Embryonic cholecystitis and defective gallbladder contraction in the Sox17-haploinsufficient mouse model of biliary atresia.

The gallbladder excretes cytotoxic bile acids into the duodenum through the cystic duct and common bile duct system. Sox17 haploinsufficiency causes biliary atresia-like phenotypes and hepatitis in late organogenesis mouse embryos, but the molecular and cellular mechanisms underlying this remain unclear. In this study, transcriptomic analyses revealed the early onset of cholecystitis in Sox17+/- embryos, together with the appearance of ectopic cystic duct-like epithelia in their gallbladders. The embryonic hepatitis showed positive correlations with the severity of cholecystitis in individual Sox17+/- embryos. Embryonic hepatitis could be induced by conditional deletion of Sox17 in the primordial gallbladder epithelia but not in fetal liver hepatoblasts. The Sox17+/- gallbladder also showed a drastic reduction in sonic hedgehog expression, leading to aberrant smooth muscle formation and defective contraction of the fetal gallbladder. The defective gallbladder contraction positively correlated with the severity of embryonic hepatitis in Sox17+/- embryos, suggesting a potential contribution of embryonic cholecystitis and fetal gallbladder contraction in the early pathogenesis of congenital biliary atresia.

Gall bladder: The metabolic orchestrator.

It is commonly held that the gall bladder (GB) is not indispensable for life. However, recent studies strongly suggest that GB removal can lead to the development of metabolic syndrome (MetS). With the recent recognition of the role of bile acids (BAs) in systemic metabolic regulation, it is worthwhile to re-examine the function of the GB, which can be regarded as the physiological "pacemaker" of BA flow. Thus, in the present study, we review the role of the GB in BA flow regulation, describe the epidemiologic evidence that associates cholecystectomy with various components of MetS, and discuss the possible mechanism behind these connections in order to demonstrate the pivotal role that GB plays in metabolic regulation.

Prospective study on changes in the donor gallbladder contraction function after left lateral lobe hepatectomy.

This study aimed to evaluate the feasibility of donor gallbladder preservation in liver transplantation. Conventional removal of the donor gallbladder is applied in a majority of pediatric liver transplantation. A total of 42 donors who underwent gallbladder preservation in liver transplantation from October 2013 to December 2015 at the Beijing Friendship Hospital, China, were enrolled for the study. The changes in gallbladder volume and the gallbladder EF of donors before and after surgery were measured through ultrasound, and the changes in the donor gallbladder contraction function before and after surgery were evaluated to help verify the feasibility of gallbladder preservation in living donor left lateral lobe hepatectomy. The gallbladder emptying index dropped to 42.67% in 2 weeks after surgery and gradually increased with the length of recovery time, which could reach 69.14% in 3 months after surgery. At that time, 97.6% of the donors were considered to have recovered their gallbladder contraction function. The gallbladder contraction function at an early stage after gallbladder preservation in liver transplantation is not obviously improved, but it can recover to a normal level in 1 month after surgery, indicating that the gallbladder preservation in hepatectomy of living donor can effectively guarantee the gallbladder contraction function.

Radiofrequency ablation of liver cancers adjacent to the gallbladder without gallbladder isolation under contrast-enhanced ultrasound monitoring: a preliminary study.

PURPOSE: The purpose of this study was to investigate the feasibility, safety and efficacy of intra-procedural contrast-enhanced ultrasound (CEUS) monitoring of the radiofrequency ablation (RFA) of liver cancers adjacent to gallbladder (GB) without GB isolation. MATERIALS AND METHODS: From May 2016 to July 2017, patients with liver cancers adjacent to GB (≤10 mm) who intended to undergo ultrasound-guided RFA without GB isolation in our hospital were prospectively enrolled. During the RFA procedures, CEUS was employed to evaluate the therapeutic response and the perfusion of the intact GB wall. The outcomes of GB and liver cancers were followed up and recorded. RESULTS: 23 patients (18 male, 5 female) with 23 liver cancers (mean 18 mm, range 8-34 mm) adjacent to GB were enrolled. There were 12 tumors that abutted the GB while 11 tumors located within 10 mm of the GB. After the RFA procedures, intra-procedural CEUS evaluation demonstrated the perfusion of the GB wall was intact in all 23 patients and technical success rate of RFA was 100% (23/23). According to the contrast-enhanced CT/MR one month after RFA, the technical efficacy rate was 100% (23/23). During the follow-up period (range: 12-23 months, median: 17 months), no local tumor progression occurred and no major complications arised. Overall survival at 1-year was 100%. Thickening of GB wall was detected in 11 patients. The thickness of GB wall returned to the pre-ablation level in five patients. CONCLUSION: CEUS-monitored RFA of liver cancers adjacent to GB without GB isolation was feasible, safe and effective.

