Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. METHODS: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. KEY RESULTS: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). CONCLUSIONS & INFERENCES: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

The relationship between complaints of night-time heartburn and sleep-related gastroesophageal reflux.

This study investigated whether the complaint of night-time heartburn (NHB) as opposed to daytime heartburn (DHB) is a reliable reflection of actual sleep-related reflux events. Three groups of individuals were studied: individuals with complaints of NHB at least twice per week (n = 24), individuals with complaints of DHB (n = 23), and normal participants without any complaints of regular heartburn during the day or night (n = 25). All three groups were studied on one occasion with combined pH monitoring and polysomnography, and subjective questionnaires about sleep disturbance and sleep quality were given to all participants. The NHB group had significantly more sleep-related reflux events compared with both DHB and control groups (P < 0.01). DHB subjects had significantly (P < 0.05) more sleep-related reflux events than normal controls. Total acid contact time (ACT) was significantly (P < 0.05) elevated in the NHB group compared with both the DHB and control group. Sleep-related ACT was also significantly (P < 0.05) elevated in the NHB group compared with the other two groups, while upright (daytime) ACT was not significantly different. The NHB group was significantly (P < 0.05) worse regarding measures of both objective and subjective sleep quality. Subjects with exclusively DHB do have sleep-related reflux that is greater than normal controls. Subjects with NHB have significantly more sleep-related reflux, and both objective and subjective sleep abnormalities compared with normal controls. Complaints of NHB reflect sleep-related reflux events and may be indicative of a more clinically significant condition.

The effect of baclofen on nocturnal gastroesophageal reflux and measures of sleep quality: a randomized, cross-over trial.

BACKGROUND: Baclofen, a GABA(b) agonist, has been shown to reduce episodes of gastroesophageal reflux (GER). To determine if baclofen would significantly reduce reflux during sleep, and also improve objective and subjective measures of sleep. METHODS: Twenty-one individuals with complaints of nighttime heartburn at least twice a week and a Carlsson GERD score of at least 5 were studied. Patients underwent polysomnography (PSG) and simultaneous esophageal pH monitoring on two occasions separated by approximately 1 week in a cross-over design. The night of each polysomnographic study, patients consumed a refluxogenic meal. Baclofen (40 mg) or placebo was given in random order 90 min prior to the start of the PSG. KEY RESULTS: Baclofen significantly reduced the number of reflux events compared with placebo. Upright and recumbent acid contact times were both reduced by baclofen vs placebo, but the differences were not significant. Regarding sleep outcomes, several variables were significantly improved by baclofen. Total sleep time and sleep efficiency increased, and wake after sleep onset decreased in the baclofen condition compared with placebo. Proportion of Stage 1 sleep was also significantly decreased on baclofen. CONCLUSIONS & INFERENCES: In addition to reducing the number of reflux events during sleep, baclofen significantly improved several measures of sleep in patients with documented GER and sleep disturbances. Baclofen could therefore be considered as a useful adjunct therapy to proton pump inhibitors (PPIs) in patients with nighttime heartburn and sleep disturbance who continue to have heartburn and/or sleep complaints despite PPI therapy.

Effects of mosapride on esophageal secondary peristalsis in humans.

BACKGROUND: Secondary peristalsis is important for the clearance of refluxate or retained food bolus from the esophagus. Mosapride is a prokinetic agent that enhances GI motility by stimulating 5-hydroxytrypatamine(4) (5-HT(4) ) receptors, but its effects on secondary peristalsis are yet unclear in humans. We aimed to investigate the effect of a 5-HT(4) agonist mosapride on esophageal distension-induced secondary peristalsis in normal subjects. METHODS: After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 15 healthy subjects. Two separate sessions with 40mg oral mosapride or placebo were randomly performed to test their effects on esophageal secondary peristalsis. KEY RESULTS: Mosapride decreased the threshold volume for triggering secondary peristalsis during rapid air distension (4.5±0.3 vs 5.3±0.4mL; P=0.04) but not slow air distension (14.3±1.2 vs 13.3±1.3mL; P=0.41). Secondary peristalsis was triggered more frequently in response to rapid air distension after application of mosapride [100% (90-100%) vs 90% (80-100%); P=0.02]. Mosapride significantly increased pressure wave amplitudes of secondary peristalsis during slow (135.4±13.8 vs 105.0±12.9mmHg; P=0.001) and rapid air distensions (124.0±11.6 vs 95.9±14.0mmHg; P=0.002). CONCLUSIONS & INFERENCES: Mosapride enhances sensitivity to distension-induced secondary peristalsis and facilitates secondary peristaltic contractility. These data provide an evidence for modulation of esophageal secondary peristalsis by the 5-HT(4) agonist mosapride, as well support for its clinical utility.

