. METHODS: Human mast cells (HuMC) were cultured from peripheral blood, phenotypically characterized, passively sensitized with allogenic IgE antibodies and finally stimulated by anti-IgE that crosslinks IgE/FcεRI complexes. Alterations in the number of cells positive for CD63 and release of histamine were quantified simultaneously by flow cytometry. RESULTS: In culture, two distinct CD45+ cell populations were identified: CD117+ CD203c+hi and CD117- CD203c+low cells. Both populations showed positivity for FcεRI, tryptase and chymase, and contained histamine. Activation resulted in a significant increase of cells positive for CD63+ up to 21% (range: 11-39) for CD117+ CD203c+hi cells (P = 0.005), and 27% (18-55) CD63+ for CD117- CD203c+low cells (P = 0.02). Baseline histamine content was higher for CD117+ CD203c+hi cells than for CD117- CD203c+low cells, respectively 994 (695-6815) Molecules of Equivalent Specific Fluorochrome V500 per cell (MESF-V500/cell) and 797 (629-4978) MESF-V500/cell (P = 0.02). After activation, CD117+ CD203c+hi cells showed significant histamine release of 578 (366-1521) MESF-V500/cell, whilst CD117- CD203c+low cells resulted in 310 (217-366) MESF-V500/cell histamine release. CONCLUSION: This study discloses that culturing HuMC from CD34+ progenitors yields 2 phenotypically distinct cell populations that display a greatly similar response upon cross-linking of IgE/FcεRI complexes. © 2016 International Clinical Cytometry Society.

Irritable bowel syndrome and visceral hypersensitivity : risk factors and pathophysiological mechanisms.

Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain and altered intestinal motility. Visceral hypersensitivity is an important hallmark feature of IBS and is believed to underlie abdominal pain in patients with IBS. The two main risk factors associated with the development of IBS are gastrointestinal inflammation and psychological distress. On a peripheral level, visceral sensitivity seems to be modulated by several mechanisms. Immune cells in the mucosal wall, such as mast cells, and enterochromaffin cells may sensitize afferent nerves by release of their mediators. Furthermore, increased mucosal permeability, altered intestinal microflora and dietary habits may contribute to this feature. On a central level, an increased prevalence of psychiatric comorbidities is demonstrated in IBS patients, alongside alterations in the hormonal brain-gut axis, increased vigilance towards intestinal stimuli and functional and structural changes in the brain. The pathogenesis of IBS is complicated and multifactorial and the treatment remains clinically challenging. Dietary measures and symptomatic control are the cornerstones for IBS treatment and may be sufficient for patients experiencing mild symptoms, alongside education, reassurance and an effective therapeutic physician-patient relationship. New pharmacological therapies are aimed at interfering with mediator release and/or blockade of the relevant receptors within the gut wall, while modulation of the intestinal flora and diet may also be of therapeutic benefit. Tricyclic anti-depressants and serotonin reuptake inhibitors act both on a central and peripheral level by modulating pain signalling pathways.

Novel nervous system mechanisms in visceral pain.

Visceral hypersensitivity is an important factor underlying abdominal pain in functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and can result from aberrant signaling from the gut to the brain or vice versa. Over the last two decades, research has identified several selective, intertwining pathways that underlie IBS-related visceral nociception, including specific receptors on afferent and efferent nerve fibers such as transient receptor potential channels (TRP) channels, opioid, and cannabinoid receptors. In this issue of Neurogastroenterology and Motility Gil et al. demonstrate that in an animal model with reduced descending inhibitory control, the sympathetic nervous system outflow is enhanced, contributing to visceral and somatic hypersensitivity. They also provide evidence that interfering with the activation of adrenergic receptors on sensory nerves can be an interesting new strategy to treat visceral pain in IBS. This mini-review places these findings in a broader perspective by providing an overview of promising novel mechanisms to alter the nervous control of visceral pain interfering with afferent or efferent neuronal signaling.

Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling.

