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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. [ABSTRACT FROM AUTHOR]

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 CB1 or CB2 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 CB1 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 CB1 receptors without affecting CB2 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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to comments made by doctor Huizinga with regards to an article published in a previous issue of this periodical.

Patients with IBD often suffer from impaired gastrointestinal motility, even at sites remote from the inflammation. We previously reported diminished gastric emptying associated with reduced gastric fundus contractility in rats with TNBS-induced colitis. The aims of the present study were (1) to exclude local gastric inflammation using MPO measurements and to rule out direct systemic influences on gastric neuromuscular function by examining the effect of TNBS-induced colitis on contractions of aortic vascular rings. Secondly (2) we tested the involvement of neuronal ganglionic (nicotinic) transmission and of extrinsic reflex pathways in impaired gastric emptying in rats with TNBS-induced colitis. Distal colitis was induced by rectal instillation of 30 mg trinitrobenzene sulphate (TNBS) in 50% ethanol 72 h prior to experiments. Gastric emptying (GE) and the geometric center (GC) of intestinal transit were measured 30 min after intragastric injection of a semiliquid bolus of Evans blue. TNBS colitis reduced gastric emptying from 38.4 ± 3.6% in controls to 22.7 ± 4.4% but had no effect on small intestinal transit. (1) Myeloperoxidase (MPO) measurements revealed no acute inflammatory changes in the stomach whereas MPO was significantly increased in the colon of TNBS rats. The study of aortic ring contractility showed no differences between control rats and rats with TNBS colitis. (2) The nicotinic receptor blocker hexamethonium (20 mg/kg ip 1 h prior to experiment) inhibited GE by 31% in controls ( P < 0.05) whereas it increased GE by 37% in TNBS rats ( P < 0.05). The GC of gastrointestinal transit was similarly affected. Extrinsic afferent innervation was abolished by capsaicin pre-treatment (50 mg/kg SC 14 days prior to experiment). Capsaicin reduced GE by 71% in control rats ( P < 0.05) while in TNBS rats its effect on GE was no longer significant (40% reduction). Capsaicin pre-treatment had comparable effects on the GC of gastrointestinal transit in controls and TNBS. In conclusion, we showed that TNBS colitis induces a pronounced gastroparesis which is not due to local gastric inflammation nor to systemic impairment of neuromuscular function. Moreover, it involves nicotinic synapses embedded in autonomic reflexes. A role for extrinsic afferent pathways sensitized by inflammatory mediators seems plausible. [ABSTRACT FROM AUTHOR]

Background & aim Since the development of knock out animals, the mouse has emerged as the model species to study GI motility. However, little information is available on the electrical and contractile activities induced by distension in the murine small intestine. In the present study we investigated the electrical and associated motor activity during distension in isolated segments of the murine small intestine. Methods Short segments of the murine small intestine were mounted in a Tyrode-superfused organ bath. Upon distension to 3.0 cmH20 periods of oscillations were generated. The electrical and contractile activities of these oscillations were recorded with a longitudinal row of 16 extracellular electrodes and a digital video camera. The electrodes recorded the slow wave and spike activities. The video camera monitored changes in intestinal configuration. Both signals were analyzed with custom-developed software. In addition the effect of verapamil (3 × 10−5) and atropine (10−5) were examined. Results Distension induced the appearance of oscillatory contractions. Motility analyses revealed that these oscillations propagated. The majority propagated aborally (50%), while others propagated in the oral (33%) or in both directions (17%). The frequencies, velocities and directions of the propagating oscillations were strongly correlated with the frequencies (R = 0.81), velocities (R = 0.83) and directions (R = 1.0) of the electrical slow wave. Atropine ( n = 4) and verapamil ( n = 4) abolished the propagating oscillations. Conclusion The distension induced propagating oscillations are caused by propagating slow waves and its accompanying action potentials. Frequency, direction and velocity of these propagating oscillations are determined by the underlying slow wave activity. These propagating oscillation are cholinergic and calcium-dependent. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Arthrofibrosis is a complication of intra-articular knee surgery which is caused by intra-articular fibrosis. To date, several preventive therapies for arthrofibrosis have been reported. This systematic review aims to summarize current knowledge about pharmacological arthrofibrosis prevention., Methods: A systematic literature search was conducted in Medline, Web of Science, and Cochrane library using the search term 'Arthrofibrosis AND prevention'. Subsequently, articles reporting the effects of a preventive pharmacological intervention against arthrofibrosis were included in this review., Results: 16 studies investigated the pharmacological prevention of arthrofibrosis of which 13 were conducted in animal models. Several drugs improved the range of motion (ROM) in animal models. Bevacizumab (ROM +39.4 degrees), nonsteroidal anti-inflammatory drugs (ROM +18.0-31.2 degrees), and rosiglitazone (ROM +19.5 degrees) significantly increased the ROM. Artesunate, mitomycin c, bevacizumab, hyaloglide, and botulinum toxin A significantly reduced adhesion scores. None of the drugs tested in humans improved the functional outcomes after joint arthroplasty. Methodological differences limited the ability to compare outcomes and, due to poor reporting of methodology, many studies had an unclear risk of bias., Conclusion: This review identified several drugs as potential candidates for arthrofibrosis prevention. These drugs modulate inflammation or alter the activity of fibroblasts. Most studies are conducted in experimental animal models and none of these results are currently translated into a clinical application. Moreover, the methodology and route of administration varied between studies. Nor were dose dependency studies conducted. Future studies should adopt a standardized approach to determine the effects of preventive pharmacological interventions on arthrofibrosis.

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., (© 2016 International Clinical Cytometry Society.)

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., (© Acta Gastro-Enterologica Belgica.)

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.

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.

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.