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PubMed2001

Immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine in gallbladder epithelium of patients with pancreaticobiliary maljunction.

OBJECTIVES: Pancreaticobiliary maljunction, an anomalous union of the pancreatic duct with the common bile duct, is a risk factor for biliary carcinoma. We hypothesized that, in patients with pancreaticobiliary maljunction, persistent regurgitation of pancreatic juice into the biliary tract induces oxidative DNA damage. We assessed the expression of an oxidative DNA base-modified product, 8-hydroxy-2'-deoxyguanosine, in gallbladder epithelium. DESIGN: Eleven noncancerous gallbladders from patients with pancreaticobiliary maljunction, 12 gallbladder carcinomas from patients without pancreaticobiliary maljunction and 14 noncancerous gallbladders from patients without pancreaticobiliary maljunction (control) were studied. METHODS: Immunohistochemistry was performed for 4-hydroxy-2-nonenal-modified protein (as a marker for lipid peroxidation), 8-hydroxy-2'-deoxyguanosine and p53 gene product. RESULTS: Stronger cytoplasmic staining of 4-hydroxy-2-nonenal-modified protein was observed in the gallbladder epithelium from patients with pancreaticobiliary maljunction than in epithelium from gallbladder cancer patients or from control subjects with normal gallbladders. Clear, strong nuclear staining of 8-hydroxy-2'-deoxyguanosine was observed in the gallbladder epithelial cells from patients with pancreaticobiliary maljunction. Densitometric quantitation revealed significantly higher expression of 8-hydroxy-2'-deoxyguanosine in gallbladder epithelial cells from patients with pancreaticobiliary maljunction (index 27.3 +/- 3.1) than in cells from patients with gallbladder carcinoma (11.4 +/- 1.5; P < 0.05) or from control subjects with normal gallbladder (6.4 +/- 1.0; P < 0.05). Positivity of p53 was 27% in gallbladder epithelium associated with pancreaticobiliary maljunction, 75% in gallbladder carcinoma epithelium and 0% in control epithelium. CONCLUSIONS: These results suggest that reactive oxygen species are produced in the gallbladder of patients with pancreaticobiliary maljunction and that oxidative DNA injury is related to carcinogenesis in these patients.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1996

Luminal cholecystokinin and gastrin cause gallbladder contraction.

Cholecystokinin-8 placed in the gallbladder lumen causes gallbladder contraction by a neurally mediated, tetrodotoxin-sensitive mechanism. We wished to determine whether other cholecystokinin-like peptides in the gallbladder lumen cause contraction and whether this response is inhibited by cholecystokinin-receptor antagonists. In this study, we measured gallbladder contraction induced by cholecystokinin-like peptides or by hepatic bile placed in the gallbladder lumen. Isolated gallbladders were suspended in an organ bath while luminal hormones were infused. Gallbladder contraction was measured by continuous monitoring of luminal pressure. Cholecystokinin-8, cholecystokinin-5, and gastrin-17 caused dose-related gallbladder contraction with similar potency when placed in the lumen. Each stimulated 70-80% maximal contraction at a luminal concentration of 10(-6) M. Cholecystokinin-receptor antagonists CR1409 and loxiglumide partially inhibited contraction caused by luminal cholecystokinin-8. Bile from fed animals, but not from fasted animals, stimulated gallbladder contraction to 36 +/- 4% of maximal when placed in the gallbladder lumen. We conclude that cholecystokinin and gastrin peptides in the gallbladder lumen cause contraction. This may be mediated through receptors of the cholecystokinin-B type, possibly on intrinsic nerves. Bile from fed animals also contains substances that stimulate gallbladder contraction when bile is placed in the gallbladder lumen. These findings suggest intrinsic nerves participate in the postprandial gallbladder response to cholecystokinin.

Animals↗

PubMed2006

Hartmann's gallbladder pouch revisited 60 years later.

