Jafar Jafari

Psychophysiological responses to pain identify reproducible human clusters

Summary Pain is a variable experience, yet the relative contributions of factors postulated to explain this effect remain unresolved. We address this knowledge gap by identifying 2 homogeneous reproducible human pain clusters. Abstract Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter‐linked polymorphic region (5‐HTTLPR) genotype were measured. Real‐time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≥ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≥ 0.001). During pain, less stimulus was tolerated (P ≥ 0.01), and there was an increase in parasympathetic tone (P ≥ 0.05). The 5‐HTTLPR short allele was over‐represented (P ≥ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≥ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.

Randomised clinical trial: pregabalin attenuates the development of acid-induced oesophageal hypersensitivity in healthy volunteers - a placebo-controlled study.

Background  Acid infusion in humans induces primary and secondary oesophageal hypersensitivity. The effects of pregabalin, a centrally‐acting modulator of voltage‐sensitive calcium channels, on development of acid‐induced oesophageal hypersensitivity remain unknown.

Deglutitive Inhibition, Latency Between Swallow and Esophageal Contractions and Primary Esophageal Motor Disorders

Swallowing induces an inhibitory wave that is followed by a contractile wave along the esophageal body. Deglutitive inhibition in the skeletal muscle of the esophagus is controlled in the brain stem whilst in the smooth muscle, an intrinsic peripheral control mechanism is critical. The latency between swallow and contractions is determined by the pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle. A wave of inhibition precedes a swallow-induced peristaltic contraction in the smooth muscle part of the human oesophagus involving both circular and longitudinal muscles in a peristaltic fashion. Deglutitive inhibition is necessary for drinking liquids which requires multiple rapid swallows (MRS). During MRS the esophageal body remains inhibited until the last of the series of swallows and then a peristaltic contraction wave follows. A normal response to MRS requires indemnity of both inhibitory and excitatory mechanisms and esophageal muscle. MRS has recently been used to assess deglutitive inhibition in patients with esophageal motor disorders. Examples with impairment of deglutitive inhibition are achalasia of the LES and diffuse esophageal spasm.

Normal esophageal pressure topography metrics for data derived from the Sandhill-Unisensor high-resolution manometry assembly in supine and sitting positions

Normal values of the esophageal motor function parameters for high‐resolution manometry (HRM‐EPT) adopted by the Chicago classification were established using the proprietary system of Given Imaging. It is conceivable that normal values of a system do not apply to data from others. Most studies using HRM were based on supine swallows, whereas deglutition occurs mostly in the upright position. We wished to establish normal values for HRM‐EPT parameters obtained with the Sandhills HRM‐EPT system and compare the results in supine and sitting positions.

Case report: Achalasia-like dysmotility secondary to oesophageal involvement of sarcoidosis

We present a case of a patient with sarcoidosis and who subsequently developed dysphagia for solids, and some difficulty in swallowing liquids. High-resolution manometry of the oesophagus showed absent peristalsis in the oesophageal body and incomplete relaxation of the lower oesophageal sphincter. The diagnosis of sarcoidosis with oesophageal involvement was made and treatment with prednisolone 30 mg OD initiated. The patient improved symptomatically and high-resolution manometry was repeated showing complete recovery of oesophageal peristalsis and a deeper relaxation of the lower oesophageal sphincter. This is thus the first description of high-resolution manometry in sarcoidosis-induced changes of the oesophagus and of the effect treatment has on these motility changes. Oesophageal involvement of sarcoidosis is extremely rare and only a few cases have been reported. The symptoms and manometric pattern of this disorder mimics that of achalasia. However, we show that treatment with prednisolone results in a completely disappearance of the symptoms of dysphagia and subsequently lead to a large improvement of oesophageal motility.

Determinants of reflux-induced chronic cough

Objective Gastro-oesophageal reflux is considered to be an important contributing factor in chronic unexplained cough. It remains unclear why some reflux episodes in the same patient causes cough while others do not. To understand more about the mechanism by which reflux induces cough, we aimed to identify factors which are important in triggering cough. Design In this multicentre study, 49 patients with reflux-associated chronic cough were analysed using 24-hour pH-impedance-pressure monitoring. The characteristics of reflux episodes that were followed by cough were compared with reflux episodes not associated with cough. Results The majority (72.4%) of the reflux episodes were acidic (pH<4). Compared with reflux episodes that were not followed by cough, reflux episodes that were followed by a cough burst were associated with a higher proximal extent (p=0.0001), a higher volume clearance time (p=0.002) and a higher acid burden in the preceding 15 min window (p=0.019) and higher reflux burden in the preceding 30 min window (p=0.044). No significant difference was found between the two groups when looking at the nadir pH, the pH drop, the acid clearance time or the percentage of reflux episodes which were acidic. Conclusions The presence of a larger volume of refluxate and oesophageal exposure to reflux for a longer period of time seems to play an important role in inducing cough, while the acidity of the refluxate seems to be less relevant. This helps explain the observation that most patients with chronic cough tend not to benefit from acid inhibitory treatment.

