A 20-year perspective--from Journal of Gastrointestinal Motility to Neurogastroenterology and Motility.

This review traces the origins of this journal as the consequence of a revolution in academic publishing that started in Oxford 50 years ago. It also traces the expansion of the field of gastrointestinal motility by the development of new methodology that prompted both the creation of learned societies and a role for a journal devoted to this field. The problems that arose because the new journal was an 'orphan journal' lacking a parent society are recounted, as are the events that eventually led to its adoption. Finally, the introduction of the term 'neurogastroenterology' into scientific and clinical parlance is explained.

Is the NHS research ethics committees system to be outsourced to a low-cost offshore call centre? Reflections on human research ethics after the Warner Report.

The recently published Report of the AHAG on the Operation of NHS Research Ethics Committees (the Warner Report) advocates major reforms of the NHS research ethics committees system. The main implications of the proposed changes and their probable effects on the major stakeholders are described.

The nocturnal jejunal migrating motor complex: defining normal ranges by study of 51 healthy adult volunteers and meta-analysis.

Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.

Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women.

BACKGROUND: Aromatase catalyses the conversion of androgens to estrogens and thus variation in the aromatase gene could contribute to female syndromes of androgen excess, such as precocious pubarche (PP) and polycystic ovarian syndrome (PCOS). METHODS: Two groups, one case-control containing girls from Barcelona, Spain with PP (n = 186) or healthy controls (n = 71), and the other a population study of young women from Oxford, UK, who volunteered for a study of normal women's health (n = 109), were genotyped at four aromatase gene haplotype-tag single nucleotide polymorphisms (SNP). Clinical features and hormone concentrations relevant to hyperandrogenism were compared across haplotypes or genotypes. RESULTS: Distributions of aromatase haplotypes (P < 0.0001) and aromatase SNP_50 genotype (P = 0.001) were significantly different between PP girls and Spanish controls. The AGGG haplotype was associated with an odds ratio (95% confidence interval) of 0.5 (0.3-0.9) (P = 0.005) for the presence of PP compared to GAGG. In 84 post-pubertal PP girls, aromatase haplotype was associated with functional ovarian hyperandrogenism (P < 0.05), independently of insulin sensitivity. In the Oxford population, SNP_50 was associated with variation in PCOS symptom score (P = 0.008) and circulating testosterone concentrations (P = 0.02). CONCLUSIONS: This study suggests that common variation at the aromatase gene (and not just rare loss-of-function mutations) is associated with androgen excess in girls and young women.

Automated quantitative analysis of nocturnal jejunal motor activity identifies abnormalities in individuals and subgroups of patients with slow transit constipation.

OBJECTIVE: Small bowel dysmotility has previously been demonstrated in some patients with slow transit constipation (STC), suggesting a generalized intestinal disorder. However, no study has addressed whether the incidence of small intestinal dysfunction differs between subgroups of patients in this heterogeneous population. Using appropriate methodology, we aimed to determine prospectively the proportion of individuals with abnormal small bowel motility, and to assess whether heterogeneity in terms of pattern of colonic transit delay (based on (111)In diethylene-triamine-pentaacetic acid (DTPA) isotope scintigraphy), or mode of onset (based on clinical history) is of importance. METHODS: Thirty-seven patients with STC underwent 24-h ambulatory jejunal manometry; data were compared with those obtained in 38 healthy controls. Automated quantitative analysis of seven variables of the nocturnal migrating motor complex was performed, to assess whether differences existed between groups, and whether individual patients had evidence of small intestinal dysmotility, defined as two or more measures of migrating motor complex variables outside the normal range. Four variables differed significantly between STC patients and controls: in phase III, propagation was slower, duration was longer, and contraction amplitude was higher; in phase II, contraction frequency was increased. Seven of 24 patients with a generalized pattern of colonic transit delay had abnormal small bowel motility compared with none of 13 with a left-sided delay (p < 0.04). These included four patients with chronic idiopathic symptoms and three with acquired symptoms. Approximately one third of patients with a generalized delay in colonic transit had evidence of jejunal enteric neuromuscular dysfunction. Individual patients with a left-sided colonic delay did not satisfy the criteria for nocturnal small bowel dysmotility, but as a group, some differences were noted from controls. In contrast to previous reports, evidence of generalized enteric dysmotility may be present irrespective of the mode of onset.

Effect of octreotide on small intestinal motility in HIV-infected patients with chronic refractory diarrhea.