BACKGROUND: Hartmann's gallbladder pouch was the subject of an article in The Lancet 60 years ago. It has regained new interest in view of laparoscopic cholecystectomy. However, different opinions exist with regard to its incidence and nature. To elucidate these discrepancies, a descriptive study was performed with regard to the incidence and morphology of Hartmann's pouch. METHODS: Gallbladders were obtained after elective laparoscopic cholecystectomy. In addition, gallbladders were obtained during routine postmortem examination. The gallbladders were divided in two groups: those with Hartmann's pouch and those without Hartmann's pouch. All the gallbladders were examined macroscopically and microscopically. Fisher's Exact Probability Test (p < 0.05, two-tailed) was used to analyze the data. RESULTS: A total of 98 gallbladders were examined: 49 obtained after laparoscopic or open cholecystectomy and 49 obtained after postmortem examination. Among the gallbladders with Hartmann's pouch (n = 51), 65% contained stones and 35% had no stones. Among the gallbladders without Hartmann's pouch, 43% contained stones and 57% had no stones. Macroscopically, in all the gallbladders with Hartmann's pouch, the pouch was observed to result from adhesions between the cystic duct and the neck of the gallbladder. After cleavage of these adhesions, the phenomenon of Hartmann's pouch was abolished in all cases. CONCLUSIONS: Hartmann's gallbladder pouch is a frequent but inconstant feature of normal and pathologic human gallbladders. There is a significant association between the presence of Hartmann's pouch and stones (p < 0.05). Adhesions between the cystic duct and the neck of the gallbladder are responsible for Hartmann's pouch. Consequently, Hartmann's gallbladder pouch is a morphologic rather than an anatomic entity.

Adult↗

PubMed1990

Mechanism of cholecystokinin-induced contraction of the opossum gallbladder.

The present study evaluated the mechanism of cholecystokinin-induced gallbladder contraction in awake opossums. Each of 19 chronic animal preparations had an indwelling gallbladder cannula for monitoring changes in gallbladder volume and a jugular catheter for administration of cholecystokinin octapeptide and drugs. An intraduodenal catheter allowed intraduodenal infusion of Isocal (Mead Johnson Laboratories, Evansville, Ind.). Bipolar electrodes in the stomach, duodenum, and jejunum enabled monitoring of the duodenal migratory myoelectric complex cycle. One-hour infusions of cholecystokinin octapeptide (10 ng/kg/min), intraduodenal Isocal (0.4 ml/min), or feeding were started 20 min after cessation of phase 3 duodenal migratory myoelectric complex activity. Bolus intravenous doses of potential pharmacological antagonists were given 10 min before and 20 min after the onset of cholecystokinin octapeptide infusion, Isocal infusion, or feeding. Each test challenge induced about 60% gallbladder emptying at 30 min and 70% at 60 min. Cholecystokinin octapeptide-induced gallbladder emptying was converted to filling by hexamethonium and nearly abolished by atropine. Similar results were obtained for gallbladder emptying induced by feeding or duodenal infusion of Isocal. Phentolamine caused a modest decrease of cholecystokinin octapeptide-induced gallbladder contraction at 30 min, whereas postprandial or Isocal-induced gallbladder contraction was unaffected. Cholecystokinin octapeptide-induced gallbladder contraction was not affected by pirenzepine, 4-diphenylacetoxy-N-methylpiperidine methiodide, prazosin, pyrilamine, cimetidine, methysergide, naloxone, or propranolol. In acute studies of anesthetized animals, gallbladder contraction induced by a D100 intravenous bolus of cholecystokinin octapeptide (800 ng/kg) was not antagonized by hexamethonium, atropine, or tetrodotoxin. It is concluded (a) that cholecystokinin-induced physiologic contraction of the opossum gallbladder occurs through neural mechanisms rather than by a direct action of cholecystokinin on gallbladder smooth muscle, and (b) that studies using pharmacologic bolus doses of cholecystokinin octapeptide and tetrodotoxin indicate that cholecystokinin receptors exist on the gallbladder smooth muscle which do not seem to have any physiological role in gallbladder emptying.

Animals↗

PubMed1997

Gallbladder motility and lithogenicity of bile in patients with choledocholithiasis after endoscopic sphincterotomy.

BACKGROUND/AIMS: Ablation of the sphincter of Oddi has been shown to inhibit gallstone formation in the prairie dog model, probably by alleviating gallbladder bile stasis. The effect of endoscopic sphincterotomy (ES) on gallbladder emptying and lithogenicity of bile has not been studied adequately in humans. We, therefore, studied the changes in gallbladder emptying and lithogenicity of bile following ES in patients with choledocholithiasis and gallbladder in situ. METHODS: Thirteen patients with choledocholithiasis with intact gallbladder underwent ES and common bile duct clearance. Eight patients had concomitant gallstones. Gallbladder emptying was studied by real time ultrasonography after stimulation by ceruletid infusion. Fasting gallbladder bile was collected during endoscopic retrograde cholangiography by placing a 7F or 8F catheter in the common bile duct and after ceruletid stimulation of gallbladder for bile microscopy and cholesterol nucleation time determination. Gallbladder emptying, nucleation time and bile microscopy were performed before ES and again between 4 and 8 weeks after ES after cholangiographic confirmation of clearance of common bile duct stones. RESULTS: Fasting and residual gallbladder volumes decreased and ejection fraction increased significantly following ES, suggesting decreased stasis and improved emptying of gallbladder. Nucleation time was prolonged and cholesterol crystal index in bile decreased after ES, suggesting decreased lithogenicity. The decrease in gallbladder volumes and increase in ejection fraction after ES were observed in both groups of patients, with or without concomitant gallstones. CONCLUSIONS: ES decreases the stasis of gallbladder bile, improves gallbladder emptying and decreases the lithogenicity of bile in patients with gallstone disease as reflected by prolongation in nucleation time. ES may find a role as an adjunct to oral bile acid therapy and extracorporeal shock wave lithotripsy in addition to a prophylactic role of preventing gallstone formation in high risk groups.