370 Effect of Azithromycin on Esophageal Hypomotility (EH) and Prediction of Response by Esophageal Stimulations Tests During High Resolution Manometry

of villus formation at embryonic day (E)14.5. This analysis revealed crack-like extensions of the lumen from the apical surface into the epithelium, which lengthen over time. The tips of these cracks are associated with dividing cells. Because of this association and a precedent for lumen-forming cell divisions in the zebrafish neural keel, we speculated that these cells might generate cracks by trafficking apical proteins to the cytokinetic plane. Using intestinal explant cultures in concert with nocodazole-mediated synchronization of the cell cycle, we examined the trafficking of the apical protein Ezrin during cell division. We found that Ezrin is deposited along the cytokinetic plane of divisions at crack tips, defining new villus domains and segregating daughter cells onto adjacent villi. We call these specialized cell divisions e-divisions (lumen extending). We also noted a second type of cell division, which functions in intestinal growth, but is not associated with apical cracks and does not define new villus domains. We have named these divisions g-divisions (growth building). Eand g-divisions differ cell biologically in several ways: localization of apical proteins, segregation of daughter cells, midbody morphology, and angle of the mitotic spindle relative to the nearest overlying apical surface. Ezrin null mice have fused villi with underlying isolated secondary lumens. Such a phenotype has been thought to support the secondary lumen model of normal villus morphogenesis, because it was believed that the loss of Ezrin perturbs their fusion with the main lumen. However, we have now determined that dividing cells in Ezrin null mice have mis-oriented mitotic spindles; we speculate that mis-orientation of e-divisions may in fact cause ectopic lumens and fused villi in this model. Indeed, the characteristic phenotype of Ezrin null mice can be recapitulated in wild-type intestines after treatment with blebbistatin, a myosin II inhibitor that results in mis-oriented spindles both in vitro and in intestinal explant cultures. This indicates that correct spindle orientation is indispensible for proper villus morphogenesis. Further understanding of this process will open up new avenues of in vitro bioengineering of intestinal surface, potentially providing life-saving therapies for those with intestinal failure.

Sa1365 Aerophagia During Meals and Postprandial Gas-Containing Reflux in Patients With GERD Not Responding to PPI

Introduction A significant number of GORD patients (30%) continue to perceive symptoms despite PPI therapy. Impedance-pH studies have shown that proximal extent of reflux and presence of gas in the refluxate are the only parameters associated with symptoms perception in refractory GORD. Increased air swallowing (aerophagia) is often suspected based on clinical evaluation. More recently, increased air swallowing between meals was demonstrated, using oesophageal impedance, in a group of patients with increased abdominal gas (x-ray). Aerophagia during meals, however, may be more relevant for GORD patients with postprandial symptoms. We hypothesised that mealtime air swallowing may impact on post-prandial reflux patterns and symptoms in patients with refractory GORD. We aimed to assess aerophagia during meals and postprandial gas reflux in GORD patients, responding or refractory to PPI. Methods Mealtime air swallows were quantified using ambulatory impedance-pH monitoring. Normal values were established from 39 healthy controls (mean age 39, range 22–62; Shay et al 2004). We studied 44 consecutive patients (mean age 48, range 19–78) with typical reflux symptoms and pathological oesophageal 24 h acid exposure. 18 were fully responsive and 26 were partially or unresponsive to PPI. Mealtime air swallows were defined as swallows with fast impedance increase (>3000Ω from baseline) in the distal recording segment. Mealtime air swallow frequency (air swallows/10 min meal) was calculated. Results There was no difference in mealtime air swallow frequency (mean±SEM 8.6±1.0 vs 8.0±0.7 per 10 min) or total mealtime air swallows (67.1±8.3 vs 54.0±5.3) between GORD patients and controls. In the GORD group, PPI-refractory patients had a higher frequency (10.5±1.4 vs 5.9±0.8, p Conclusion GORD patients had similar mealtime air swallowing to controls, but both groups had large inter-individual variability. Within GORD patients, PPI non-responders had more mealtime air swallowing than responders. Consequently non-responders had more reflux episodes containing gas, an important factor in reflux perception in GORD patients, who have hypersensitivity to oesophageal distension. Mealtime air swallowing may be amenable to behavioural therapy as an “add on” treatment in patients with incomplete response to PPI and objective aerophagia during meals. Competing interests None declared.