BACKGROUND: Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis. METHODS: Trinitrobenzene sulfonic acid (TNBS)-colitis was monitored individually by colonoscopy to confirm colitis and follow convalescence and endoscopic healing in each rat. Experiments were performed in controls, rats with acute colitis and in postcolitis rats. Colonic afferent mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs), and by making extracellular afferent recordings from splanchnic nerve bundles in vitro. Multiunit afferent activity was classified into single units identified as low threshold (LT), wide dynamic range (WDR), high threshold (HT), and mechanically insensitive afferents (MIA). KEY RESULTS: During acute TNBS-colitis, VMRs were significantly increased and splanchnic nerve recordings showed proportionally less MIA and increased WDR and HT afferents. Acute colitis gave rise to an enhanced spontaneous activity of both LT and MIA and augmented afferent mechanosensitivity in LT, WDR and HT afferents. Postcolitis, VMRs remained significantly increased, whereas splanchnic nerve recordings showed that the proportion of LT, WDR, HT and MIA had normalized to control values. However, LT and MIA continued to show increased spontaneous activity and WDR and HT remained sensitized to colorectal distension. CONCLUSIONS & INFERENCES: Visceral hypersensitivity in vivo is associated with sensitized splanchnic afferent responses both during acute colitis and in the postinflammatory phase. However, splanchnic afferent subpopulations are affected differentially at both time points.

Cell-Free DNA: An Upcoming Biomarker in Transplantation.

After organ transplantation, donor-derived cell-free DNA (ddcfDNA) can be detected in the recipient's blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker. In this review, we summarize published research on ddcfDNA in the transplantation field thereby elaborating on its clinical utility.

Histamine H4 receptors in the gastrointestinal tract.

Histamine is a well-established mediator involved in a variety of physiological and pathophysiological mechanisms and exerts its effect through activation of four histamine receptors (H1-H4). The histamine H4 receptor is the newest member of this histamine receptor family, and is expressed throughout the gastrointestinal tract as well as in the liver, pancreas and bile ducts. Functional studies using a combination of selective and non-selective H4 receptor ligands have rapidly increased our knowledge of H4 receptor involvement in gastrointestinal processes both under physiological conditions and in models of disease. Strong evidence points towards a role for H4 receptors in the modulation of immune-mediated responses in gut inflammation such as in colitis, ischaemia/reperfusion injury, radiation-induced enteropathy and allergic gut reactions. In addition, data have emerged implicating H4 receptors in gastrointestinal cancerogenesis, sensory signalling, and visceral pain as well as in gastric ulceration. These studies highlight the potential of H4 receptor targeted therapy in the treatment of various gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and cancer.

Sleep-disordered breathing and pulmonary function in obese children and adolescents.

OBJECTIVE: Obese children have an increased risk of developing obstructive sleep apnea syndrome (OSAS) compared to normal-weight children. In obese children, OSAS is more frequently associated with oxygen desaturations, which might be caused by pulmonary function abnormalities. Our goal was to investigate the association between OSAS and pulmonary function in obese children and adolescents. METHODS: There were 185 children included and distributed in groups based on their obstructive apnea-hypopnea index (151 controls, 20 mild OSAS, and 14 moderate-to-severe OSAS). All subjects underwent polysomnography and pulmonary function testing. RESULTS: Several differences in pulmonary function were observed between groups. Vital capacity (VC) and forced expired volume in 1s (FEV1) were significantly decreased in patients with moderate-to-severe OSAS, as were expiratory reserve volume (ERV), total lung capacity, and functional residual capacity (FRC). Correlations between FEV1, FRC, and ERV with OSAS severity remained significant independent of the degree of adiposity. Correlations between FEV1/VC and sleep-related respiratory parameters did not persist after correction for adiposity. CONCLUSION: An association between awake pulmonary function and sleep-related respiratory parameters could be observed in our population of obese children. These results suggest that OSAS severity is correlated with a diminished lung function. However, the level of obesity remains an important confounding factor in both OSAS severity and pulmonary function.

Development and psychometric evaluation of a dutch questionnaire for the assessment of anorectal and lower urinary tract symptoms.

BACKGROUND AND STUDY AIMS: Epidemiological studies have shown a frequent coexistence of symptoms and diseases affecting the anorectum and lower urinary tract. To further investigate combined symptoms and pathology of both pelvic viscera we developed a self-reported questionnaire, in Dutch, which extensively evaluates habits, complaints and symptoms of both viscera. We describe the construction and the psychometric properties of this questionnaire. PATIENTS AND METHODS: This prospective study was conducted in 56 patients with anorectal symptoms, 41 patients with lower urinary tract symptoms and in a control group of 91 people. The following psychometric properties of the questionnaire were evaluated: content validity, construct validity, criterion validity, test-retest reliability and internal consistency. RESULTS: The questionnaire covered all important domains, was well interpreted and showed good acceptability (content validity). The questionnaire clearly differentiated the patient populations (construct validity). The criterion validity of the questionnaire was excellent. The test-retest reliability of the questionnaire was acceptable in all three the study populations (overall median kappa: 0.64; Inter Quartile Range: 0.56-0.75; mean agreement: 88%). The internal consistency of both anorectal and lower urinary tract symptom questions was high (Crohnbach's alpha of 0.78 and 0.80 respectively). CONCLUSIONS: This questionnaire is a valid and reliable instrument for the assessment of anorectal and lower urinary tract symptoms. It can provide further insights into the epidemiology of concomitant bowel and bladder disorders and, accordingly, can contribute to a more efficient diagnostic and therapeutic approach in patients with such disorders.