Effects of capsaicin-containing red pepper sauce suspension on esophageal secondary peristalsis in humans.

BACKGROUND: Capsaicin-sensitive afferents have been implicated in the modulation of gastrointestinal sensorimotor functions. Secondary peristalsis is important for the clearance of retained refluxate or material from the esophagus. The aim of this study was to evaluate the effects of capsaicin-containing red pepper sauce suspension on esophageal secondary peristalsis in healthy adults. METHODS: After a baseline recording of esophageal motility, secondary peristalsis was generated by slow and rapid mid-esophageal injections of air in 10 healthy subjects. Two separate sessions with saline and capsaicin-containing red pepper sauce were randomly performed to test their effects on esophageal secondary peristalsis. KEY RESULTS: Infusion of capsaicin significantly increased pressure wave amplitude during rapid (P = 0.002) and slow air infusions (P = 0.01). After capsaicin, the threshold volume to generate secondary peristalsis was significantly decreased during rapid (P < 0.05) and slow air infusions (P = 0.02). Infusion of saline did not affect any parameters of secondary peristalsis during rapid or slow air infusion. The administration of capsaicin was accompanied by the occurrence of heartburn in all subjects. CONCLUSIONS & INFERENCES: The acute administration of capsaicin-containing red pepper sauce suspension enhances sensitivity to distension-induced secondary peristalsis and facilitates secondary peristaltic contractility. These data suggest the involvement of capsaicin-sensitive afferents in the modulation of esophageal distension-induced secondary peristalsis in humans.

Review article: sleep-related gastro-oesophageal reflux as a distinct clinical entity.

BACKGROUND: Many patients with chronic gastro-oesophageal reflux disease (GERD) have frequent nighttime heartburn as well as sleep-related gastro-oesophageal reflux (GOR). Sleep-related GOR has been shown to play an important role in the development of oesophagitis and other complications of GOR. AIM: To present a conceptual argument that nighttime heartburn and associated sleep-related GOR should be recognized as a distinct clinical entity deserving special attention with regard to the diagnosis and treatment of GERD. METHODS: The data presented come from surveys of GERD patients as well as from physiological studies to include studies monitoring oesophageal pH and spontaneous reflux events during polysomnographically (PSG) monitored sleep. RESULTS: Evidence is presented to show that nighttime heartburn is prevalent and its occurrence separates patients from those who have heartburn most exclusively in the daytime. The evidence presented also supports the notion that nighttime heartburn sufferers have a more complicated disease and they have a greater risk of developing oesophagitis and other respiratory complications. The data also show that responses to acid mucosal contact are quite different during sleep compared to responses measured during the waking state. CONCLUSIONS: Nighttime heartburn and GOR represent a distinct clinical entity which deserves specific attention in the diagnosis and optimal treatment of GERD.

Night-time and daytime atypical manifestations of gastro-oesophageal reflux disease: frequency, severity and impact on health-related quality of life.

