Association between human rhinovirus C and severity of acute asthma in children.

A new and potentially more pathogenic group of human rhinovirus (HRV), group C (HRVC), has recently been discovered. We hypothesised that HRVC would be present in children with acute asthma and cause more severe attacks than other viruses or HRV groups. Children with acute asthma (n = 128; age 2-16 yrs) were recruited on presentation to an emergency department. Asthma exacerbation severity was assessed, and respiratory viruses and HRV strains were identified in a nasal aspirate. The majority of the children studied had moderate-to-severe asthma (85.2%) and 98.9% were admitted to hospital. HRV was detected in 87.5% and other respiratory viruses in 14.8% of children, most of whom also had HRV. HRVC was present in the majority of children with acute asthma (59.4%) and associated with more severe asthma. Children with HRVC (n = 76) had higher asthma severity scores than children whose HRV infection was HRVA or HRVB only (n = 34; p = 0.018), and all other children (n = 50; p = 0.016). Of the 19 children with a non-HRV virus, 13 had HRV co-infections, seven of these being HRVC. HRVC accounts for the majority of asthma attacks in children presenting to hospital and causes more severe attacks than previously known HRV groups and other viruses.

The fate of patients who undergo "preoperative" ERCP to clear known or suspected bile duct stones.

BACKGROUND: There is debate as to whether recurrent biliary complications are more common in patients who do not have elective cholecystectomy after endoscopic retrograde cholangiopancreatography (ERCP) management of common bile duct (CBD) stones. The aim of this study was to determine the fate of patients with intact gallbladders who have had CBD stones removed at ERCP, and to assess their risk of recurrent biliary symptoms. METHODS: We retrospectively identified all patients in our large tertiary center population with intact gallbladders who had an ERCP for CBD stones from December 1999 to March 2002. We determined which patients had subsequent elective cholecystectomy, and the outcomes of patients who did not have elective surgery. RESULTS: 309 patients had CBD stones at ERCP during the study period, of which 139 had intact gallbladders at the time of ERCP. Of these 139 patients 59 had subsequent elective cholecystectomy, 11 by open operation and 48 laparoscopically. Of these 139 patients, 27 had cholecystectomy planned; 47 patients were managed with a wait-and-see strategy, 30 of whom were poor surgical candidates. Of these 47 patients in whom a wait-and-see policy was adopted, 9 (19%) developed complications including recurrent pain and/or abnormal liver function tests (LFTs), recurrent biliary colic, and pancreatitis. Eight of these nine patients were from the poor surgical candidate group. Sphincterotomy had been performed at initial ERCP in all patients. CONCLUSIONS: Over half of our population of 139 patients with CBD stones at ERCP and intact gallbladders had actual or planned elective cholecystectomy. For those patients in whom a decision to wait-and-see was made, almost 20% developed complications. Elective cholecystectomy after a finding of choledocholithiasis is supported by many and is a common strategy in our experience. Recurrent biliary complications are relatively common in those who do not undergo elective cholecystectomy, especially those patients who represent a high operative risk.

Serial viral infections in infants with recurrent respiratory illnesses.

To better understand the viral aetiology of recurrent and prolonged illnesses, nasal secretions were prospectively collected from 285 infants at increased risk of developing asthma. Of these, 27 infants had recurrent (at least five) moderate-to-severe respiratory illnesses (MSIs). The viral aetiology of the 150 MSIs and 86 scheduled visits was analysed by molecular diagnostics. The demographic and clinical data were compared with infants who had 0-4 MSIs. Frequently ill infants had higher exposure to other children and more wheezing illnesses than less symptomatic children. Viruses were detected in 136 (91%) out of 150 MSIs, 14 (67%) out of 21 mild illnesses and 29 (45%) out of 65 asymptomatic visits. Human rhinovirus was the most common aetiological agent (61, 43 and 35% in MSIs, mild illnesses and asymptomatic visits, respectively). Mixed viral infections were generally associated with more severe illnesses (27, 0 and 5%, respectively). Among the 27 frequently ill infants, only eight (5.3%) out of 150 MSIs were prolonged (> or =2 weeks duration). Considering all samples, detection of the same virus strain > or =2 weeks apart was unusual (5.3% of all 244 positive findings). Human rhinovirus infections occur early, pervasively and repetitively in these high-risk infants. Infants with prolonged or recurrent respiratory illnesses most often have a series of infections rather than persistent infection with one virus strain.