Octreotide has been used to treat HIV-associated diarrhea. We aimed to assess the effect of octreotide on small intestinal motility in a group of HIV infected individuals with chronic diarrhea. Small intestinal motility was measured continuously for 48 hr by ambulatory strain gauge manometry in 12 HIV seropositive subjects with chronic diarrhea. During the second 24-hr period, intravenous octreotide was administered (100 microg every 8 hr). Postprandial and nocturnal fasting motility data were compared before and during administration of octreotide. Octreotide was associated with increased numbers of migrating motor complexes (MMCs) (7.25 vs 4.92, P = 0.03), and a relative decrease in the duration of phase II (22% vs 49.8, P = 0.03) during nocturnal fasting activity. Postprandial activity was absent in half of the subjects and the duration significantly reduced in the remainder. In conclusion, octreotide has a significant effect on small intestinal motility in HIV-infected individuals with diarrhea, which may influence intestinal transit.

Delayed gastric emptying in human immunodeficiency virus infection: correlation with symptoms, autonomic function, and intestinal motility.

Gastric emptying may be delayed in HIV infection. We aimed to characterize the pattern of gastric emptying in HIV seropositive subjects and correlate the findings with symptoms, as well as to identify possible etiological factors. Solid gastric emptying was measured using scintigraphy in 54 HIV seropositive subjects and 12 HIV seronegative controls. Gastrointestinal symptoms were evaluated using a standardized numerical score, and autonomic function was assessed using spectral analysis of heart rate variability. Fasting and postprandial duodenojejunal activity was recorded using strain gauge manometry catheters. Gastric emptying rate, but not lag phase, was significantly delayed in HIV-infected subjects, particularly those with enteric infections and more advanced disease. Delayed gastric emptying did not correlate with symptoms, autonomic dysfunction, or small intestinal motility. In conclusion, abnormalities found in autonomic function and gastric emptying in HIV infection are multifactorial in nature. The contribution of upper gastrointestinal motor dysfunction to gastric symptoms in such individuals is unclear.

Human small bowel motor activity in response to liquid meals of different caloric value and different chemical composition.

Previous animal studies have shown that the nature and duration of postprandial motility in the small bowel depend both on the caloric load and the chemical composition of a meal. It is not clear whether this is also true for the human small bowel. Therefore we investigated the motor activity of the human small bowel in response to nutrient liquids of different caloric value and different chemical composition. Ten human volunteers underwent three separate, 24-hr ambulatory manometry studies. They drank water, a pure glucose solution, and Intralipid 10% in volumes of both 300 and 600 ml. The caloric value of the nutrient liquids was 330 and 660 kcal, respectively. Records were analyzed visually for the reappearance of phase III of the MMC after ingestion of a test liquid, and a validated computer program calculated the incidence and amplitude of contractions during the postprandial period. Neither duration of the postprandial interval nor the mean incidence or mean amplitude of contractions were different between the fat and the carbohydrate solutions, but phase III reappeared significantly later after ingestion of the nutrient liquids than after water (P = 0.0002). Duration of the postprandial interval also depended on the volume or the caloric load of a liquid meal (P = 0.0012). Mean incidence of contractions tended to be higher after ingestion of nutrient liquids than after water (P = 0.059). We conclude that in ambulant subjects, small bowel motor activity in response to chemically diverse liquid meals is remarkably uniform. This is true for the duration of the postprandial motor activity, as well as the incidence and amplitude of contractions during that period. The caloric value of a liquid meal, however, regulates the duration of the postprandial interval in the human small bowel.

Effect of viscous fiber (guar) on postprandial motor activity in human small bowel.