BACKGROUND: Respondents with gastro-oesophageal reflux disease (GERD) report having a variety of atypical manifestations. The relationship between these manifestations and disease severity, night-time GERD and functioning has not been determined. AIM: To determine if atypical manifestations are related to increased disease severity, night-time GERD and decreased functioning. METHODS: A web survey among US adults was conducted, using a validated GERD screener. Frequency of night-time and daytime typical symptoms (acid regurgitation and heartburn) and atypical manifestations were assessed. Respondents were classified as night-time GERD or daytime GERD based on typical symptom frequency. Prevalence of frequent atypical manifestations (> or =2 days or nights/week) was assessed. RESULTS: Gastro-oesophageal reflux disease cases had a higher prevalence of each atypical manifestation (P < 0.05 for all) compared with controls. Night-time GERD respondents had a higher prevalence of atypical manifestations compared with daytime GERD respondents (P < 0.05 for most manifestations) and the prevalence of atypical manifestations increased with GERD symptom severity (P < 0.05 for most). Those with atypical manifestations reported lower functioning scores (P < 0.05 for most). CONCLUSIONS: Respondents with typical GERD symptoms commonly report atypical manifestations, especially those with night-time symptoms and those with greater underlying GERD severity. Respondents with GERD and atypical manifestations had more impaired functioning than those with typical symptoms only.

Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity.

BACKGROUND: Effects of frequent nocturnal symptoms of gastro-oesophageal reflux disease (GERD-FNS) on health-related quality of life (HRQOL) and work productivity are not well documented. AIM: To assess symptom severity, production loss, and HRQOL among employed adults with and without GERD-FNS. METHODS: Using several validated outcome measures in a web survey design, GERD was pre-specified as GERD Symptom and Medication Questionnaire score >9, and > or =1 episode of heartburn or acid regurgitation during the preceding week. GERD-FNS patients were those reporting > or =2 symptom-nights during the previous week; their outcomes were compared with those of patients having minimal or no nocturnal symptoms (GERD-NNS) and vs. non-GERD controls. RESULTS: Data were collected from 1002 GERD patients (476 GERD-FNS, 526 GERD-NNS) and 513 controls. Severe symptoms were more common, sleep abnormalities were more frequent (P < 0.0001) and SF-36 scores lower (P < 0.05, all scores) among GERD-FNS patients vs. GERD-NNS patients. GERD-related work loss was greater among those with GERD-FNS vs. GERD-NNS (P < 0.0001). Work loss and functional limitations were more pronounced when comparing GERD-FNS cases vs. non-GERD controls. CONCLUSION: Employed adults with frequent nocturnal GERD report more severe symptoms, and are associated with impaired sleep, HRQOL and work productivity compared with controls and patients with minimal or no nocturnal symptoms.

The effect of acid suppression on sleep patterns and sleep-related gastro-oesophageal reflux.

BACKGROUND: Several studies have demonstrated that night-time gastro-oesophageal reflux affects sleep quality, and thereby impairs daytime functioning. AIM: To determine whether treatment with a proton-pump inhibitor (rabeprazole) would improve both objective and subjective measures of sleep. METHODS: Individuals with complaints of significant gastro-oesophageal reflux disease were studied by polysomnography and 24-h pH monitoring on two separate nights. On one occasion, participants received 20 mg rabeprazole b.d., and on another they received placebo. Both study conditions were preceded by a week of treatment with either rabeprazole or placebo. The order of treatments was randomized. RESULTS: Rabeprazole significantly reduced overall acid reflux, but it did not significantly reduce night-time acid contact. Rabeprazole treatment significantly improved subjective indices of sleep quality. There were no significant differences on objective measures of sleep between placebo and rabeprazole treatment. CONCLUSIONS: Consistent with other studies of pharmacological treatments for gastro-oesophageal reflux, subjective measures of sleep improved with heartburn medication but objective measures were not affected.

Review article: sleep and its relationship to gastro-oesophageal reflux.

Gastro-oesophageal reflux disease (GERD) is among the most common gastrointestinal conditions in the USA. For most symptomatic patients, reflux events occur during both daytime and night-time hours. Whereas daytime reflux events tend to be frequent but brief, reflux events that occur during sleep are comparatively less frequent but significantly longer. Longer oesophageal acid-clearance and acid-mucosal contact times during sleep are at least partly due to several physiological changes associated with sleep, including dramatic declines in saliva production and frequency of swallowing, decreased conscious perception of heartburn and consequent arousal and clearance behaviours, and slower gastric emptying. Obstructive sleep apnea syndrome and obesity seem to predispose some patients to nocturnal GERD, and the presence of either of these conditions may help to identify patients with symptoms consistent with GERD. Recognition and treatment of night-time GERD are important because it can be associated with decreased quality of life (including sleep disruption) and increased risk of serious oesophageal and respiratory complications.