Adult↗

PubMedDate not supplied

Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele.

Fourteen dogs with enlarged gallbladders and immobile stellate or finely striated bile patterns on ultrasound are described. Smaller breeds and older dogs were overrepresented, with 4/14 Cocker Spaniels. Most dogs presented for nonspecific clinical signs such as vomiting, anorexia and lethargy. Abdominal pain, icterus and hyperthermia were the most common findings on physical examination. All dogs except one had serum elevation of total bilirubin and/or alkaline phosphatase, alanine aminotransferase and gamma glutamyl transferase. All dogs were diagnosed with a gallbladder mucocele upon histologic and/or macroscopic evaluation. Ultrasonographically, mucoceles are characterized by the appearance of the stellate or finely striated bile patterns and differ from biliary sludge by the absence of gravity dependent bile movement. On ultrasound, gallbladder wall thickness and wall appearance were variable and nonspecific. The cystic or common bile duct were normal sized in 5 dogs although all 5 had evidence of biliary obstruction at surgery or necropsy. Loss of gallbladder wall integrity and/or gallbladder rupture were present in 50% of the dogs, all located in the fundus. Gallbladder wall discontinuity on ultrasound indicated rupture whereas neither bile patterns predicted the likelihood of gallbladder rupture. Pericholecystic hyperechoic fat or fluid were suggestive of but not diagnostic for a gallbladder rupture. Cholecystectomy appears to be an appropriate treatment for mucoceles, if not to treat a gallbladder rupture, at least in most dogs to prevent it since gallbladder wall necrosis was identified by histology in 9 of 10 dogs. Mucosal hyperplasia was present in all gallbladders examined histologically. Positive aerobic bacterial culture was obtained from bile in 6 of 9 dogs. Cholecystitis was diagnosed histologically in 5 dogs and 4 dogs had signs of gallbladder infection solely upon bacterial bile culture. Gallbladder infection was not present with all the mucoceles suggesting that biliary stasis and mucosal hyperplasia may be the primary factors involved in mucocele formation. Based on the results of our study, we suggest two alternate courses of action in the presence of a distended gallbladder with an immobile ultrasonographic stellate or finely striated bile pattern: a cholecystectomy when clinical or biochemical signs of hepatobiliary disease are present or a medical treatment (antibiotics and choleretics) and patient monitoring by follow-up ultrasound examinations when the patient does not have clinical or biochemical abnormalities. An aerobic bile culture should be obtained in all patients, by ultrasound-guided fine needle aspirate or at surgery.

Animals↗

PubMed2001

Laparoscopic cholecystectomy for polypoid lesions of the gallbladder: a clinicopathologic study.

The size and number of gallbladder polyps are used to differentiate between benign and malignant lesions before surgery and to determine whether surgery is necessary for the lesion. Since 1987, laparoscopic cholecystectomy has been widely used as the management method of choice for gallbladder lesions. The results of a clinicopathologic study of polypoid lesions of the gallbladder, based completely on laparoscopically resected gallbladder tissue, have not yet been evaluated fully. Data from 123 patients with polypoid lesions of the gallbladder treated by laparoscopic cholecystectomy were reviewed retrospectively. The gallbladders were classified into four histologic groups. Clinical features, maximal diameter, and the number of lesions were compared among the groups. The mean age of patients with adenoma and cancer was significantly greater than that of patients with cholesterol polyps and other lesions. More women than men had a neoplasm (adenoma and cancer). Patients in the neoplasm group tended to have a single lesion. The mean maximal diameter of neoplasms was significantly larger than that of lesions in the nonneoplasm group. All seven malignant lesions that were detected measured at least 1.5 cm. Univariate analysis showed that polypoid lesions of the gallbladder with neoplastic lesions correlated significantly with age, sex, size, and number of the lesions. Univariate analysis also showed that malignancy in polypoid lesions of the gallbladder correlated significantly with age, size, and number of the lesions. Multivariate logistic regression analysis showed that the age of the patient and the size of the lesion (> or = 1.0 cm) are two independent factors in predicting neoplastic lesions in polypoid lesions of the gallbladder. The size of the lesion (> or = 1.5 cm) is the only independent factor in predicting malignancy in the polypoid lesions of the gallbladder as shown by multivariate logistic regression analysis. Laparoscopic cholecystectomy is a safe and feasible method for gallbladder polypoid lesions. Neoplastic change in polypoid lesions of the gallbladder should be considered when a patient older than 50 years of age has a polypoid lesion larger than 1.0 cm. Cancer should be suspected when a polypoid lesion of the gallbladder is larger than 1.5 cm, and an aggressive surgical approach is warranted so that early gallbladder cancer can be detected and patients can have an increased chance of cure.