The influence of processing factors and non-atopy-related maternal and neonate characteristics on yield and cytokine responses of cord blood mononuclear cells.

RATIONALE: Several studies have evaluated the associations between cord blood cellular responses and atopic diseases in children, but the results of these studies are inconsistent. Variations in blood processing factors and maternal and infant characteristics are typically not accounted for and may contribute to these inconsistencies. METHODS: Cord blood samples were obtained from 287 subjects participating in the Childhood Origins of ASThma project, a prospective study of children at high risk for the development of asthma/allergies. Mononuclear cells were stimulated with phytohaemagglutinin (PHA), phorbal myristate acetate/ionomycin or a suspension of killed staphylococcus, and IFN-gamma, IL-10 and IL-13 were quantitated by ELISA. Cell yields and cytokine production were related to processing factors and maternal and infant characteristics. RESULTS: The strongest relationships between independent variables and cell yield or cytokine responses occurred with the season of birth. The highest median cell yields were seen in fall, and the lowest in summer (difference of 47%, P=0.0027). Furthermore, PHA-induced IL-5 and IL-13 responses were approximately 50% higher in spring and summer than in fall or winter (P<0.0001). Clots in the cord blood samples were associated with a reduced median cell yield (42% reduction, P<0.0001), and an increased PHA-induced IL-10 secretion (27% increase, P=0.004). CONCLUSIONS: These data suggest that season of collection, and to a lesser extent clotting in samples, affect cord blood mononuclear cell yield and cytokine responses. Careful documentation and analysis of processing and environmental variables are important in understanding biological relationships with cytokine responses, and also lead to greater comparability among studies using these techniques.

Enterogastrone-like effect of peptide YY is vagally mediated in the dog.

Intraluminal fat inhibits gastric secretion through as yet undetermined mechanisms which involve release of one or more hormonal enterogastrones. As intraluminal fat releases Peptide YY (PYY) in amounts sufficient to inhibit meal-stimulated acid secretion, this ileo-colonic peptide exhibits the characteristics required of an enterogastrone. The present study seeks to determine the mechanism by which PYY inhibits acid secretion by examining the effects of PYY on gastric acid stimulated by pentagastrin, histamine, and bethanechol. In addition, effects of PYY on the acid response to sham feeding and distention of a denervated gastric pouch were examined. A dose of PYY (400 pmol X kg-1 X h-1) was employed that reproduced blood levels observed after intestinal perfusion with oleic acid and inhibited the acid secretory response to an intragastric meal by 35 +/- 6%. This same dose of PYY maximally inhibited histamine- and pentagastrin-stimulated acid secretion by 28 +/- 7% (P less than 0.05), and 17 +/- 4% (P less than 0.05), respectively. Although PYY had no effect on bethanechol-stimulated secretion it markedly inhibited the secretory response to sham feeding, maximally reducing secretion by 90 +/- 4% (P less than 0.01). We speculate that PYY acts by inhibiting acetylcholine release from vagal nerve fibers rather than by inhibiting acetylcholine's action on the parietal cell. The demonstration that PYY virtually abolishes cephalic phase acid secretion while having little if any effect on the response to exogenous secretogogues gives PYY unique characteristics among the known hormonal inhibitors of gastric secretion.

Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach.

In humans and dogs, it is known that motilin regulates phase III contractions of migrating motor complex (MMC) in the fasted state. In rats, however, motilin and its receptor have not been found, and administration of motilin failed to induce any phase III-like contractions. Ghrelin was discovered as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) from the rat stomach. Ghrelin promotes gastric premature phase III (phase III-like contractions) in the fasted state in rats. We hypothesized that endogenous ghrelin regulates spontaneous phase III-like contractions in rats. Strain gauge transducer was sutured on the antrum and a catheter was inserted into the jugular vein. We studied the effects of i.v. administration of ghrelin and a GHS-R antagonist on gastric phase III-like contractions in conscious rats. Plasma level of ghrelin was measured by a radioimmunoassay. Ghrelin augmented spontaneous phase III-like contractions and a GHS-R antagonist significantly attenuated the occurrence of spontaneous phase III-like contractions. During the phase I period, plasma ghrelin level increased to its peak then returned to basal level, subsequently phase III-like contractions were observed. These results suggest that endogenous ghrelin regulates gastric phase III-like contractions in rats.