Both caloric value and chemical composition of a meal have been shown to regulate postprandial small bowel motility in dog. In the same species, duration of and contractile activity within the postprandial period also depends on mean viscosity. It is unknown, however, whether meal viscosity and fiber content also regulate small bowel motor activity in man. In human volunteers, we therefore studied the effect of guar gum on small bowel motor response to liquid and solid meals. Twenty-six prolonged ambulatory small bowel manometry studies were performed in 12 volunteers. A total of 620 hr of recording were analyzed visually for phase III of the MMC and a validated computer program calculated the incidence and amplitude of contractions after ingestion of water (300 ml), a pure glucose drink (300 ml/330 kcal) or a solid meal (530 kcal) with and without 5 g of guar gum. Addition of 5 g of guar gum did not significantly delay reappearance of phase III after ingestion of water (59 +/- 11 vs 106 +/- 21 min; P = 0.09). However, guar gum significantly prolonged duration of postprandial motility pattern both after the glucose drink (123 +/- 19 vs 199 +/- 24 min; P < 0.05) and after the solid meal (310 +/- 92 vs 419 +/- 22 min; P = 0.005). Contractile activity during these periods was not affected by guar gum. This was true for mean incidence of contractions after water (1.9 +/- 0.3 vs 1.8 +/- 0.5 min-1), after the glucose drink (1.6 +/- 0.4 vs. 1.7 +/- 0.3 min-1) and after the solid meal (2.4 +/- 0.4 vs 2.6 +/- 0.4 min-1). Likewise, mean amplitude of contractions was not affected by guar gum after water (22.8 +/- 1.4 vs 20.9 +/- 1.9 mm Hg), after the glucose drink (20.5 +/- 1.4 vs 21.3 +/- 1.2), and after the solid meal (20.3 +/- 1.5 vs 21.5 +/- 1.6 mm Hg). Thus a guar gum-induced increase in chyme viscosity markedly prolonged duration of postprandial motor activity in the human small bowel. Contractile activity within the postprandial period, however, was not affected. We suggest that the postprandial motility pattern persisted longer after the more viscous meals, because gastric emptying and intestinal transit were delayed by guar gum. We conclude that it is essential to define meal viscosity and fiber contents when studying postprandial small bowel motility.

Daytime and night time motor activity of the small bowel after solid meals of different caloric value in humans.

BACKGROUND: Meals disrupt the interdigestive pattern of small bowel motor activity and convert it into the postprandial pattern. Previous studies have shown that duration of postprandial motor activity depends on the caloric value of a meal, but results from two recent human studies suggested that there is a caloric ceiling, above which an additional increase in the caloric load fails to prolong the postprandial period further. AIM: To investigate the hypothesis of a caloric ceiling by studying daytime motor activity of the human small bowel in response to five solid meals, covering a wide range of calories. METHODS: Eight healthy male volunteers underwent five separate, ambulatory small bowel manometry studies and had a total of 80 meals. For lunch, volunteers ate between one and five portions of a solid meal (220, 440, 660, 880, or 1100 kcal). Ten hours later and 30 minutes before they went to bed, they ate either two or four portions of the same meal (440 kcal or 880 kcal). Recordings were analysed visually for phase III of the migrating motor complex and a validated computer program calculated incidence and amplitude of contractions. RESULTS: Apart from two versus three portions (440 kcal v 660 kcal), postprandial motor activity was significantly prolonged by each 220 kcal increase in the caloric load of the lunch (168 (SEM 14), 305 (22), 298 (23), 368 (36), and 398 (38) min). Mean incidence of contractions was significantly different only between the two extremes tested: 220 kcal and 1100 kcal (2.9 (0.3) v 4.5 (0.6) min-1). Amplitude of contractions did not depend on meal size. Daytime and night time postprandial activity were not significantly different. This was true for duration of fed activity, as well as mean incidence and amplitude of contractions during the postprandial period. CONCLUSION: Caloric value of a meal regulates duration of the fed activity in the human small bowel over a wide range of calories, and-for caloric loads up to 1100 kcal-there is no maximum duration of postprandial motor activity. Furthermore the postprandial small bowel motor activity is very similar between daytime and night time.

Comparison of the small bowel motor response to solid and liquid meals in man.

Interdigestive motor activity has been studied extensively both in the human and canine small intestine. The more irregular postprandial pattern, however, has rarely been studied. In particular, physiological studies in humans are lacking. Thus it is unknown whether the physical state of a meal affects the duration of the postprandial motor activity or contractile activity during the postprandial period. 8 healthy male volunteers, aged 19-38 years, underwent a single ambulatory 24-hour manometry study. During the study, volunteers had two physiological meals. The solid meal consisted of pasta with vegetables, and the liquid meal was a vanilla milk drink. The two meals were both palatable, isocaloric (660 kcal) and had an identical fat content (32%). Recordings were analyzed visually for phase III of the migrating motor complex and a validated computer program calculated the mean frequency and amplitude of contractions as well as the mean area under the curve (AUC). The postprandial period was significantly shorter after the liquid meal compared to the solid meal (196 +/- 43 vs. 298 +/- 23 min; p < 0.04). During the postprandial period, the mean incidence of contractions (2.0 +/- 0.5 vs. 3.7 +/- 0.4 min(-1); p < 0.02) and the mean AUC (132 +/- 32 vs. 236 +/- 27 mm Hg x s x min(-1); p < 0.02) were significantly lower after the liquid meal. The mean amplitude of contractions during the total postprandial period, however, was not significantly different between the two test meals (19.3 +/- 0.6 vs. 18.6 +/- 0.8 mm Hg). We conclude that human small bowel motor activity differs markedly between solid and liquid meals. Thus the postprandial pattern persists longer after solid meals, and this may have been due to the slower gastric emptying of solids as opposed to liquids. Furthermore the small bowel contracts far more frequently after solid meals.