Evidence that the adenosine triphosphate-binding cassette G5/G8-independent pathway plays a determinant role in cholesterol gallstone formation in mice.

UNLABELLED: The adenosine triphosphate-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated variants in ABCG5/G8 have been identified in humans. Although ABCG5/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice. We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5/G8 pathway. To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [(3) H]sitostanol- and [(14) C]cholesterol-labeled high-density lipoprotein (HDL). We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. The 6-hour recovery of [(14) C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [(3) H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. CONCLUSIONS: The ABCG5/G8-independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL-derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (Hepatology 2016;64:853-864).

Mechanism of resveratrol-induced relaxation in the human gallbladder.

BACKGROUND: Resveratrol is a polyphenolic compound extracted from plants and is also a constituent of red wine. Resveratrol produces relaxation of vascular smooth muscle and may prevent cardiovascular diseases. Although resveratrol has been reported to cause relaxation of the guinea pig gallbladder, limited data are available about the effect of resveratrol on the gallbladder smooth muscle in humans. The purpose of this study was to investigate the relaxation effects of resveratrol in human gallbladder muscle strips. METHODS: We studied the relaxant effects of resveratrol in human gallbladder. In addition, we also investigated mechanism of resveratrol-induced relaxation in human gallbladder by tetraethylammonium (a non-selective potassium channels blocker), iberiotoxin (an inhibitor of large conductance calcium-activated potassium channel), glibenclamide (an ATP-sensitive potassium channel blocker), charybdotoxin (an inhibitor of large conductance calcium-activated potassium channels and slowly inactivating voltage-gated potassium channels), apamine (a selective inhibitor of the small conductance calcium-activated potassium channel), KT 5720 (a cAMP-dependent protein kinase A inhibitor), KT 5823 (a cGMP-dependent protein kinase G inhibitor), NG-Nitro-L-arginine (a competitive inhibitor of nitric oxide synthase), tetrodotoxin (a selective neuronal Na+ channel blocker), and ω-conotoxin GVIA (a selective neuronal Ca2+ channel blocker). RESULTS: The present study showed that resveratrol has relaxant effects in human gallbladder muscle strips. In addition, we found that resveratrol-induced relaxation in human gallbladder is associated with nitric oxide, ATP-sensitive potassium channel, and large conductance calcium-activated potassium channel pathways. CONCLUSIONS: This study provides the first evidence concerning the relaxant effects of resveratrol in human gallbladder muscle strips. Furthermore, these results demonstrate that resveratrol is a potential new drug or health supplement in the treatment of biliary colic.

CAV1 Prevents Gallbladder Cholesterol Crystallization by Regulating Biosynthesis and Transport of Bile Salts.

Cholesterol gallstone disease (CGD) is a hepatobiliary disorder which results from a biochemical imbalance in the gallbladder bile. Here we show that loss of CAV1 sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary cholesterol concentration and decreased biliary bile salt secretion in CAV1(-/-) mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. At the signaling level, the ERK/AP-1 pathway seems to mediate the effects of CAV1 on biliary BA homeostasis and might be developed as a therapeutic target for CGD. We propose that CAV1 is an anti-lithogenic factor and that the CAV1(-/-) mice may offer a convenient CGD model to develop therapeutic interventions for this disease. J. Cell. Biochem. 117: 2118-2127, 2016. © 2016 Wiley Periodicals, Inc.

A New Reliable Method for Evaluating Gallbladder Dynamics: The 3-Dimensional Sonographic Examination.