Laparoscopic distal pancreatectomy with splenic preservation.

BACKGROUND: The technique of distal pancreatectomy has been well described, both with en bloc resection of the spleen and with splenic preservation. Splenic preservation during pancreatic tail resection is desirable when oncologically appropriate, yet it is technically challenging, particularly with laparoscopic approaches. Skeletonization of the splenic artery and vein is associated with longer operative times and greater potential for bleeding. The authors report their experience with splenic preservation during laparoscopic pancreatic resection using ligation of the splenic vessels and preservation of the short gastric vessels. METHODS: A retrospective chart review was performed for all patients who underwent attempted laparoscopic pancreatic resection at Duke University Medical Center from July 2002 to October 2005. Charts were analyzed for demographic information, length of hospital stay, conversion, splenic preservation, and postoperative complications. RESULTS: A total of 12 laparoscopic distal pancreatic resections were attempted for three men and nine women with a mean age was 55.8 years (range, 33-74 years). All 12 patients underwent distal pancreatectomy, 8 with splenic preservation. The spleen was removed from three patients using splenic hilar lesions that prevented splenic salvage. One patient required splenectomy secondary to more than 50% ischemia of the spleen. No patients with preoperatively diagnosed malignancy underwent splenic salvage. The final pathologic diagnosis included neuroendocrine tumors (n = 2), cystic serous (n = 4) and mucinous (n = 2) neoplasms, intraductal papillary mucinous neoplasm (IPMN) (n = 1), pancreatitis (n = 2), and adenocarcinoma (n = 1). Two patients underwent conversion to open surgery for thickened parenchyma secondary to chronic pancreatitis (17%). There were no other conversions. There were three chemical leaks (25%) diagnosed by elevated drain amylase and low volume output, which were managed with intraoperatively placed drains removed at the initial postoperative clinic visit. There were three higher volume leaks (25%) that required extended or percutaneous drainage, with eventual removal. The average blood loss was 215 ml (range, 50-700 ml). The average operative time was 3 h and 41 min (range, 2 h 15 min to 5 h 58 min). The average length of hospital stay was 4 days (range, 2-7 days). CONCLUSION: Splenic preservation should be performed when technically possible to decrease the morbidity of laparoscopic distal pancreatectomy. The choice to ligate the splenic vessels allows for shorter operative times with minimal perioperative morbidity and blood loss while maintaining the spleen.

Impaired gastric motor activity after abdominal surgery in rats.

Postoperative ileus (POI) is a transient bowel dysmotility that occurs following abdominal surgery. Several mechanisms have been proposed such as neural reflex and inflammatory changes. We focused on gastric motility after abdominal surgery in rats. To investigate the time course of gastric motility after surgery, gastric motility was continuously recorded before, during and after surgery. After laparotomy, terminal ileum was manipulated for 10 min. Gastric motility was recorded by a strain gauge transducer implanted on the serosal surface of the stomach. To investigate whether peripheral sympathetic nerve is involved in the pathogenesis of POI, effects of guanethidine and celiac ganglionectomy were tested on the postoperative gastric motility. Although isoflurane anaesthesia reduced the gastric motility to 40%, the motility recovered immediately when isoflurane was withdrawn. Intestinal manipulation reduced the postoperative gastric motility for 3-24 h after surgery, compared with preoperative levels. Guanethidine administration and celiac ganglionectomy restored the impaired gastric motility. Feeding increased the gastric motility in each group. It is suggested that the pathogenesis of postoperative gastric ileus induced by intestinal manipulation involves viscero-sympathetic pathways. Intestinal manipulation causes impaired gastric motility via inhibitory sympathetic efferent pathway. Feeding may improve the postoperative gastric motility.

Percutaneous cervical oesophageal cannulation in the dog for the performance of prolonged oesophageal pH and manometric studies.