Detection of gastric slow wave uncoupling from multi-channel electrogastrogram: validations and applications.

Current methodology of single channel electrogastrography is unable to detect coupling or uncoupling of gastric slow waves, which is crucial for gastric emptying. In this study, a new methodology, called cross-spectral analysis method, was established to compute the coupling percentage of multi-channel gastric slow waves recorded using serosal electrodes and electrogastrogram (EGG). Two experiments were performed to validate the method and demonstrate its applications in clinical research. In experiment 1, simultaneous recordings of gastric slow waves were made in five dogs from serosal electrodes and cutaneous electrodes. In experiment 2, four-channel fasting EGGs were made in 10 volunteers for 30 min during waking and 30 min during non-rapid eye movement (REM) sleep. The validation study (experiment 1) showed that the slow wave coupling calculated from the EGGs was correlated with that computed from the serosal recordings. The gastric slow wave coupling percentages detected from both serosal and cutaneous recordings were significantly impaired during vasopressin infusion (6.3 +/- 2.6 vs 62.4 +/- 6.3, P < 0.001 for serosal recordings; 6.7 +/- 3.0 vs 57.2 +/- 2.7, P < 0.001 for cutaneous recordings), and the coupling percentages respectively calculated from serosal and cutaneous recordings were significantly correlated during the baseline recording period (R = 0.922, P < 0.05) and vasopressin infusion period (R = 0.916, P < 0.05). In experiment 2, the gastric slow wave became less coupled when healthy volunteers fell asleep. The percentage of slow wave coupling calculated from the EGGs was 68.2 +/- 17.9% during waking but 41.9 +/- 20.8 during non-REM sleep (P < 0.05). The method developed in this study is reliable for the detection of slow wave uncoupling from multi-channel EGGs. Gastric slow wave coupling is impaired during vasopressin infusion and sleep. These data suggest that this method has potential applications in physiological and clinical studies.

The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the suppression of nocturnal oesophageal and gastric acidity.

BACKGROUND: It has been presumed that nocturnal acid breakthrough may pose a risk for the development of nocturnal gastro-oesophageal reflux. AIM: To investigate the occurrence of gastro-oesophageal reflux and acid breakthrough during polygraphically monitored sleep under conditions of powerful acid suppression with omeprazole 20 mg b.d. and an additional dose of ranitidine at bedtime. METHODS: Nineteen individuals with symptomatic gastro-oesophageal reflux disease were studied. Each individual was studied on two occasions subsequent to 1 week of 20 mg of omeprazole treatment b.d. Subjects underwent 24-h oesophageal and gastric pH recording, with polysomnographic monitoring. Participants received either 150 mg ranitidine at bedtime or placebo, prior to a provocative meal. RESULTS: Ranitidine administration resulted in a significant (P < 0.01) reduction in the percentage of time the intragastric pH < 4.0. There was no significant difference with regard to measures of gastro-oesophageal reflux, and reflux events were not noted to occur with a significantly greater frequency during periods of nocturnal acid breakthrough compared with control intervals without acid breakthrough. CONCLUSIONS: The administration of 150 mg ranitidine at bedtime did not significantly alter the occurrence of sleep-related gastro-oesophageal reflux.

Efficacy of a motilin receptor agonist (ABT-229) for the treatment of gastro-oesophageal reflux disease.

BACKGROUND: ABT-229 is a potent motilin agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. AIM: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. METHODS: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. RESULTS: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. CONCLUSION: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.

Selectivity of protein oxidative damage during aging in Drosophila melanogaster.