Oesophageal acid and salivary secretion: is chewing gum a treatment option for gastro-oesophageal reflux?

The presence of acid in the oesophagus has been shown to stimulate salivary secretion, but the relevance of this oesophago-salivary reflex for acid clearance in physiological and pathological gastro-oesophageal reflux (GOR) is unknown. This study was designed to investigate the interrelation between oesophageal acid and both resting and stimulated salivary secretion. In 10 healthy volunteers, the acid clearance times after bolus infusion of 20 ml of 0.1 N hydrochloric acid were measured by means of ambulatory oesophageal pH monitoring. With a constant swallowing rate and resting salivary flow, the acid clearance time was significantly longer with dry as opposed to wet swallows (12.6 +/- 2.6 vs. 6.9 +/- 1.9 min; p = 0.01). When the salivary flow was doubled by chewing a gum base (26.0 +/- 3.4 vs. 13.2 +/- 2.0 ml/15 min; p = 0.005), the acid clearance time was markedly shortened (6.9 +/- 1.9 vs. 2.3 +/- 0.2 min; p = 0.02). As compared with water control, salivary flow, pH, and protein content were not affected by a bolus infusion of hydrochloric acid. This was true both for resting and gum-stimulated salivary secretion. Our study suggests that an oesophago-salivary reflex becomes effective only in prolonged episodes of GOR. This may explain why the water brash phenomenon is not regularly experienced by all reflux patients. Our study also suggests that chewing gum might be a non-pharmacological treatment option for some patients with symptomatic GOR.

Electrical activity of the sensory afferent pathway in the enteric nervous system.

In this paper we develop a mathematical model for the electrical activity of the afferent pathway, formed from the coupled primary and secondary sensory neurons. The primary sensory neuron possesses the electrical properties of AH neurons and morphological characteristics of Dogiel type II neurons; the secondary sensory neuron displays the tonic type of electrical behavior and has morphological features of Dogiel type III neurons. Free nerve endings of the mechanoreceptor form the receptive field of the pathway. Based on the general principles of the Hodgkin-Huxley description of excitable cells, the model simulates the following sequence of events: stretch of the receptive field initiates the dendritic potential at the mechanoreceptors; the excitation causes soma action potential development at the primary sensory neuron which is followed by soma action potential generation at the secondary sensory neuron. Numerical calculation have shown that the model is capable of reproducing different electrical patterns within the pathway under normal physiological conditions and after treatment with charybdotoxin, iberiotoxin, tetrodotoxin, omega-conotoxin GVIA, A1-A2 purinoceptor agonists, a protein kinase C activator, and a delta-opioid receptor agonist. Comparison of the computational results with the results of experiments conducted on the neurons of the submucous and myenteric plexi of the small bowel demonstrates their good qualitative and quantitative agreement.

Model predictions of myoelectrical activity of the small bowel.

A mathematical model for the periodic electrical activity of a functional unit of the small intestine is developed. Based on real morphological and electrophysiological data, the model assumes that: the functional unit is an electromyogenic syncytium; the kinetics of L, T-type Ca2+, mixed Ca(2+)-dependent K+, potential sensitive K+ and Cl- channels determines electrical activity of the functional unit; the basic neural circuit, represented by a single cholinergic neurone, provides an excitatory input to the functional unit via receptor-linked L-type Ca2+ channels. Numerical simulation of the model has shown that it is capable of displaying the slow waves and that slight modifications of some of the parameters result in different electrical responses. The effects of the variations of the main parameters have been analyzed for their ability to reproduce various electrical patterns. The results are in good qualitative and quantitative agreement with results of experiments conducted on the small intestine.

The effect of barium sulphate on small bowel motility in man.