Traditional methods for obtaining oesophageal access in experimental animals are unsuitable for prolonged (24 h) oesophageal pH evaluation, a procedure that is commonly employed in the assessment of human patients suspected of having gastroesophageal reflux disease. In the present study, we describe a six-year experience with a technique of percutaneous oesophagostomy for the performance of serial 24 h oesophageal pH and manometric studies involving 62 dogs and a total of 208 oesophageal cannula placement procedures. The results indicate a considerable improvement over previously described techniques with respect to simplicity of surgical technique, associated morbidity, oesophagostomy management, animal conditioning, and avoidance of chemical and excessive physical restraints in animals undergoing oesophageal pH and manometric evaluation.

Role of neuropeptides in the regulation of feeding behavior: a review of cholecystokinin, bombesin, neuropeptide Y, and galanin.

The purpose of this report is to provide a review of four peptides (cholecystokinin, bombesin, neuropeptide Y, galanin) and their role in feeding behavior. Cholecystokinin (CCK) and bombesin (BBS) are considered satiety peptides, and neuropeptide Y (NPY) and galanin (GAL) have been proposed as appetite peptides. For the purposes of this review, satiety refers to the physiological cessation of feeding, and appetite refers to the drive to eat and exists in gradations.

Physiological satiety implications of gastrointestinal antiobesity surgery.

This manuscript reviews the known satiety signals and the impact of antiobesity surgery on these physiological satiety mechanisms. Satiety signals originate from the stomach and small bowel to stop eating behavior. Stomach signals (gastric distension) produce early satiety by releasing hypothalamic cholecystokinin (CCK). The intermeal interval is probably mediated by peripheral CCK released by a threshold level of intraluminal calories. Anti-obesity operations probably rely little on these physiological satiety signals. Gastric balloons and gastroplasty produce nonphysiological gastric distension whereas intestinal bypass causes malabsorption. Gastric bypass combines supramaximal gastric distension with taste aversion from dumping. Future physiological manipulation of the satiety cascade will lead to improve obesity intervention.

Magnetic-resonance imaging used for determining fat distribution in obesity and diabetes.

Computed-tomography scanning and magnetic-resonance imaging (MRI) have been used to quantify intraabdominal and subcutaneous fat depots. In this study MRI was used to define fat-distribution patterns in 24 obese females with non-insulin-dependent diabetes (NIDDM) and 12 females with simple obesity. Subjects had anthropometric measurements and single-slice abdominal scans performed at the umbilicus. In addition, in 10 of the nondiabetic females, measurements were repeated after 10 wk of a very-low-calorie diet. Nondiabetic females had significantly less intraabdominal fat (P less than 0.01) than did the diabetics but had equivalent subcutaneous fat. There was no significant relationship between waist-to-hip ratio and intraabdominal fat, subcutaneous fat, or their ratio. After a weight loss of 10.6 +/- 3.8 kg there were significant decreases in both intraabdominal and subcutaneous fat (P less than 0.01). Weight loss is associated with decreases in fat in both depots.

Relation of obesity, high sodium intake, and eccentric left ventricular hypertrophy to left ventricular exercise dysfunction in essential hypertension.

PURPOSE: To elucidate determinants of abnormal left ventricular functional responses to exercise in hypertensive patients. PATIENTS AND METHODS: One hundred twenty-seven patients with uncomplicated essential hypertension were studied by rest and exercise radionuclide angiography and by echocardiography at rest. RESULTS: The 24 patients with subnormal left ventricular ejection fraction at peak exercise (less than 54%) were similar in age and rest and exercise blood pressures to the 103 with normal exercise ejection fraction, but were more obese (p less than 0.005) and had greater left ventricular mass (p less than 0.03) and internal dimensions (p less than 0.001). The parallel increase in left ventricular chamber size and mass (eccentric hypertrophy) in the group of patients with exercise dysfunction was associated with higher resting end-systolic wall stress (p less than 0.001) and abnormal increases of end-systolic left ventricular volume from rest to peak exercise (p less than 0.001). Multivariate analysis revealed that exercise left ventricular dysfunction was independently associated with higher left ventricular mass (p less than 0.0005), end-systolic wall stress (p less than 0.001), dietary sodium intake (p less than 0.01), and body mass index (p less than 0.03). CONCLUSION: Among patients with uncomplicated essential hypertension, abnormal functional responses to exercise are strongly associated with eccentric ventricular hypertrophy, obesity, and high sodium intake.

Comparison of classification of the severity of hypertension by blood pressure level and by World Health Organization criteria in the prediction of concurrent cardiac abnormalities and subsequent complications in essential hypertension.