Adenocarcinoma↗

PubMed1999

[Expression of P-glycoprotein in benign and malignant gallbladder neoplasms].

OBJECTIVE: To evaluate the relationship between P-glycoprotein expression and anti-cancer drug resistance of gallbladder carcinoma and the use of P-glycoprotein as a biomarker of gallbladder carcinoma, the expression of P-glycoprotein was detected in benign and malignant gallbladder neoplasms and normal gallbladder tissues. METHODS: Alkaline phosphatase anti-alkaline phosphatase (APAAP) method was used to detect the expression of P-glycoprotein in different gallbladder tissues (gallbladder carcinoma, 26 cases; benign gallbladder neoplasm, 14 cases; and normal gallbladder tissue, 9 cases). The relationship between expression of P-glycoprotein, TNM stages and other clinical data of gallbladder carcinoma was also analyzed. RESULTS: Immunohistochemical staining with a monoclonal antibody JSB-1, P-glycoprotein was positive in 76.9% (20/26) of gallbladder carcinomas, in 35.7% (5/14) of benign gallbladder neoplasms and in 33.3% (3/9) of normal gallbladder tissues (P < 0.05). With another monoclonal antibody UIC-2, the positive rates were 69.2% (18/26), 21.4% (3/14) and 11.1% (1/9), respectively (P < 0.01). There was no significant correlation between P-glycoprotein expression and gallbladder carcinoma TNM staging. CONCLUSION: The results suggest that P-glycoprotein probably plays an important role in the poor response of gallbladdar carcinoma to chemotherapeutic agents. In addition, P-glycoprotein may be used a valuable biomarker of gallbladder carcinoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

[Study on genetic instability of nm23H1 gene in Chinese with original gallbladder tumor].

The aim of this study was to examine the microsatellite instability (MSI) and loss of heterozygosity (LOH) of locus D17S396 on chromosome 17 and their influence on the expression of nm23H1 in gallbladder tumors, which may provide experimental basis for the tumor occurrence and metastasis. Techniques such as DNA extraction from formalin-fixed paraffin-embedded tissues, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), ordinary silver stain were used to study MSI and LOH of locus D17S396. Envision immunohistochemistry and Leica-Qwin computer imaging techniques were used to assess the expression of gene nm23H1. In our experiment, the frequency of genetic instability of malignant gallbladder tumors was 42.55%, which was higher than that of gallbladder adenomas, while there were no genetic instability occurred in chronic cholecystitis tissue. The frequency of LOH seemed higher with the deteriorism of gallbladder tumor. Among 47 gallbladder carcinomas, the frequency of LOH and MSI were different between different differentiation cases (P < 0.05), and the frequency of LOH in liver and lymph node metastasis cases was significantly higher than those without metastasis (P < 0.01). Moreover, the frequency of LOH was higher in stage Nevin IV and V when compared with stage I, II and III. However, the frequency of MSI showed contrary correlation with some clinicopathologic characteristics. The expression of nm23H1 in gallbladder carcinoma, gallbladder adenoma and chronic cholecystitis tissue were different (P < 0.05). The case with lymph node metastasis showed significantly lower nm23H1 expression than those without lymph node metastasis (P < 0.01). Nevin stage IV and V also exhibited lower nm23H1 expression levels compared with stage I, II and Ill. Furthermore, there was no difference in nm23H1 protein expression intensity analyzed by computer imaging techniques. In gallbladder carcinomas, the positive frequency of nm23H1 protein in LOH positive group was lower than that of LOH negative group (P < 0.05). The results indicated that the genetic instability of nm23H1 gene might be implicated in pathogenesis and progression of gallbladder tumor. Both MSI and LOH of nm23H1 gene controlled the development of gallbladder tumor independently in different paths. MSI may be an early stage molecule marker of gallbladder carcinoma. LOH may be molecule marker for the deteriorism of gallbladder tissue, which could inhibit the expression of nm23H1 in local tissue of gallbladder carcinoma and endow it with high aggressive and poor prognosis. Increasing the amount of nm23H1 protein expression could effectively restrain gallbladder carcinoma metastasis and improve prognosis of patients.