OBJECTIVES: The purpose of this study was to compare conventional 2-dimensional (2D) B-mode sonography with 3-dimensional (3D) sonography for assessing gallbladder volume and contractility. METHODS: Gallbladder volume and contractility were evaluated in 32 healthy volunteers after fasting and abstinence from smoking for 8 hours and after a standardized balanced liquid meal. The gallbladder was evaluated with 2D sonography (with the use of the ellipsoid method) and with 3D sonography using a volumetric matrix probe. Both measurements were made by an operator who was skilled in sonography and an unskilled operator. The group of volunteers was subdivided into 2 subgroups including 16 participants, which represented the "2 moments" of acquisition by the techniques, particularly for the unskilled operator. RESULTS: The postprandial volumes obtained with 3D sonography were significantly lower in comparison to the volumes obtained with 2D sonography (P= .013), and there was a significant difference between the measurements made by the skilled and unskilled operators only for 2D sonography (P< .001), whereas between the 2 moments of acquisition by the 3D technique, there was no significant difference. The reproducibility of the technique for evaluation of gallbladder volumes was higher for 3D sonography than 2D sonography, particularly for the postprandial evaluation. CONCLUSIONS: The new 3D sonographic method using a volumetric matrix probe is a simple, reliable, and more reproducible technique than conventional 2D sonography, even if performed by an unskilled operator, and it allows a reliable stimulation test for a gallbladder dynamic study.

[NERVOUS REGULATION OF BILIARY TRACT MOTILITY].

Aim: The study of mechanisms of regulation of biliary tract motility by divisions of autonomic nervous system (ANS). Material and methods: Experiments were carried out on rabbits, chinchillas weighing 3.5-4 kg using gentle methods of treatment of experimental animals. Electromotor activity of electromotor (EMA) of the gallbladder and sphincter of Oddi was recorded. Irritation of the nerve produces an electrical pulse duration of 2 ms, the amplitude of 1.5-15 V, frequency of 10 Hz. Results: The mechanism of vagal inhibition of sphincter of Oddi motility and unidirectional stimulatory influence of ANS divisions on the motility of the gallbladder and sphincter of Oddi was studied. It was established that in the mechanism of vagal inhibition of sphincter of Oddi motility involved intramural adrenergic neurons synaptically connected with preganglionic parasympathetic fibers. At the stimulatory effect of vagus on biliary tract motility serotonergic intramural neurons are involved transmitting excitation to serotonin receptors of effector tissue.

Pain provocation and low gallbladder ejection fraction with CCK cholescintigraphy are not predictive of chronic acalculous gallbladder disease symptom relief after cholecystectomy.

INTRODUCTION: Chronic acalculous gallbladder disease (CAGD) falls within the spectrum of diseases associated with gallbladder dysmotility. Cholecystokinin-cholescintigraphy (CCK-CS) has been used to evaluate for CAGD, with a gallbladder ejection fraction (GBEF) of <35 % being indicative of gallbladder dysfunction. The reproduction of biliary colic upon administration of CCK has been cited as indicative of CAGD. Our purpose was to determine whether low GBEF or reproduction of pain during CCK-CS was predictor of surgical outcomes related to resolution of symptoms or as a correlate to gallbladder pathology. METHODS: A retrospective review of patients was performed to evaluate adults with a diagnosis of CAGD who underwent CCK-CS prior to surgical intervention. CPT and ICD-9 coding queries were used to identify the patient population. Patients with cholelithiasis were excluded. RESULTS: Sixty-four patients met inclusion criteria. Two patients were lost to follow-up and were excluded. During CCK-CS, 41 patients (66 %) reported symptoms similar to their presenting complaint. Twenty-one patients reported no symptoms with CCK-CS. There was no significant relationship between gallbladder pathology and either GBEF or reproduction of symptoms with CCK-CS (p = 0.14). About 81 % of patients (n = 50) had relief of symptoms following cholecystectomy. Sixty-six percentage of patients (n = 33) with long-term symptom relief after cholecystectomy had reproduction of symptoms with CCK-CS. Nineteen percentage of all patients (n = 12) had long-term symptom recurrence despite surgery. Eight of these patients (66 %) had symptom reproduction with CCK-CS. There was no significant correlation with either the GBEF or symptoms reproduction with CCK-CS as a predictor of postoperative outcome (p = 0.12). CONCLUSION: Provocation of pain by CCK-CS and low GBEF are unreliable predictors of postoperative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease.