The use of colonoscopy to follow the inflammatory time course of TNBS colitis in rats.

BACKGROUND AND STUDY AIMS: Animal models of colitis are widely used to study the pathogenesis of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). However techniques allowing sequential assessment of colonic inflammation over time, without the need to sacrifice the animal, are required. This study evaluated in vive colonoscopy to follow the evolution of colitis in rats in comparison with the more commonly used post-mortem macroscopic, microscopic and biochemical assays of inflammation. METHODS: Colitis was induced in rats by a single intrarectal instillation of trinitrobenzene sulphonic acid (TNBS). Using a baby upper gastrointestinal endoscope, the severity of colitis was monitored at days 3, 10, 28 and 56 after the induction of colitis. Inflammation was scored by colonoscopy based on the degree of ulceration, extent of inflammation, mucosal bleeding, oedema and stenosis. During follow-up, rats were randomly selected for postmortem macroscopic and microscopic histology and myeloperoxidase (MPO) assessment of the colon. RESULTS: Colonoscopy showed signs of severe mucosal inflammation in the distal colon 3 days after induction of TNBS colitis. Subsequently, colitis subsided at days 10 and 28 with complete endoscopic remission at day 56. During the acute phase of inflammation, endoscopic findings were consistent with the post-mortem inflammatory parameters (macroscopic and microscopic histopathology, MPO colonic activity). A strong correlation between endoscopy and macroscopy remained even during the chronic phase of inflammation. CONCLUSIONS: Our findings suggest that routine endoscopy is a reliable method for monitoring the development and follow-up of the degree of TNBS colitis in rats.

Teaching conceptions and approaches to teaching of medical school faculty: the difference between how medical school teachers think about teaching and how they say that they do teach.

BACKGROUND: It is often assumed that the way teachers approach their teaching is determined by the way they think about learning. This study explores how teachers of an undergraduate medical programme (UMP) think about learning, how they approach teaching and whether their conceptions of learning relate to their teaching approaches. METHODS: Quantitative data of academic teachers involved in the undergraduate programme in medicine were collected and analysed. We used a questionnaire designed to measure teachers' conceptions of their own learning (COL) and of student learning as well as teachers' approaches to teaching (AT). RESULTS: Teachers of the medical undergraduate programme hold a variety of COL, of how students learn and their AT. No significant correlations were found between teachers' conceptions of learning and their AT. CONCLUSIONS: Although UMP teachers' ideas on learning and teaching are very diverse, some of their conceptions are interrelated. Teachers' ideas on their own learning is sometimes - but not always - related to how they think about student learning. But most importantly, the way UMP teachers think about learning is not automatically converted into the way they approach teaching.

Evaluating the effectiveness of curriculum change. Is there a difference between graduating student outcomes from two different curricula?

BACKGROUND: Changing a curriculum raises the question whether the results, new curriculum student outcomes, are different from old curriculum student outcomes. AIMS: To see whether different curricula produce different outcomes, we compared test and questionnaire results of two cohorts. We wanted to know if there is a difference on knowledge and skills test results, and on the number of times students practiced their skills during their final internships. METHOD: We used two validated test instruments: the Dutch Progress Test (PT) and the Objective Structured Clinical Examination (OSCE). For reporting their skills practice, we asked students of both cohorts to fill out a basic skills questionnaire. RESULTS: We found no significant difference between both cohorts on the results of their knowledge test and their report on skills practice. On the OSCE, students from the new curriculum cohort scored significantly higher than old curriculum students. CONCLUSION: Curriculum change can lead to improvements in graduating students' outcome results.

Differential role of tachykinin NK3 receptors on cholinergic excitatory neurotransmission in the mouse stomach and small intestine.