Adult↗

PubMed1994

Noninvasive evaluation of kinetics of gallbladder emptying and filling in the dog. A real-time ultrasonographic study.

Patterns of gallbladder contraction induced by a meal or cerulein were examined by means of real-time ultrasonography in conscious dogs. The postprandial gallbladder emptying was characterized by two parameters of the power-exponential function: the gallbladder half emptying time T1/2 = 47.3 +/- 4.7 min and the curve shape parameter S = 0.866 +/- 0.036. Cerulein infused at stepwise increasing rates of 0.7, 2.2, 7.4, 22.2, and 66.5 pmol/kg/hr, administered each for 10 min, evoked a gallbladder contraction to 87.4 +/- 3.8%, 66.7 +/- 2.4%, 44.5 +/- 1.5%, 25.9 +/- 2.1%, and 11.9 +/- 2.0% of the basal volume, respectively. The dependence of the gallbladder emptying on the dose of cerulein was described by the equation of linear regression y - 21.33 [ln(dose + 1)] + 95.81 (r = -0.963, P < 0.001). Accordingly, the cerulein dose required to evoke a 50% reduction of the gallbladder volume amounted to 7.6 pmol/kg/hr (95% confidence interval: 6.8-8.6 pmol/kg/hr). A plateau at the level of about 44% of the basal gallbladder volume characterized the time-course of the gallbladder emptying between 20 and 60 min of the infusion at a constant rate of 7.4 pmol/kg/hr. On the other hand, the 1-hr infusion of 22.2 pmol/kg/hr evoked a continuous decrease in the gallbladder volume with a nadir of 10.2 +/- 0.7% achieved at 60 min. Refilling of the gallbladder, contracted after a 1-hr infusion of cerulein, was complete within 30 and 60 min after the end of infusion for rates of 7.4 pmol/kg/hr and 22.2 pmol/kg/hr, respectively. The time course of the gallbladder filling after cessation of 1-hr infusion of cerulein at 7.4 pmol/kg/hr was described by the equation of linear regression of relative gallbladder volumes vs time: y = 1.732x + 48.61 (r = 0.739, P < 0.001). Refilling of the gallbladder was faster during the first 30 min (y = 2.191x + 7.13, r = 0.885, P < 0.001) and slower between 30 and 60 min (y = 1.218x + 74.97, r = 0.533, P < 0.001) after the end of a 1-hr infusion of cerulein at a rate of 22.2 pmol/kg/hr.

Animals↗

PubMed2004

[Gallbladder kinetics in the black African subject with and without cholelithiasis. An ultrasonographic study].

PURPOSE: Gallbladder hypomotility could play a significant role in the process of lithogenesis, but this role has yet to be defined in black African populations. This role was assessed by measuring gallbladder emptying after stimulation by a fat meal in a group of black African subjects with and without cholelithiasis. MATERIALS AND METHODS: Fifteen subjects with cholelithiasis and thirty controls divided in two pools were studied. Gallbladder emptying was stimulated by fat meals of 610 and 740 Kcal, and was measured with ultrasound for a period of 120 min. RESULTS: The mean fasting gallbladder Volume of the subjects with lithiasis was significantly superior to that of the controls. Compared to what has been previously published in Caucasian subjects, gallbladder emptying was generally more rapid in our study. Further more, gallbladder emptying was significantly better in the control group than in the group of subjects with cholelithiasis. Two groups of subjects with cholelithiasis were isolated. The first group had poor gallbladder emptying and normal fasting gallbladder Volume; the second had normal gallbladder emptying but significantly increased fasting gallbladder Volume. CONCLUSION: Impaired gallbladder emptying and/or increased fasting gallbladder Volume probably play a role in lithogenesis. Hypomotility seems to play a significant role only for those subjects with normal fasting gallbladder Volume.

Adult↗

PubMed1997

Effect of endoscopic sphincterotomy on gallbladder motility.