Functional MR cholangiography of the cystic duct and sphincter of Oddi using gadoxetate disodium: is a 30-minute delay long enough?

PURPOSE: To determine if excreted contrast is consistently visualized in the gallbladder and duodenum after a 30-minute delay using gadoxetate disodium-enhanced MRI in patients without hepatobiliary disease. MATERIALS AND METHODS: Twenty-two patients without evidence of liver or biliary disease underwent gadoxetate disodium-enhanced magnetic resonance imaging (MRI) from February 17, 2009 through October 3, 2011. The mean age was 45 years (range 25-72). T1-weighted hepatobiliary phase images at 5, 10, 20, and 30 minutes after contrast injection were reviewed in consensus by two radiologists to determine the delay at which enhancement of the gallbladder and duodenum first occurred. RESULTS: Thirteen of 22 (59.1%) patients demonstrated duodenal filling by 20 minutes and 16/22 (72.7%) filled by 30 minutes. The mean time to duodenal enhancement was 19.9 minutes (range 11.4-30.2 min). Seventeen of 22 (77.3%) patients demonstrated gallbladder filling by 20 minutes and 21/22 (95.5%) filled by 30 minutes. The mean time to gallbladder enhancement was 16.5 minutes (range 4.4-30.2 min). CONCLUSION: A significant number of normal patients do not show duodenal filling by 30 minutes, while the majority fill the gallbladder by 30 minutes using functional MR cholangiography (fMRC) with gadoxetate disodium. These findings will guide fMRC protocol design for patients with suspected acute cholecystitis and sphincter of Oddi dysfunction.

Muscarinic receptor M3 mediates human gallbladder contraction through voltage-gated Ca2+ channels and Rho kinase.

OBJECTIVE: Muscarinic receptors mediate contraction of the human gallbladder through unclear receptor subtypes. The aim of the present study was to characterize muscarinic acetylcholine receptors mediating contraction of the human gallbladder. MATERIALS AND METHODS: Contraction of human gallbladder muscle strips caused by agonists carbachol and muscarine was measured and the inhibition of carbachol-induced contraction by muscarinic receptor antagonists was evaluated. Reverse transcription polymerase chain reaction was performed to determine the existence of muscarinic receptor subtypes. RESULTS: Carbachol and muscarine caused concentration-dependent contraction of gallbladder strips. Four receptor antagonists, including atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), methoctramine, and pirenzepine, inhibited the carbachol-induced contraction. The relative inhibitory potency of these receptor antagonists was atropine > 4-DAMP > methoctramine > pirenzepine. The antagonist affinity estimates (pA(2) values) correlated with the known affinities at M(3), M(4), and M(5) muscarinic receptors. In addition, the M(4)-selective antagonist muscarinic toxin 3 did not inhibit and the M(5)-selective positive allosteric modulator VU0238429 did not potentiate carbachol-induced gallbladder contraction. This suggests that M(3) muscarinic receptors mediate the muscarinic response predominantly. The contractile response of carbachol was attenuated by the voltage-gated Ca(2+) channel inhibitor nifedipine and Rho-kinase inhibitor H-1152, but not affected by protein kinase C inhibitor chelerythrine. This implies the involvement of voltage-gated Ca(2+) channel and Rho kinase but not protein kinase C. CONCLUSIONS: These results suggest a major role of M(3) muscarinic receptors mediating the human gallbladder contraction through voltage-gated Ca(2+) channels and Rho kinase. M(3)-selective muscarinic receptor antagonists could be of therapeutic importance in the treatment of biliary motility disorders.

Identification of a hormonal basis for gallbladder filling.

The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is actively regulated by an endocrine pathway and suggest a postprandial timing mechanism that controls gallbladder motility.

A comparison of the effects of various sex steroids on cholecystokinin- and KCl-induced tension in female guinea pig gallbladder strips.