Dysphagia in patients with the joint hypermobility syndrome

Introduction The Joint Hypermobility Syndrome (JHS) is a relatively frequent inherited connective tissue disorder characterised by marked joint hyperextensibility and extra-articular manifestations. Recent work suggests that gastrointestinal (GI) symptom prevalence may be as high as 86%1 in these patients, and that many of them have evidence of GI dysmotility.2 Dysphagia is a symptom which is not uncommon in these patients, but which has never been formally studied. In general terms, dysphagia is either due to a structural abnormality of the oesophagus or a motility problem. Methods A single-centre retrospective observational study was carried out to characterise the cause of non-structural dysphagia in patients with JHS. JHS patients who were referred to the upper GI physiology unit and who complained of dysphagia were identified. Their HRM and 24-h pH-metry traces were analysed to characterise oesophageal motility, presence of a hiatus hernia, lower oesophageal sphincter (LOS) pressure and presence of gastro-oesophageal reflux (GOR). Results 17 patients with JHS and dysphagia were referred by the rheumatologists to our unit in 1 year: 76% female; age range: 12–58. None had evidence of a structural cause for the dysphagia on either gastroscopy or barium studies. 10 (59%) had an oesophageal dysmotility to account for their dysphagia – out of these one had achalasia; the other 9 (53%) had oesophageal hypomotility with 7 having frequent hypotensive peristalsis and 2 having intermittent hypotensive peristalsis. 33% of those with hypomotility had a normal Multiple Rapid Swallow test (MRS). 7 of the 17 patients (41%) had normal oesophageal motility and 6 of these had reflux studies: 50% had GOR, 17% had a hypersensitive oesophagus and the remaining 33% had normal studies. Only 2 patients (12%) had hiatus hernias and both of these had oesophageal hypomotility and no GOR. Conclusion This is the first study of upper GI physiology in patients with JHS and non-structural dysphagia. Oesophageal hypomotility is common in these patients and those patients with normal MRS are likely to show the best response to prokinetics. 50% of those with normal motility had pathological GOR and would benefit from high dose proton pump inhibitor therapy. The remainder had normal studies, suggesting hypersensitivity which may respond to treatment with neuromodulators such as amitriptyline. Only 12% of patients had a hiatus hernia, which is in contrast to previous studies.3 Further prospective studies are required to understand the pathophysiology and management options for dysphagia in JHS.

Objective Assessment of Aerophagia During Meals in Normal Subjects and Patients With Post-Prandial Bloating and Belching

Introduction Many patients attending GI physiology units for assessment of dysphagia and GORD also complain of postprandial bloating and/or belching. Excessive fasting aerophagia has been recently described in patients with severe continuous bloating and belching. Exaggerated air swallowing during meals might be more relevant for postprandial symptoms but, thus far, objective assessment of prandial aerophagia and normal values are lacking. Oesophageal impedance can detect air swallowing. We aimed to quantify aerophagia during meals in asymptomatic subjects and patients with postprandial bloating and belching. Methods We assessed aerophagia during meals using ambulatory impedance-pH monitoring in 39 healthy, asymptomatic controls (from the US-Belgian MII-pH Normal value study, Shay et al . 2004; mean age in original study 39, range 22–62) to establish normal 95% confidence intervals. We identified 38 patients (mean age 43, range 17–74) with postprandial bloating and/or belching who attended the GI physiology unit for assessment of dysphagia or GORD as primary symptoms. Mealtime air swallows were visually identified when swallows were associated with antegrade flow and fast impedance increase (at least 3000 Ω from baseline) in the most distal recording segment. A score of air swallows/10 min mealtime was calculated for each subject. In patients with mealtime exaggerated air swallowing (above 95th percentile of normal values) we examined for evidence of concomitant fasting aerophagia. Results The 95% percentile range of mealtime aerophagia in normal subjects was 6.8 to 9.4 episodes/10 min, mean 8.1. Patients had significantly higher mealtime air swallowing rates than controls (mean 11.8 episodes/10 min, SEM 1.0, p = 0.003 ). There was no significant difference between predominant bloating and belching subgroups. Only 4 of 23 patients with exaggerated mealtime air swallowing had concomitant fasting aerophagia. Conclusion We established normal values of mealtime air swallowing using oesophageal impedance. Patients with postprandial bloating and/or belching exhibit increased aerophagia during meals. Most of these patients do not have fasting aerophagia. Exaggerated air swallowing during meals can now be objectively detected and biofeedback techniques can be attempted to modify such behaviour as a potential therapeutic strategy for these patients with functional GI symptoms.