In experimental animals, sphincterotomy facilitates passage of solids from the gallbladder and inhibits gallstone formation apparently by improvement in gallbladder emptying. In humans, however, gallbladder emptying has not been studied following endoscopic sphincterotomy (ES) in patients with gallstones. We therefore prospectively studied resting and cerulin-stimulated gallbladder volumes by real time ultrasonography in 15 patients of choledocholithiasis with gallbladder in situ (eight with and seven without gallbladder calculi) before and after (after bile duct clearance) ES. ES significantly lowered resting gallbladder volume (21.2 +/- 10.6 vs 11.1 +/- 5.0; P < 0.0001) and cerulin-stimulated residual gallbladder volume (10.8 +/- 5.6 vs 4.4 +/- 2.1; P < 0.0001). ES also significantly increased the gallbladder ejection fraction (47.3 +/- 12.1% vs 58.8 +/- 11.1%; P < 0.0001). The rate constant for gallbladder emptying after cerulin infusion also increased significantly after ES (-0.022/min vs -0.031/ min; P < 0.0001). Significant improvement in gallbladder motility was observed in both groups of patients with and without gallbladder calculi. ES significantly improves gallbladder motility in humans.

Adult↗

PubMedDate not supplied

Misoprostol induces gallbladder contraction during fasting, but does not influence postprandial emptying: an ultrasound study in healthy subjects.

OBJECTIVE: The aim of this study was to evaluate the effect of the PGE1 analogue, Misoprostol, on gallbladder fasting volume and meal-stimulated emptying. Prostaglandins' effects on the gallbladder were studied principally regarding mucus production during lithogenesis. In the few in vitro and in vivo studies, contradictory results concerning their influence upon gallbladder motility were obtained. SUBJECTS: 13 healthy subjects, 8 females, 5 males, aged 23.4 years (ranges 22-25). METHODS: Gallbladder volumes were assessed by ultrasound, after measuring the three diameters of the gallbladder in two perpendicular planes, using a conventional 2D equipment and a 3D equipment, after the 3D-reconstruction of the gallbladder. The volumes were calculated by means of the ellipsoid formula. Gallbladder emptying variables (residual volume, ejection fraction, area under emptying curve) were assessed during 90 minutes after a test meal (14 g fat, 425 kcal). Gallbladder emptying was evaluated in each subject on three different days: without prior Misoprostol administration, after 200 mg Misoprostol, and after 400 mg Misoprostol. Misoprostol was given orally as a single dose, 60 minutes before the meal. The two-tailed Student's t test for paired observations was used to compare the results. RESULTS: Misoprostol induced a significant decrease of the gallbladder fasting volume: from 12.8 +/- 4.4 (SD) ml (controls) to 9.1 +/- 3.6 ml (200 mg Misoprostol) and 5.4 +/- 2.6 ml (400 mg Misoprostol). Gallbladder meal-stimulated emptying was not influenced by Misoprostol. CONCLUSIONS: Our results indicated that, in healthy subjects, misoprostol induced a dose-dependent gallbladder emptying in the fasting state, but did not influence gallbladder postprandial emptying. Pre-prandial Misoprostol administration might be useful to treat gallbladder stasis in patients with chronic constipation, thus preventing gallstone formation.

Adult↗

PubMed2002

Nucleus raphe obscurus participates in regulation of gallbladder motility through vagus and sympathetic nerves in rabbits.

The aim of the present study is to investigate if the nucleus raphe obscurus (NRO) participate in regulating the gallbladder motility in rabbits. Rabbits were fasted for about 20-24 hours. After anesthetization with urethane, an incision was made at the middle of the abdomen and the gallbladder was exposed. A frog bladder connected with force transducer was inserted into the gallbladder through a small incision at the funds to record gallbladder motility (tonic contraction and phasic contraction). Glutamate and other chemicals were microinjected into NRO through a vitreous tube attached to a microsyringe. We found both the tonic contraction and phasic contraction of the gallbladder were enhanced after the glutamate was injected into NRO. GABA inhibited gallbladder motility if administrated in the same way. Microinjection of ketamine, NMDA (N-methyl-D-aspartate) receptor antagonist, into NRO inhibited the phasic contraction of gallbladder. Administration of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione), a non-NMDA receptor antagonist, enhanced the gallbladder tonic contraction. Pretreatment of ketamine into NRO attenuated the effect of glutamate, while pretreatment of CNQX had no effect on it. Intravenous injection of atropine or vagotomy completely abolished the effect of glutamate on gallbladder phasic contraction, while intravenous injection of phentolamine or transecting the spinal cord at T3-4 inhibited that on tonic contraction. Intravenous injection of propranolol did not influence the glutamate effect. These results suggested that glutamate in NRO participates in regulating the motility of the gallbladder through NMDA receptor. When excited, the NMDA receptors in NRO enhance the phasic contraction of the gallbladder through vagus nerve and peripheral M-receptors, and enhance the tonic contraction of the gallbladder through sympathetic nerve and peripheral alpha-receptors. GABA in NRO is also involved in the regulation of gallbladder motility.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

[The kinetics of canine gallbladder before and after feeding and cerulein administration].