Estrogen (E) has been shown to have an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. During pregnancy E and progesterone (P) levels are elevated. A biliary stasis may develop during pregnancy that is characterized by an increase in the fasting and residual volumes and by a decrease in emptying capacity. This study investigates the effect of 17ß-estradiol (E2), dihydrotestosterone (DHT), P, 17-hydroxyprogesterone (17-P), and a P metabolite, 20α-hydroxyprogesterone (20-P) on contraction in female guinea pig gallbladder strips. DHT, P, 17-P, 20-P, and E2 each induced a concentration-dependent relaxation of cholecystokinin octapeptide (CCK) induced tension. DHT, E2, and P also induced a concentration-dependent relaxation of KCl-induced tension. When the response to E2 was compared to strips from young female guinea pigs with those taken from guinea pigs in late pregnancy, there was no significant difference in the response to either 50 or 100 µM E2; however, 10 µM E2 caused a significant increase (p<0.05) in the amount of relaxation in strips from pregnant guinea pigs. Treatment of the strips from young guinea pigs with PKA inhibitor 14-22 amide myristolated had no significant effect on the E2-induced relaxation. Treatment of the strips with 2-APB, an inhibitor of IP3 induced Ca(2+) release, produced a significant (p<0.001) increase in the amount of E2-induced relaxation when either CCK or KCl were used. Neither KT5823, a PKG inhibitor, nor L-NMMA, a nitric oxide (NO) synthase inhibitor, had a significant effect on the E2-induced relaxation. Bisindolymaleimide IV and chelerythrine Cl(-), PKC blockers, were used in combination with no significant effect on the amount of CCK-induced tension, but significantly (p<0.01) increased the amount of E2-induced relaxation. When either E2 or P were added to the chambers 3 min prior to either CCK or KCl, a significant decrease (p<0.001) in the amount of tension generated was observed. The inhibition of extracellular Ca(2+) entry mediates both P-induced and E2-induced relaxation of CCK- and KCl-induced tension in female guinea pig gallbladder strips.

The role of the gallbladder in humans.

The basic function of the gallbladder in humans is one of protection. The accumulation of the primary bile acids (cholic acid and chenodeoxycholic acid) in the gallbladder reduces the formation of the secondary bile acids (deoxycholic acid and lithocholic acid), thus diminishing their concentration in the so-called gallbladder-independent enterohepatic circulation and protecting the liver, the stomach mucosa, the gallbladder, and the colon from their toxic hydrophobic effects. The presence or absence of the gallbladder in mammals is a determining factor in the synthesis of hydrophobic or hydrophilic bile acids. Because the gallbladder contracts 5-20 min after food is in the stomach and the "gastric chyme" moves from the stomach to the duodenum 1-3 h later, the function of the gallbladder bile in digestion may be insignificant. The aim of this article was to provide a detailed review of the role of the gallbladder and the mechanisms related to bile formation in humans.

Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis.

Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3H-sitostanol along the length of the small intestine following intraduodenal instillation,we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P <0.05) by LD but not slowed further by helicobacter infection (males, 9.4±0.5 (uninfected), 9.6±0.5 (infected) on LD compared with 12.5±0.4 and 11.4±0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice. Intestinal hypomotility promotes cholelithogenesis by augmenting formation of deoxycholate, a pro-lithogenic secondary bile salt, and increasing the fraction of intestinal cholesterol absorbed.

Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages.

