Computational analysis of the flow of bile in human cystic duct.

Computational fluid dynamic (CFD) simulations of the three-dimensional flow structures in realistic cystic ducts have been performed to obtain quantitative readings of the flow parameters to compare with clinical measurements. Resin casts of real patients' cystic ducts lumen that possess representative anatomical features were scanned to obtain three-dimensional flow domains that were used in the numerical analysis. The convoluting nature of the studied cystic ducts resulted in strong secondary flow that contributed towards a dimensionless pressure drop that is four times higher than those of a straight circular tube of an equivalent length and average diameter. The numerical pressure drop results across the cystic duct compared very well with those obtained from clinical observations which indicate that CFD is an appropriate tool to investigate the flow and functions of the biliary system. From the hydrodynamic point of view, the cystic duct lumen seems to serve as a passive resistor that strives to provide a constant amount of resistance to control the flow of bile out of the gallbladder. This is mainly achieved by the coupling of the secondary flow effects and bile rheology to provide flow resistance.

A proposal for the annotation of recurrent colorectal cancer: the 'Sheffield classification'.

AIM: Current classification systems of large bowel cancer only refer to metastatic disease as M0, M1 or Mx. Recurrent colorectal cancer primarily occurs in the liver, lungs, nodes or peritoneum. The management of each of these sites of recurrence has made significant advances and each is a subspecialty in its own right. The aim of this paper was to devise a classification system which accurately describes the site and extent of metastatic spread. METHOD: An amendment of the current system is proposed in which liver, lung and peritoneal metastases are annotated by 'Liv 0,1', 'Pul 0,1' and 'Per 0,1' in describing the primary presentation. These are then subclassified, taking into account the chronology, size, number and geographical distribution of metastatic disease or logoregional recurrence and its K-Ras status. CONCLUSION: This discussion document proposes a classification system which is logical and simple to use. We plan to validate it prospectively.

Enzymatic function of multiple origins regulates the progression of colorectal cancer and the development of metastases.

Enzymes play a crucial role in the progression of colorectal cancer and the development of metastases. They facilitate malignant cell invasion through the degradation of the extracellular matrix, the rupture of the basement membrane and the derangement of cell-cell adhesion. Furthermore, they promote tumour cell migration and support the evolution of metastatic lesions in the liver and other organs, through multiple molecular mechanisms, including growth factor release and angiogenesis. Urokinase plasminogen activator system, matrix metalloproteinases, heparanase and autocrine motility factor constitute important enzymatic complexes which assist colorectal cancer growth, with potential clinical applications in the diagnosis and treatment of the disease.

Non-Newtonian bile flow in elastic cystic duct: one- and three-dimensional modeling.

Bile flow is thought to play an essential role in the pathophysiological genesis of cholelithiasis (gallstone formation) and in gallbladder pain. In this paper, we extend our previous study of the human biliary system (Li et al., 2007, J. Biomech. Eng., 129:164-173) to include two important factors: the non-Newtonian properties of bile, and elastic deformation of the cystic duct. A one-dimensional (1D) model is analyzed and compared with three-dimensional (3D) fluid-structure interaction simulations. It is found that non-Newtonian bile raises resistance to the flow of bile, which can be augmented significantly by the elastic deformation (collapse) of the cystic duct. We also show that the 1D model predicts the pressure drop of the cystic duct flow well for all cases considered (Newtonian or non-Newtonian flow, rigid or elastic ducts), when compared with the full 3D simulations.

Investigation of the functional three-dimensional anatomy of the human cystic duct: a single helix?

Clinical research into the formation of gallstones has indicated that the anatomy of the cystic duct is one of a number of factors contributing to the formation of gallstones. The cystic duct allows low-viscosity hepatic bile to enter the gallbladder under low pressure and the expulsion of a more viscous gallbladder bile, but little is known about this transport mechanism and the effect of anatomical variations in structure. This article describes the variation in geometry of the cystic duct, obtained from acrylic resin casts of the neck and first part of the cystic duct in gallbladders removed for gallstone disease and obtained from patients undergoing partial hepatectomy for metastatic disease. The data obtained allowed us to formulate a number of standard terms for describing cystic duct morphology and demonstrate that the term "spiral valve" is only partially correct when describing the duct anatomy. In over half of the casts, spiraling was not the dominant feature of the cystic duct. Additionally, the term valve implies active resistance to flow in one direction, whereas the internal baffles of the cystic duct would serve to regulate bile flow in both directions. These data are useful for realistic 3D modeling of fluid-structure interactions of the flow of bile in the human cystic duct.

The flow of bile in the human cystic duct.