In the previous studies in men and dogs, gallbladder contractility, contraction time, initial and residual volumes as well as ejection and refilling fractions have been determined. However, no basic scope of the characteristics of contractile gallbladder activity has been determined and no parameters measured in basic experimental conditions, necessary for this purpose, have been proposed what was the aim of present work. Twenty two experiments were performed on four healthy mongrel dogs weighing 12-16 kg each. Dogs were fasted 18-20 h before start of the experiment. Animals were examined in lying position with the use of apparatus Microimager 2000 M 200 812 with sectorial sound, 3.5 MHz. After control gallbladder measurements, animals were fed with different meals or 30 min infusion of cerulein at the dose 20 ng/kg was started. Four types of meals were used. Meal 1: dry food 300 g + 200 cc of tap water per animal. Meal 2: canned food 300 g + 200 cc of tap water per animal. Meal 3: dry food 100 g + + canned food 200 g + sunflower oil 100 ml per animal. Meal 4: dry food 300 g + canned food 300 g + sunflower oil 30 ml per animal. Ultrasonographical gallbladder imaging was performed in each experiment every 10 min and was continued during 2 hours after stimulus application. Length, width and height of the gallbladder was measured on gallbladder images, then gallbladder volumes were estimated using the method of Dodds and finally, gallbladder kinetic parameters were calculated. Meals 1 and 2 did not evoke statistically significant gallbladder contractions. After meal no. 3 gallbladder significantly contracted, for about 1.5 h. Meal no. 4 caused gallbladder contraction duration of which exceeded time of investigation while maximal strength of contraction was similar to that in response to meal no. 3. Following cerulein infusion, subsequent parameters of gallbladder kinetics, i.e. initial, residual and terminal volumes, ejection and refilling fractions as well as contraction time were similar to those after meal no. 3 while gallbladder refilling time was significantly longer than after meal no. 3.

Animals↗

PubMed1980

Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux.

To accurately quantitate dynamic events associated with gallbladder filling and emptying, we developed a cholescintigraphic technique in which the radionuclide 99mTc-HIDA excreted in bile was externally measured by a gamma camera interfaced to a computer programmed for data processing. Changes in activity with time were measured over the liver, bile ducts, gallbladder, small intestine, and stomach. The first 60 min were used to detect activity filling the gallbladder. Cholecystokinin was then infused at 0.020 U/kg/min for 30 min to initiate gallbladder contraction, while monitoring the evacuation of radionuclide into the small intestine and/or stomach. The stomach region was defined by a 99mTc-sulphur colloid swallow. With computer assistance, we were able to measure the rate at which the gallbladder filled, the fraction of liver activity that partitioned into the gallbladder instead of the duodenum, the rate of gallbladder empyting, and any gastric reflux. In 12 fasting, healthy subjects, three-fourths of the hepatic activity entered the gallbladder. After a 5-min time lag, gallbladder empyting commenced in response to the cholecystokinin, ejecting half its contents in 12 min, but still having a residual 25% after 30 min. Gallbladder evacuation was definitely slower in 6 patients with cholelithiasis, although filling appeared normal. One patient with gallstones underwent a repeat study after 4 mo on chenodeoxycholic acid therapy: Gallbladder filling, and especially emptying, deteriorated. Gastric reflux occurred only in 2 patients with gastroenterostomies who refluxed 2% of their gallbladder contents into the gastric remnant. Quantitative cholescintigraphy offers a new objective means to define gallbladder function and document bile reflux.

Adult↗

PubMed1998

Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union.