The purpose of the present study was to determine whether oxidation of various proteins during the aging process occurs selectively or randomly, and whether the same proteins are damaged in different species. Protein oxidative damage to the proteins, present in the matrix of mitochondria in the flight muscles of Drosophila melanogaster and manifested as carbonyl modifications, was detected immunochemically with anti-dinitrophenyl-group antibodies. Aconitase was found to be the only protein in the mitochondrial matrix that exhibited an age-associated increase in carbonylation. The accrual of oxidative damage was accompanied by an approx. 50% loss in aconitase activity. An increase in ambient temperature, which elevates the rate of metabolism and shortens the life span of flies, caused an elevation in the amount of aconitase carbonylation and an accelerated loss in its activity. Exposure to 100% ambient oxygen showed that aconitase was highly susceptible to undergo oxidative damage and loss of activity under oxidative stress. Administration of fluoroacetate, a competitive inhibitor of aconitase activity, resulted in a dose-dependent decrease in the life span of the flies. Results of the present study demonstrate that protein oxidative damage during aging is a selective phenomenon, and might constitute a mechanism by which oxidative stress causes age-associated losses in specific biochemical functions.

The peroxiredoxin gene family in Drosophila melanogaster.

Five peroxiredoxin genes have been identified in Drosophila melanogaster on the basis of a genome-wide search. Three of the genes (DPx-4156, DPx-4783, and DPx-5037) fall into the 2-Cys subgroup, while the other two (DPx-2540 and DPx-6005) belong to the 1-Cys subgroup. Using cDNAs, all five were expressed in E. coli and the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol. The three 2-Cys Prx were also shown to be active in the thioredoxin system and were, consequently, classified as thioredoxin peroxidases. Antisera raised against the DPx-4783 recombinant protein crossreacted with all family members and recognized protein species of the predicted sizes (22-27 kD). All five family members, when individually overexpressed in Drosophila S2 cells, conferred some resistance to H(2)O(2) treatment, as measured by cell viability. Functional diversification of the Drosophila peroxiredoxin family members was suggested by two lines of evidence: (i) the patterns of mRNA accumulation varied for the different genes during development and (ii) recombinant proteins fused to an epitope tag and overexpressed in Drosophila cells, differed in subcellular localizations--three proteins occurred in the cytosol, one was localized to the mitochondria, and one was found to be secreted.

The role of age and salivation in acid clearance in symptomatic patients with gastro-oesophageal reflux disease.

BACKGROUND: Cisapride has been shown to have not only prokinetic effects, but also salivary stimulating effects. Both of these mechanisms play an important role in the acid clearance of the oesophagus. AIM: To access the efficacy of cisapride in facilitating acid clearance in patients with symptomatic gastro-oesophageal reflux disease. METHODS: Fifteen older adults and 15 younger adults with symptomatic gastro-oesophageal reflux disease completed the study. The acid clearance test was accomplished by infusing 15 mL of 0.1 N HCl into the distal oesophagus, and the number of swallows was determined to achieve an oesophageal pH of 4.0. This was accomplished under baseline conditions and salivary stimulation with a peppermint lozenge. After 1 week of treatment with cisapride (10 mg, q.d.s.), the acid clearance test was repeated. RESULTS: The lozenge produced a significant decrease in the number of swallows compared to baseline in both groups (P < 0.01). There was a significant decrease in the number of swallows after the treatment with cisapride compared to baseline in both groups (P < 0.01). No significant difference was found in the number of swallows when comparing cisapride with lozenge. CONCLUSIONS: Cholinergic stimulation of salivation is an effective means of facilitating oesophageal acid clearance. Drugs, such as 5 hydroxytriptamine (5-HT)4-receptor agonists, should be considered as potentially important compounds in the treatment of gastro-oesophageal reflux disease.

Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.

OBJECTIVE: To investigate the psychological (affective and symptomatic) and physiological (autonomic and cortisol) responses to postprandial mental stress in women with irritable bowel syndrome (IBS). It was hypothesized that patients with IBS would show exaggerated autonomic and cortisol responses to the psychological stressor and that the stressor would enhance gastrointestinal symptoms. METHOD: Twenty-four women with IBS and 20 healthy women participated in the two-day study protocol. Both days were identical, with the exception that on one day, a stressful mental task was completed after ingestion of a standard meal. Heart rate variability, cortisol, affective, and symptomatic responses were measured before and after application of the stressor. RESULTS: Patients with IBS demonstrated increased negative affect at baseline and in response to the stressor. Gastrointestinal symptoms were not affected by the stressor. Appraisal of the stressor by patients with IBS was not different from that of controls. There were no group differences in the autonomic response to the stressor. There was no overall cortisol response to the stressor in either group. CONCLUSIONS: Patients with IBS respond with greater negative affect to postprandial psychological stress as well as to food intake alone, and they can be distinguished from controls on the basis of self-report data. Patients with IBS cannot be differentiated from controls on the basis of the pattern of changes in sympathetic activation after the mental stressor. The stressor used in this study did not elicit a cortisol response in either group.