OBJECTIVE: To determine whether classification of the severity of hypertension according to the World Health Organization (WHO) system, which utilizes additional clinical and laboratory findings, is superior to classification by blood pressure level alone in predicting prognostically important cardiac structural abnormalities and the risk of subsequent complications in asymptomatic subjects. DESIGN: Two-hundred and twenty adults with uncomplicated essential hypertension underwent baseline clinical evaluation and echocardiography; 88% were subsequently followed for a mean of 11.6 years. SETTING: University hospital. RESULTS: Left ventricular mass index and relative wall thickness were slightly greater in patients in the highest diastolic or systolic blood pressure stratum than in WHO stage II hypertensives, but these results were statistically non-significant. High peripheral resistance index was best identified by diastolic blood pressure level. Receiver operating characteristic curve analysis showed that all three methods had similar test performance in predicting abnormal left ventricular mass index, left ventricular geometry, relative wall thickness and peripheral resistance. During follow-up the proportion of patients who had a clinical event or died increased with increasing severity stratum in all three clinical classification systems, but the trends were statistically non-significant. Risk stratification by echocardiographic left ventricular mass index was most successful in identifying patients at very high and very low risk of subsequent morbid events and all-cause mortality. CONCLUSION: Classification of hypertension severity by blood pressure level has similar, although limited, effectiveness at a lower cost than the WHO criteria in identifying patients with adverse cardiac changes and an impaired long-term prognosis. Echocardiographic measurement of left ventricular mass index was more successful than other classifications in predicting subsequent morbid events.

The other estrogen receptor in the plasma membrane: implications for the actions of environmental estrogens.

Environmental or nutritional estrogenic toxicants are thought to mediate developmental and carcinogenic pathologies. Estrogen receptor (ER) measurements are currently used to predict hormonal responsiveness; therefore all ER subpopulations should be considered. We have been involved in the immunoidentification and characterization of membrane steroid receptors in several systems and have recently shown that binding of estradiol (E2) to a subpopulation of ERs (mER) residing in the plasma membrane of GH3 pituitary tumor cells mediates the rapid release of prolactin (PRL). Here we review these findings and present other important characterizations of these receptors such as trypsin and serum susceptibility, movement in the membrane, confocal localization to the membrane, binding to and function of impeded ligands, and immunoseparation of cells bearing mER. We plan to use this system as a model for both the physiological and pathological nongenomic effects of estrogens and estrogenic xenobiotics. Specifically, it should be useful as an in vitro assay system for the ability of estrogenic xenobiotics to cause rapid PRL release as an example of nongenomic estrogen effects.

Review article: evaluation of drugs in experimental gut distension models.

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristics of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT3 receptor antagonist, alosetron.

Management of biliary complications after heart transplantation.

BACKGROUND: Immunosuppression increases the risk of biliary complications in heart transplant recipients. METHODS: Patients undergoing heart transplantation since 1986 who were at risk for cholelithiasis (n = 60) were retrospectively studied. RESULTS: Cholestatic jaundice developed in all patients after the operation because of biliary obstruction from cholelithiasis, cyclosporine toxicity, Imuran toxicity, or Gilbert's disease. The incidence of cholelithiasis or sludge was 42% (n = 25 of 60). Gallstones developed within 1.8 +/- 1.1 years in 17% of patients (n = 8 of 48) with a normal pretransplantation ultrasonogram. Biliary colic or gallstone pancreatitis developed 2 +/- 1.2 years after transplantation in 58% of patients (n = 7 of 12) with asymptomatic gallstones diagnosed before transplantation. The overall incidence of cholecystectomy or cholecystectomy with Roux-en-Y cystojejunostomy was 40% (n = 24). Both open cholecystectomy (n = 5) and laparoscopic cholecystectomy (n = 19) were performed without significant complications. Recovery is significantly more rapid (p < 0.05) after laparoscopic cholecystectomy versus open cholecystectomy (1 week versus 3 weeks). CONCLUSIONS: This analysis indicates that transplant candidates who have gallstones on pretransplantation evaluation or in whom gallstones develop after transplantation should undergo laparoscopic cholecystectomy at the earliest time in their posttransplantation course (i.e., 3 months) regardless of their symptomatic status. Removal of the diseased gallbladder not only simplifies the evaluation of cholestatic jaundice by eliminating the need for multiple ultrasonograms to exclude acute cholecystitis or choledocholithiasis but also safely minimizes the risk of the development of severe biliary complications.