BACKGROUND: Recent studies have shown that anomalous pancreaticobiliary ductal union (APBD) is an important risk factor for the development of gallbladder carcinoma. Epithelial hyperplasia of the gallbladder is one of the characteristic changes, but it is not clear whether epithelial hyperplasia is a premalignant lesion that could lead to cancer in APBD patients. METHODS: Twenty-four APBD patients were classified into two types: patients with bile duct dilation (dilated type) (n 13) and patients without dilation (undilated type) (n = 11). Resected gallbladders obtained from APBD patients and control patients without APBD were examined histologically and with immunohistochemical techniques for the detection of p53 and Ki-67 (as a cell proliferation marker). K-ras mutations were examined using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis. The patients were also classified, according to extent of epithelial hyperplasia, as having high grade or low grade hyperplasia. RESULTS: Fifteen (63%) of 24 APBD patients had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. The incidence of epithelial hyperplasia was significantly higher in the gallbladders of undilated-type APBD patients (91%) than in those of dilated-type patients (38%) (P < 0.01). Three of 24 APBD patients (13%) had gallbladder carcinoma, and 2 of the 3 gallbladder carcinomas (67%) were accompanied by diffuse epithelial hyperplasia of the gallbladder. Among 21 nonneoplastic gallbladders, diffuse epithelial hyperplasia was observed in all (100%) of the undilated-type APBD and in 4 (33%) of 12 dilated-type APBD (P < 0.001). High grade hyperplasia was observed in 7 of 11 patients (64%) with undilated-type APBD and 2 of 13 patients (15%) with dilated-type APBD (P < 0.05). The incidence of high grade hyperplasia increased with age among patients older than 35 years. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. High grade hyperplasia had a significantly higher Ki-67 LI than low grade hyperplasia (P < 0.001). Two (22%) of 9 high grade hyperplasia cases had K-ras mutations, whereas none of 6 low grade hyperplasia cases had. The types of K-ras mutations in codon 12 were GTT (Val) and GAT (Asp) in each case of hyperplasia; these were identical to those of concomitant carcinomas. Neither hyperplastic nor normal mucosa exhibited p53 overexpression. CONCLUSIONS: The results of this study suggest that hyperplasia of the gallbladder mucosa in APBD patients is an early change that, because of the increased proliferative activity and presence of K-ras mutations, could be considered a premalignant lesion of the gallbladder. An increased cell population of epithelial hyperplasia may predispose the mucosa to mutational events, resulting in an increased risk for the development of gallbladder carcinoma in APBD patients.

Adolescent↗

PubMed1997

DNA synthesis, cell proliferation index in normal and abnormal gallbladder epithelium.

The observation of mitotic figures in the epithelium of the normal gallbladder is exceptional because cell renewal is occurring at a very slow rate. It is only after using 3H-thymidine and autoradiography to observe the cells in DNA synthesis that evidence of a significant epithelial cell replication has been provided. Because numerous mitotic figures and increased 3H-thymidine uptake have been observed after intraluminal introduction of foreign bodies or after ligation of the common bile duct in animals, mechanical distension has been supposed to represent an important trigger factor of cell proliferation in this hollow organ. An increased epithelial cell renewal was also observed in human gallbladders of patients with a complete obstruction of the common bile duct causing the distension. However, the absence of correlation between the degree of gallbladder distension and the proliferative response was suggesting that factors other than distension could be involved. In studies on experimental lithiasis cell proliferation appeared to be enhanced in the gallbladder epithelium of mice fed on a cholesterol-cholic acid-rich lithogenic diet. The fact that the increase in proliferative activity was preceding the formation of gallstones was another indication that factors other than mechanical stimulation by stretching or by the stones may stimulate cell renewal in this organ. Factors in the bile of animals receiving a lithogenic diet could be involved which might cause cellular death and, hence, a regenerative reaction. Direct mitogenic effect of an unknown factor in the bile of these animals is an alternative possibility. On the other hand the stimulating effect of postprandial hormones on gallbladder cell renewal suggested by the observation of a DNA synthesis peak after feeding has been established. Synthetic cholecystokinin analogues have been shown to increase the proliferative activity and to induce epithelial hyperplasia in this organ. In one recent study using fundusectomy to increase the serum gastrin levels, a significant proliferative stimulation in the gallbladder was also observed. In human gallbladder mitotic activity in gallbladders with gallstones in much higher than in the controls. No correlation between stone number, weight or volume and the proliferative activity was put in evidence, whereas cell renewal appeared to be more influenced by the composition of the stones than by their physical presence. Epithelial DNA synthesis activity was, namely, much higher in gallbladders with cholesterol stones than in those with pigment stones. Whether increased cell turnover and, hence, cellular shedding into the lumen could represent a nucleating factor for cholesterol stones is an attractive working hypothesis. Considering the very high frequency of gallstones in man and also the frequent association of gallbladder cancer and lithiasis, further studies on mitotic activity in this organ are required. In conclusion, data from animal experiments and in vitro studies on human gallbladders indicate that gallbladder epithelial cell proliferation may be influenced by several mechanical, chemical and hormonal factors. The list of these factors is still incomplete while their possible role in gallbladder disease is a fascinating exploration field for future research.

Animals↗