Stem/progenitors have been identified intrahepatically in the canals of Hering and extrahepatically in glands of the biliary tree. Glands of the biliary tree (peribiliary glands) are tubulo-alveolar glands with mucinous and serous acini, located deep within intrahepatic and extrahepatic bile ducts. We have shown that biliary tree stem/progenitors (BTSCs) are multipotent, giving rise in vitro and in vivo to hepatocytes, cholangiocytes or pancreatic islets. Cells with the phenotype of BTSCs are located at the bottom of the peribiliary glands near the fibromuscular layer. They are phenotypically heterogeneous, expressing transcription factors as well as surface and cytoplasmic markers for stem/progenitors of liver (e.g. SOX9/17), pancreas (e.g. PDX1) and endoderm (e.g. SOX17, EpCAM, NCAM, CXCR4, Lgr5, OCT4) but not for mature markers (e.g. albumin, secretin receptor or insulin). Subpopulations co-expressing liver and pancreatic markers (e.g. PDX1(+)/SOX17(+)) are EpCAM(+/-), and are assumed to be the most primitive of the BTSC subpopulations. Their descendants undergo a maturational lineage process from the interior to the surface of ducts and vary in the mature cells generated: pancreatic cells in hepatopancreatic ducts, liver cells in large intrahepatic bile ducts, and bile duct cells along most of the biliary tree. We hypothesize that there is ongoing organogenesis throughout life, with BTSCs giving rise to hepatic stem cells in the canals of Hering and to committed progenitors within the pancreas. The BTSCs are likely to be central to normal tissue turnover and injury repair and to be key elements in the pathophysiology of liver, pancreas and biliary tree diseases, including oncogenesis.

Preventing gastric sieving by blending a solid/water meal enhances satiation in healthy humans.

Separation of solids and liquids within the stomach allows faster gastric emptying of liquids compared with solids, a phenomenon known as sieving. We tested the hypothesis that blending a solid and water meal would abolish sieving, preventing the early rapid decrease in gastric volume and thereby enhancing satiety. We carried out 2 separate studies. Study 1 was a 2-way, crossover, satiety study of 22 healthy volunteers who consumed roasted chicken and vegetables with a glass of water (1008 kJ) or the same blended to a soup. They completed satiety visual analogue scales at intervals for 3 h. Study 2 was a 2-way, crossover, mechanistic study of 18 volunteers who consumed the same meals and underwent an MRI to assess gastric emptying, gallbladder contraction, and small bowel water content (SBWC) at intervals for 3 h. In Study 1, the soup meal was associated with reduced hunger (P = 0.02). In Study 2, the volume of the gastric contents after the soup meal decreased more slowly than after the solid/liquid meal (P = 0.0003). The soup meal caused greater gallbladder contraction (P < 0.04). SBWC showed a biphasic response with an initial "gastric" phase during which SBWC was greater when the solid/liquid meal was consumed (P < 0.001) and a later "small bowel" phase when SBWC was greater when the soup meal was consumed (P < 0.01). Blending the solid/liquid meal to a soup delayed gastric emptying and increased the hormonal response to feeding, which may contribute to enhanced postprandial satiety.

A quasi-nonlinear analysis of the anisotropic behaviour of human gallbladder wall.

Estimation of biomechanical parameters of soft tissues from noninvasive measurements has clinical significance in patient-specific modeling and disease diagnosis. In this work, we present a quasi-nonlinear method that is used to estimate the elastic moduli of the human gallbladder wall. A forward approach based on a transversely isotropic membrane material model is used, and an inverse iteration is carried out to determine the elastic moduli in the circumferential and longitudinal directions between two successive ultrasound images of gallbladder. The results demonstrate that the human gallbladder behaves in an anisotropic manner, and constitutive models need to incorporate this. The estimated moduli are also nonlinear and patient dependent. Importantly, the peak stress predicted here differs from the earlier estimate from linear membrane theory. As the peak stress inside the gallbladder wall has been found to strongly correlate with acalculous gallbladder pain, reliable mechanical modeling for gallbladder tissue is crucial if this information is to be used in clinical diagnosis.

Physiology of FGF15/19.

This chapter will review the various biological actions of the mouse fibroblast growth factor 15 (Fgf15) and human fibroblast growth factor 19 (FGF19). Unlike other members of the fibroblast growth factor (FGF) family, the Fgf15 and FGF19 orthologs do not share a high degree of sequence identity. Fgf15 and FGF19 are members of an atypical subfamily of FGFs that function as hormones. Due to subtle changes in tertiary structure, these FGFs have low heparin binding affinity enabling them to diffuse away from their site of secretion and signal to distant cells. FGF signaling through the FGF receptors is also different for this sub-family, requiring klotho protein cofactors rather than heparin sulfate proteoglycan. Mouse Fgf15 and human FGF19 play key roles in enterohepatic signaling, regulation of liver bile acid biosynthesis, gallbladder motility and metabolic homeostasis.