Opposing central and peripheral actions of brain-gut peptides: a basis for regulation of gastric function.

The existence of an increasing number of peptides in both the gut and the brain provides the basis for the concept of a brain-gut axis. However, to date, no unifying hypothesis has been put forward to explain the physiologic significance of this remarkable phenomenon. The present study examines the central and peripheral actions on gastric function of cholecystokinin octapeptide (CCK-8), somatostatin, and bombesin, all of which exist in both the gut and brain. Intravenous infusion of CCK-8, in doses of 50, 100, and 200 pmol X kg-1 X hr-1, caused 28%, 38%, and 52% inhibition, respectively, of the rate of gastric emptying of a liquid meal in dogs. By contrast, the injection of 32, 64, and 128 pmol X kg-1 into the lateral cerebral ventricle of these dogs accelerated gastric emptying by 6%, 26%, and 32%, respectively. Bombesin, which stimulated gastric acid secretion in a dose-dependent manner but which had no effect on the submaximal acid response to pentagastrin when administered peripherally, inhibited in a dose-dependent manner the submaximal response to pentagastrin when given centrally, with a maximal inhibition of 66% +/- 5%, at a dose of bombesin of 180 pmol X kg-1. Similarly, somatostatin-14 caused graded inhibition of pentagastrin-stimulated acid secretion when it was administered peripherally but caused dose-dependent augmentation of the acid response when it was given centrally. Maximal inhibition of 51% of the pentagastrin response occurred with a peripheral dose of somatostatin of 800 pmol X kg-1 X hr-1. By contrast, maximal augmentation of the pentagastrin response of 78% occurred when a dose of 400 pmol X kg-1 of the peptide was injected into the lateral ventricle. We conclude that CCK-8, bombesin, and somatostatin have opposing actions on gastric function when administered centrally and peripherally. We propose that this phenomenon may be common to all neuropeptides of the brain-gut axis and may provide a basis for central regulation of gut function.

The use of somatostatin and its analogs in the treatment of surgical disorders.

Somatostatin is a naturally occurring peptide with a wide spectrum of biologic actions, most of which are inhibitory in nature. It has wide distribution, and within the gastrointestinal tract is is found in the pancreas, the stomach, intestinal mucosa, and myenteric neurons. It appears to function as a classic circulating hormone, as well as both a paracrine or locally acting agent and a neurocrine agent. Because of its inhibitory actions on gut endocrine, secretory, and motor functions, it has potential applicability in the treatment of a variety of disorders of interest to the surgeon. Indeed, it has been used successfully in the management of upper gastrointestinal hemorrhage, secretory diarrhea, short bowel syndrome, pancreatitis, gastrointestinal fistulas, and peptide-secreting tumors of the gut (apudomas). This review discusses physiology, pathophysiology, and therapeutic applications of somatostatin that may be important in surgical practice.

Interactions of vasoactive intestinal polypeptide and cholecystokinin octapeptide on the control of gallbladder contraction.

The gallbladder is supplied by three types of vagal fibers: cholinergic, cholecystokinin (CCK)-ergic, and vasoactive intestinal polypeptide (VIP)-ergic. Most previous studies on the interaction of VIP and CCK on gallbladder contraction have been in vitro. In this study we evaluate this interaction more fully in vivo using six dogs with chronic bile fistula. Dose-response curves were constructed to CCK-8 alone and to VIP alone. The effect of graded doses of VIP on maximal response to CCK-8 was also studied. CCK-8 caused the expected dose-related stimulation of gallbladder contraction, while graded doses of VIP had the opposite effect. VIP also caused a dose-related inhibition of the maximal response to CCK-8, decreasing bilirubin output from 39 +/- 8 to 15 +/- 3 mg/hr (p less than 0.05). The corollary to these findings is that gallbladder tone and contraction is regulated by the interplay of stimulatory cholinergic-CCK-ergic and inhibitory VIP-ergic fibers. Further, a plausible explanation for the variable effects of vagotomy on gallbladder contraction is that variable proportions of these opposing fibers are cut.