BACKGROUND AND PURPOSE: Tachykinin NK(3) receptors are widely expressed in the mouse gastrointestinal tract but their functional role in enteric neuromuscular transmission remains unstudied in this species. We investigated the involvement of NK(3) receptors in cholinergic neurotransmission in the mouse stomach and small intestine. EXPERIMENTAL APPROACH: Muscle strips of the mouse gastric fundus and ileum were mounted in organ baths for tension recordings. Effects of NK(3) agonists and antagonists were studied on contractions to EFS of enteric nerves and to carbachol. KEY RESULTS: EFS induced frequency-dependent tetrodotoxin-sensitive contractions, which were abolished by atropine. The cholinergic contractions to EFS in the stomach were enhanced by the NK(3) antagonist SR142801, but not affected by the NK(3) agonist senktide or neurokinin B. The cholinergic contractions to EFS in the small intestine were not affected by SR142801, but dose-dependently inhibited by senktide and neurokinin B. This inhibitory effect was prevented by SR142801 but not by hexamethonium. SR142801, senktide or neurokinin B did not induce any response per se in the stomach and small intestine and did not affect contractions to carbachol. CONCLUSIONS AND IMPLICATIONS: NK(3) receptors modulate cholinergic neurotransmission differently in the mouse stomach and small intestine. Blockade of NK(3) receptors enhanced cholinergic transmission in the stomach but not in the intestine. Activation of NK(3) receptors inhibited cholinergic transmission in the small intestine but not in the stomach. This indicates a physiological role for NK(3) receptors in mouse stomach contractility and a pathophysiological role in mouse intestinal contractility.

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats.

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25-5 mg kg(-1)) or its vehicle (hydroxypropyl-beta-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6-S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Adelta-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Adelta-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition.

Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB receptors and fatty acid amide hydrolase.

Sepsis is an inflammatory condition that is associated with reduced propulsive gastrointestinal motility (ileus). A therapeutic option to treat sepsis is to promote intestinal propulsion preventing bacterial stasis, overgrowth and translocation. Recent evidence suggests that anti-oxidants improve sepsis-induced ileus. Cannabidiol, a non-psychotropic component of Cannabis sativa, exerts strong anti-oxidant and anti-inflammatory effects without binding to cannabinoid CB(1) or CB(2) receptors. Cannabidiol also regulates the activity of fatty acid amide hydrolase (FAAH) which is the main enzyme involved in endocannabinoid breakdown and which modulates gastrointestinal motility. Because of the therapeutic potential of cannabidiol in several pathologies, we investigated its effect on sepsis-induced ileus and on cannabinoid receptor and FAAH expression in the mouse intestine. Sepsis was induced by treating mice with lipopolysaccharides for 18 h. Sepsis led to a decrease in gastric emptying and intestinal transit. Cannabidiol further reduced gastrointestinal motility in septic mice but did not affect gastrointestinal motility in control mice. A low concentration of the CB(1) antagonist AM251 did not affect gastrointestinal motility in control mice but reversed the effect of cannabidiol in septic mice. Sepsis was associated with a selective upregulation of intestinal CB(1) receptors without affecting CB(2) receptor expression and with increased FAAH expression. The increase in FAAH expression was completely reversed by cannabidiol but not affected by AM251. Our results show that sepsis leads to an imbalance of the endocannabinoid system in the mouse intestine. Despite its proven anti-oxidant and anti-inflammatory properties, cannabidiol may be of limited use for the treatment of sepsis-induced ileus.

Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors.

Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent-like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent-like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or L-nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR-142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB-366791, iodo-resiniferatoxin (iodo-RTX) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB-366791 reduced contractions both to capsaicin and carbachol. Iodo-RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration-dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1-mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity.

Review article: gastrointestinal sensory and motor disturbances in inflammatory bowel disease - clinical relevance and pathophysiological mechanisms.

BACKGROUND: It is well known that inflammation has a profound impact on the neuromuscular apparatus of the gastrointestinal tract during the inflammatory insult and in periods of remission, at the site of inflammation and at distance from this site. The importance of this interaction is illustrated by the higher prevalence of functional gut disorders in patients with inflammatory bowel disease. AIMS: To document the epidemiological and clinical significance of functional alterations of gut motility and sensitivity in patients with inflammatory bowel disease and to formulate potential pathophysiological mechanisms. RESULTS AND CONCLUSIONS: Functional gut disorders occur frequently in patients with inflammatory bowel disease, both during inflammatory episodes and in periods of remission, and have a major impact on their quality of life. The clinical manifestations of these motility and sensitivity disorders vary and are often difficult to treat, mainly because therapeutic guidelines and specific diagnostic tests to distinguish inflammatory bowel disease from functional gut disorders are lacking. Chronic bowel inflammation results in a complicated interaction between neuroendocrine serotonin-predominant cells of the mucosa, inflammatory cells (particularly mast cells) in the submucosa, the intrinsic and extrinsic innervation and the muscular apparatus including the interstitial cells of Cajal. The outcome of this interaction is a perturbation of gastrointestinal motor function, both locally and at distance from the site of inflammation and during both acute inflammation and remission.

TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats.

Rats with experimental colitis suffer from impaired gastric emptying (GE). We previously showed that this phenomenon involves afferent neurons within the pelvic nerve. In this study, we aimed to identify the mediators involved in this afferent hyperactivation. Colitis was induced by trinitrobenzene sulfate (TNBS) instillation. We determined GE, distal front, and geometric center (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. We evaluated the effects of the transient receptor potential vanilloid type 1 (TRPV1) antagonists capsazepine (5-10 mg/kg) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 1-10 mg/kg) and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (150 microg/kg). To determine TRPV1 receptor antagonist sensitivity, we examined their effect on capsaicin-induced relaxations of isolated gastric fundus muscle strips. Immunocytochemical staining of TRPV1 and RT-PCR analysis of TRPV1 mRNA were performed in dorsal root ganglion (DRG) L6-S1. TNBS-induced colitis reduced GE but had no effect on intestinal motility. Capsazepine reduced GE in controls but had no effect in rats with colitis. At doses that had no effects in controls, BCTC and CGRP-(8-37) significantly improved colitis-induced gastroparesis. Capsazepine inhibited capsaicin-induced relaxations by 35% whereas BCTC completely abolished them. TNBS-induced colitis increased TRPV1-like immunoreactivity and TRPV1 mRNA content in pelvic afferent neuronal cell bodies in DRG L6-S1. In conclusion, distal colitis in rats impairs GE via sensitized pelvic afferent neurons. We provided pharmacological, immunocytochemical, and molecular biological evidence that this sensitization is mediated by TRPV1 receptors and involves CGRP release.

Clinical skills training in a skills lab compared with skills training in internships: comparison of skills development curricula.

CONTEXT: The necessity of learning skills through "integrated skills training" at an undergraduate level has been supported by several studies. The University of Antwerp implemented undergraduate skills training in its renewed curriculum in 1998, after it was demonstrated that Flemish students did not master their medical skills as well as Dutch students who received "integrated skills training" as part of their undergraduate medical course. AIM: The aim of this study was to compare the skill outcome levels of two different student populations: students who had been trained in basic clinical skills mainly through clinical internships in year 7 with students who had learned these skills through an integrated longitudinal programme in a special learning environment in years 1-5 prior to their internship experience. STUDY SAMPLE: Students of the traditional curriculum learned skills through a 75 hour programme in years 4 and 5, through plenary sessions followed by a 12 month period of internships during which skills could be further practiced. We tested this group right after completion of their internships. Students from the renewed curriculum followed a 200 hour intensive small group skills training programme offered in years 1-5. This group was tested before starting their internships. RESULTS: On global OSCE-scores, renewed curriculum students had significantly higher overall scores (p<0.001) and they scored significantly higher at 6 of 15 stations. There was no significant difference at 8 stations, while traditional curriculum students scored better at station 1. DISCUSSION: 5 years and 200 hours of integrated undergraduate skills training is more effective as a method of learning basic clinical skills, compared to learning these skills through 75 hours of traditional skill training and reinforcement of these skills in 12 month clinical internships, when measured by means of an OSCE.

Experimental pancreatitis disturbs gastrointestinal and colonic motility in mice: effect of the prokinetic agent tegaserod.

Acute pancreatitis remains a potentially life-threatening disease associated with gastrointestinal motility disturbances. Prokinetic agents may be useful to overcome these motility disturbances. In this study, we investigated the effect of acute necrotizing pancreatitis (ANP) on gastrointestinal motility in female mice and evaluated the effect of tegaserod, a prokinetic 5-hydroxytryptamine-4 (5HT4) receptor agonist. ANP was induced by feeding mice a choline-deficient ethionine-supplemented diet during 72 h. In vivo intestinal motility was measured as the geometric centre (GC) of 25 glass beads 30-120-360 min after gavage. Colonic peristaltic activity was studied using a modified Trendelenburg set-up. ANP significantly decreased GC 30-120-360 min after bead gavage, associated with a significant increase of myeloperoxidase in the proximal small intestine and colon, but not in the stomach or distal small intestine. Tegaserod significantly ameliorated GC 360 min after bead gavage in control and pancreatitis mice. In isolated colonic segments, ANP significantly decreased the amplitude of peristaltic waves and increased the interval between peristaltic contractions. Tegaserod normalized the disturbed interval. In conclusion, ANP impairs gastric, small intestinal and colonic motility in mice. Tegaserod improves ANP-induced motility disturbances in vivo and in vitro, suggesting a therapeutic benefit of prokinetic 5HT4 receptor agonists in the treatment of pancreatitis-induced ileus.