Antioxidant status and stress resistance in long- and short-lived lines of Drosophila melanogaster.

The purpose of this study was to understand the nature of the biochemical and physiological variations between genetically different lines of Drosophila melanogaster. Selection for early or delayed reproduction has given rise to lines with substantial and heritable differences in longevity. The hypotheses tested were that either: (i) a compensatory slowing of metabolism, (ii) increased antioxidative enzyme activities, or (iii) elevated resistance to stressful conditions underlie these differences in longevity. The metabolic rate, metabolic potential (i.e. total amount of oxygen consumed during average lifespan) and speed of walking were all greater in long-lived than in short-lived flies, but there was no enhancement of antioxidant defenses. In fact, catalase activity was significantly lower in the long-lived flies. Long life was largely maintained under heat stress and starvation conditions, and was maintained to a lesser extent upon exposure to paraquat, a superoxide radical generator. In contrast, the 'short-lived' flies had a longer lifespan under cold stress and hyperoxia, also an inducer of radical generation. These results contradict the first two hypotheses and suggest that alleles underlying either long or short life are linked with enhanced resistance to specific kinds of stress, which may account for the preservation of these alleles in the parental population.

Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.

OBJECTIVE: As the primary link between brain and gut, autonomic and endocrine dysfunction may play a role in the pathophysiology of the irritable bowel syndrome (IBS). The aim of this study was to assess autonomic, endocrine, and symptomatic responses to food intake in diarrhea-predominant and constipation-predominant IBS patients, compared to normals. METHODS: Twelve women with diarrhea-predominant or alternating IBS (IBS-D), 12 women with constipation predominant IBS (IBS-C), and 20 healthy women participated. GI symptoms, saliva cortisol concentration, heart rate, and heart rate variability were assessed at baseline and after a meal. Spectral analysis of heart rate variability was used as a measure of the sympathovagal regulation of the heart rate. RESULTS: Both groups of IBS patients showed a significant postprandial increase in GI symptoms. IBS-D showed a significant increase in the low frequency/high frequency band ratio and a decrease in the high frequency band power during the first postmeal period, which was significantly different, not only from controls, but also from IBS-C. IBS-D also showed a significant postprandial increase in cortisol, which was not evident in controls or IBS-C. There was a significant correlation between the vagal response and the postprandial increase in GI symptoms in IBS-D (r = 0.6, p < 0.05). CONCLUSIONS: These findings support the notion that the IBS symptom groups are characterized by different physiological responses to visceral stimuli, and point to a role of autonomic pathways in IBS symptomatology.

Catalase expression in Drosophila melanogaster is responsive to ecdysone and exhibits both transcriptional and post-transcriptional regulation.

In the present study, we have examined catalase protein and mRNA levels and the factors that may regulate catalase expression in Drosophila melanogaster during development. Both mRNA and protein changes are in general accord with variations in ecdysteroid titer during development. Differences in mRNA and protein accumulation profiles, particularly in embryos and young adults, suggest that catalase may be regulated at both transcriptional and post-transcriptional levels. It was possible to induce catalase expression by administering exogenous 20-hydroxyecdysone (Ec) in culture at certain stages of development (usually at time points corresponding to previously observed hormone and catalase peaks). Experiments with exogenous administration of Ec, cycloheximide, and actinomycin D suggest a complex interplay of factors affecting catalase expression. In cultured third instar larvae, superinduction of catalase occurred in the presence of both Ec and cycloheximide. If ecdysteroid production was suppressed prior to antibiotic treatment by temperature upshift of the conditional mutant dre4(e55), superinduction occurred mostly at the protein level. In cultured adult abdomens, we observed induction by Ec and superinduction in the presence of hormone and translation or transcription inhibitors. Unlike what was observed in larvae, superinduction of catalase protein was dramatically more pronounced in control flies.