OBJECTIVE: To investigate the effect of barium sulphate on small bowel motor activity. METHODS: Nine healthy male volunteers underwent two separate, ambulatory 24 h manometry studies. Jejunal motor activity was recorded during fasting and after ingestion of 300 ml volumes of barium, water or a glucose solution (1380 kJ). Recordings were analysed visually for recurrence of phase III of the migrating motor complex, and a validated computer program was used to calculate the incidence and amplitude of contractions. RESULTS: Phase III reappeared 71 +/- 10 min after ingestion of barium sulphate. This interval was not significantly different after the intake of water (60 +/- 8 min) or in the fasted state (88 +/- 21 min), but it was significantly shorter than after ingestion of a glucose solution (136 +/- 17 min). The mean incidence of contractions after ingestion of barium was 3.0 +/- 0.5/min. This was significantly higher than that observed after water (1.9 +/- 0.4/min) and also significantly higher than during fasting (1.5 +/- 0.3/min), but not significantly different from the incidence of contractions after ingestion of a glucose solution (2.2 +/- 0.4/min). The mean amplitude of contractions after ingestion of barium was 24.2 +/- 1.4 mmHg. This was significantly higher than the amplitude of contractions during fasting (19.5 +/- 1.0 mmHg), but not significantly different from that after water intake (23.7 +/- 1.3 mmHg) or after ingestion of a glucose solution (21.4 +/- 1.3 mmHg). CONCLUSION: Small bowel motor activity after ingestion of barium sulphate differs distinctly both from the interdigestive and from the postprandial motor pattern. Barium suspensions do not interrupt the migrating motor complex with a typical 'fed' pattern, but contractions are more frequent after ingestion of barium than after the intake of water and are both more frequent and of greater force than the contractions observed during the fasted state.

Physiological and symptomatic outcome after laparoscopic gastric fundoplication.

The complications of open antireflux operations may be reduced by laparoscopic techniques. Fifteen patients of median age 42 (range 16-79) years with gastro-oesophageal reflux underwent laparoscopic fundoplication. Preoperative and postoperative assessment was by clinical scoring, oesophageal pH measurement and manometry. Median (range) operating time was 115 (60-210) min and hospital stay 3 (1-6) days, with no conversions to open operation and only one minor wound infection. Four patients had occasional reflux symptoms on postoperative assessment at a median of 7 weeks and nine had occasional dysphagia. Median DeMeester symptom scores improved from 4 to 1.5 (P = 0.001). There were significant increases in both lower oesophageal sphincter pressure and length. The nocturnal proportion of time at pH < 4 decreased from 9.6 to 0.05 per cent (P = 0.02), although the drop in total proportion of time at pH < 4 (10.4 to 2.2 per cent) was not statistically significant (P = 0.08). Early objective results of laparoscopic fundoplication show improved symptoms, decreased acid reflux and altered lower sphincter function. The procedure combines the benefits of early mobilization and reduced morbidity with the efficacy of the traditional open operation.

Effect of cisapride on distal colonic motility in the early postoperative period following left colonic anastomosis.

PURPOSE: This study was designed to investigate the modulatory effect of cisapride on colonic motility in the postoperative period. METHODS: A prospective, double-blind, randomized, placebo-controlled trial of 14 patients undergoing left colonic anastomosis was carried out. Manometric probes were positioned with transducers on either side of the anastomosis, and colonic activity was recorded continuously for a median of 98 (range, 72-144) hours using an ambulatory system. Quantitative indices of motility were calculated with an automated analysis program. RESULTS: Isolated waveform activity returned at a median of 1.8 (interquartile range, 1-3) hours and motor complex activity at 24 (interquartile range, 19-30) hours in the placebo group and at similar times in the cisapride group. All motility variables except mean amplitude increased significantly with time in both groups. In the cisapride group the motility index was significantly increased compared with the placebo group (P = 0.03), resulting from an increase in percentage duration of activity (P = 0.002). Activity index, mean amplitude of waveforms, and number of waves greater than 50 cm H2O did not differ between groups. In contrast to placebo, cisapride significantly increased the median number of waves greater than 13 cm H2O and percentage duration of activity distal to the anastomosis compared with proximally. The return of bowel sounds (median, 43, interquartile range, 24-48 hours vs. 67, 29-69 hours; P = 0.2) or first passage of flatus (78, 54-94 hours vs. 94, 81-105 hours; P = 0.1) did not differ between groups. CONCLUSIONS: Although cisapride may have a differential effect on the colon proximal and distal to an anastomosis and significantly increases some indices of motility in the early postoperative period, these are unlikely to be of any clinical relevance.