Clinical studies suggest that the flow of bile in the biliary system may be a contributing factor in the pathogenesis of cholelithiasis, but little is known about its transport mechanism. This paper reports a numerical study of steady flow in human cystic duct models. In order to obtain parametric data on the effects of various anatomical features in the cystic duct, idealised models were constructed, first with staggered baffles in a channel to represent the valves of Heister and lumen. The qualitative consistency of these findings are validated by modelling two of the real cystic ducts obtained from operative cholangiograms. Three-dimensional (3D) models were also constructed to further verify the two-dimensional (2D) results. It was found that the most significant geometric parameter affecting resistance is the baffle clearance (lumen size), followed by the number of baffles (number of folds in the valves of Heister), whilst the least significant ones are the curvature of the cystic duct and the angle between the neck and the gallbladder. The study presented here forms part of a larger project to understand the functions of the human cystic duct, especially the influence of its various anatomical structures on the resistance to bile flow, so that it may aid the assessment of the risk of stone formation in the gallbladder.

Active relaxation of human gallbladder muscle is mediated by ATP-sensitive potassium channels.

BACKGROUND: Active and significant relaxation of the human gallbladder must be one of the facets of its motility during both the filling and emptying cycle. Conflicting reports about the presence or significance of nitric oxide have been reported in the literature. The aim of this study was to investigate the role of nitric oxide and K(ATP) channels in human gallbladder muscle using isolated strips from human gallbladder. METHODS: Full thickness strips were obtained from 56 human gallbladders and suspended under isometric tension in organ baths. The effect of nitric oxide donors and inhibitors on cholecystokinin octapeptide- and carbachol-induced contraction was examined. In separate experiments the effect of the K(ATP) channel activator, cromakalim, and the inhibitor, glibenclamide, were determined. RESULTS: Cromakalim induced a significant relaxation of agonist-induced contraction in human gallbladder in vitro, an effect which was abolished by the K(ATP) channel inhibitor glibenclamide. No evidence of significant nitric oxide involvement in relaxation was observed. CONCLUSIONS: This study has demonstrated the presence of K(ATP) channels in human gallbladder for the first time. These are capable of causing significant relaxation in the presence of hormonal and muscarinic agonists and may represent a major pathway for gallbladder relaxation.

In vitro responses of gallbladder muscle from patients with acalculous biliary pain.

BACKGROUND: Diagnosis and identification of patients with acalculous biliary pain, who would benefit from surgery, remains a significant clinical problem. The cholecystokinin (CCK) provocation test helps diagnosis, but lack of consistency limits its usefulness. AIM: To characterize the response of gallbladder muscle strips, from patients with acalculous biliary pain, to hormonal and muscarinic stimulation and to compare these with strips from gallstone patients and normal controls. PATIENTS: Eleven patients with acalculous biliary pain were studied, 5 had a positive CCK test. Eight gallbladders from gallstone patients and 6 from partial hepatectomies were used for comparison. METHODS: Muscle strips from the body and neck of the gallbladder were suspended in organ baths and dose-response curves were constructed for CCK-8 and carbachol. RESULTS: In the acalculous group the strips from the body were less sensitive to carbachol than those of the neck. CONCLUSION: Since we found no differences in the CCK responses for the groups, it casts doubt over the effectiveness of the CCK test to diagnose acalculous biliary pain. Since carbachol sensitivity was different, it might be that a similar test using muscarinic stimulation would help in the diagnosis of this difficult group of patients.

The relationship between in vivo emptying of the gallbladder, biliary pain, and in vitro contractility of the gallbladder in patients with gallstones: is biliary colic muscular in origin?

BACKGROUND: This study sought to determine whether there is a positive correlation between gallbladder emptying, biliary pain, and in vitro contractility. METHODS: Ultrasound measurements were carried out on 25 gallstone patients. The response of gallbladder strips to 1.75*10(-11) to 5.25*10(-7) M cholecystokinin-8 was recorded. In a second study 23 patients filled in pain questionnaires, and in vitro studies were again carried out. RESULTS: Of five patients with no gallbladder emptying, four had in vitro contraction. Overall, a significant, positive linear correlation was found (P < 0.0001). In the second study in vitro contractility showed a positive linear correlation with pain. CONCLUSION: Gallbladder emptying correlates with contractility. However, since most 'non-contractors' can contract, we suggest the term 'non-emptying' or 'emptying' to describe gallbladder dynamics. The positive correlation between pain and contractility suggests that biliary pain has a muscular component.

Seamless tiling of amorphous silicon photodiode-TFT arrays for very large area X-ray image sensors.

We propose a method for producing a truly seamless tiled image sensor from four identical subarrays, such that the resulting tiled image sensor has no missing pixels. Four standard amorphous silicon photodiode-TFT (thin film transistor) arrays are cut parallel to the bus-bars, in the space between the bus-bar and the preceding pixel electrode. The cut is done in such a way that it is adjacent to the pixel electrode on the active plate. The four subarrays are then rotated by 90 degrees, with respect to their neighbors, and butted together. In this way, the seam between each tile has no adjacent bus-bar, and it is possible to reproduce the pixel pitch between neighboring tiles, with an acceptable alignment tolerance of the tiles. We have demonstrated the feasibility of the method, with the aid of a small prototype, based on a 192 x 192 pixel array, with a 200-microm pitch. Some image processing is necessary to rotate the images back for display on a conventional display monitor. This can cause artefacts, in some fast moving scenes, in which case an alternative scheme, which uses two mirror image arrays, each rotated by 180 degrees, can be used. However, for static X-ray images and most images in dynamic medical X-ray applications this is not necessary and we can obtain good quality seamless images, free from any significant artefacts.

Effect of cisapride on oesophageal motility and duodenogastro-oesophageal reflux in patients with Barrett's oesophagus.

OBJECTIVE: Both gastric acid and duodenal juice have been implicated in Barrett's oesophagus. The aim of this study was to look at duodenal reflux in the oesophagus together with motility characteristics in a group of patients with Barrett's oesophagus and compare them with a mild oesophagitis group and to assess the effect of cisapride on any abnormalities. DESIGN: A prospective study comparing the two groups of patients was carried out. METHODS: Twenty patients with histologically proven Barrett's oesophagus and 20 patients with Savary-Miller grade 2 oesophagitis were studied. Standard oesophageal manometric measurements were carried out and on a separate occasion duodenogastro-oesophageal reflux (DGOR) was measured over a 4-h period using a sodium ion selective electrode. Patients with more than 5% DGOR were given cisapride (10 mg four times daily) and the studies repeated after 7 days of treatment. RESULTS: Barrett's patients showed more DGOR, 12.2% of the study time compared to 5.1% in the mild oesophagitis group, P = 0.012, but manometric findings were not significantly different. Sixteen patients were treated with cisapride. DGOR was reduced in 8 out of 12 Barrett's patients and 2 out of 4 oesophagitis patients, and proximal amplitude and distal oesophageal pressures were significantly elevated (P = 0.05 and P = 0.03, respectively). CONCLUSION: Monitoring of sodium ions in the oesophagus shows that patients with Barrett's oesophagus have significantly more DGOR than patients with uncomplicated oesophagitis and cisapride may be effective in removal of this reflux.

In vitro contractility of stimulated and non-stimulated human gallbladder muscle.

In an attempt to define, more clearly, the nature of gallbladder contraction we obtained muscle strips from human gallbladder wall, removed at cholecystectomy. Samples were taken from various areas of the gallbladder to seek evidence of a dominant axis of contraction. The strips were stimulated with increasing concentrations of cholecystokinin-8 (CCK-8) and carbachol, and, to determine maximal contractile force, 0.25 M potassium chloride. No differences were seen between samples taken from the long-itudinal, circular and oblique axes. In a second series of experiments, samples were taken from the body and neck regions of the gallbladder. In these, it was seen that the samples from the body contracted more forcefully than those of the neck tissue and that they were more sensitive to carbachol stimulation. The difference in response to CCK-8 measured in the strips from the body and cystic duct/neck of the gallbladder cannot be explained by a difference in sensitivity to CCK-8, but is mainly due to the difference in the amount of muscle tissue present. Strips from the body are more sensitive to muscarinic stimulation that those from the neck. Overall, there is a functional difference in sensitivity between the body and neck which would serve to facilitate bile flow into the common bile duct during gallbladder contraction.

Effects of piezoelectric lithotripsy on human DNA.

Genomic DNA was extracted from excised gallbladder mucosa, obtained shortly after a single treatment piezoelectric lithotripsy. Control samples were obtained from age and sex-matched patients who had received no lithotripsy. No DNA fragmentation was demonstrable on agarose gel electrophoresis. Suspensions of cultured lymphoblasts were subjected to different shock wave doses and the percentage of cells surviving the treatment was assessed immediately and the rate of cell death monitored over the following 7 h. The proportion of cells surviving the treatment decreased with increasing shock wave doses, but subsequent rate of cell death was no different from controls. DNA, extracted from the intact surviving cells, again showed no evidence of fragmentation on electrophoresis, but the DNA extracted from the supernatant showed extensive fragmentation.

Continuous monitoring of sodium ion concentration in the human stomach--a new technique for the detection of duodenogastric reflux.

Measurement of sodium ion concentration in gastric juice offers a simple means of detecting duodenogastric reflux (DGR). Using aspirated gastric juice, we measured sodium ion concentration, bile acid levels and phospholipase A2 activity and found that sodium ion levels increase along with these other standard markers during DGR. Following this, using a sodium ion selective electrode and a portable data logger, continuous recordings of sodium ion concentration were made in the human stomach. These studies demonstrated the ability of sodium ion monitoring to detect major DGR episodes in the body of the stomach.

Extracorporeal shock wave lithotripsy of gall stones: an in vitro comparison between an electrohydraulic and a piezoceramic device.

A comparative study of the effectiveness of two types of lithotripter in fragmenting gall bladder stones is reported. The machines used were a Piezolith 2300, which generates shock waves by the piezoceramic principle, and a Dornier MPL 9000, which produces the shock waves by underwater spark discharge. With each machine, corresponding stones of 45 pairs of weight and volume matched calculi (median volume 0.5 cm3, median diameter 10.5 mm) obtained at cholecystectomy were treated. All stones were successfully disintegrated (fragments smaller than 2 mm) with up to 5400 (median 628) shocks with the Piezolith and 3450 (median 428) shocks with the MPL 9000 lithotripters. With the Piezolith, operating at the highest power setting, a 1.65 fold median higher number of shocks was required for stone fragmentation than with the MPL 9000 at a medium power setting. Stone volume seemed to be the only determinant which affected ease of fragmentation; composition and density of the stones as assessed by computed tomography did not seem to be governing factors.

The lessons from in vitro lithotripsy for the clinical treatment of gallstones.

Fifty-eight gallbladder stones were treated in vitro, using a Wolf Piezolith 2300 lithotripter, to discover whether complete fragmentation (i.e., no particles greater than 2 mm diameter) could be achieved by lithotripsy alone. In 16 stones this was accomplished with up to 6000 shocks being administered. The degree of fragmentation was judged first by eye during the experiment and then by both microscopy and sieving of the debris. Eye judgement proved to be an unreliable indicator with 23 of the 42 stones in the failed lithotripsy group receiving 6000 shocks or less. Cholesterol analysis and high resolution radiography revealed no significant differences between the successfully and unsuccessfully fragmented stones, but X-ray diffractometry did show a higher incidence of inorganic calcium salts in the latter group. This study shows that lithotripsy can successfully fragment gallbladder stones, but that a minimum of 6000 shocks, using the Piezolith 2300, should be given to ensure adequate treatment. Additionally, the presence of radiopaque stones does not necessarily preclude successful treatment by this method.

Serum phospholipase A2 activity in acute pancreatitis: an early guide to severity.

Daily measurements of serum phospholipase A2 activity were carried out on 73 consecutive patients admitted to hospital with acute pancreatitis. During the first 6 days there were significant differences in activity in those patients predicted as severe by multiple prognostic criteria when compared with those with mild disease. Follow-up studies at 6 weeks showed no difference between those graded as mild and those graded as severe at the time of attack. In the patients with elevated activity, nine had this at the time of admission and all were raised within 24 h. Elevated activity correlated well with the clinical outcome and showed good agreement with the multiple prognostic criteria in the prediction of severe disease. It is suggested that measurement of serum phospholipase A2 activity may provide a simple test for the early identification of most patients with severe acute pancreatitis.

Phospholipase A2 activity in taurocholate-induced acute pancreatitis in the rat model.

The activity of phospholipase A2 (PA2) was measured in the plasma of rats after the induction of acute pancreatitis. Buffered sodium taurocholate (3.75% w/v), injected into the pancreatico-biliary duct, was used to induce acute pancreatitis. Blood was taken at 1-h intervals for the measurement of phospholipase A2, glucose, lipase, and arterial gases. Plasma lipase was markedly elevated in the test groups, indicating acute pancreatitis, but no significant difference in PA2 activity was seen between the controls and the test group. However, in four animals the PA2 activity was elevated and in all cases this was accompanied by a low arterial pO2. This supports the theoretical role of PA2 in the pathogenesis of the respiratory complications observed in severe acute pancreatitis.

Management of bleeding varices in the elderly.

In 207 consecutive patients the outcome of bleeding varices was compared in those aged under 65 (n = 146) and those aged over 65 (n = 61). All patients were seen during seven years and were treated by active initial and maintenance sclerotherapy. Alcoholic cirrhosis was commoner in younger patients (68 (47%) v 12 (20%] and cryptogenic cirrhosis commoner in older patients (21 (34%) v 19 (13%]. Mortality due to the first bleed was dependent on the severity of liver disease and was unrelated to age. Survival corrected for age (life table analysis) was 65% at one year and 60% at two years for both groups of patients. It is concluded that patients should not be denied active treatment for bleeding varices on the basis of age alone. In order to obtain optimum results early endoscopy and sclerotherapy is essential.