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.

One-dimensional models of the human biliary system.

This paper studies two one-dimensional models to estimate the pressure drop in the normal human biliary system for Reynolds number up to 20. Excessive pressure drop during bile emptying and refilling may result in incomplete bile emptying, leading to stasis and subsequent formation of gallbladder stones. The models were developed following the group's previous work on the cystic duct using numerical simulations. Using these models, the effects of the biliary system geometry, elastic property of the cystic duct, and bile viscosity on the pressure drop can be studied more efficiently than with full numerical approaches. It was found that the maximum pressure drop occurs during bile emptying immediately after a meal, and is greatly influenced by the viscosity of the bile and the geometric configuration of the cystic duct, i.e., patients with more viscous bile or with a cystic duct containing more baffles or a longer length, have the greatest pressure drop. It is found that the most significant parameter is the diameter of the cystic duct; a 1% decrease in the diameter increases the pressure drop by up to 4.3%. The effects of the baffle height ratio and number of baffles on the pressure drop are reflected in the fact that these effectively change the equivalent diameter and length of the cystic duct. The effect of the Young's modulus on the pressure drop is important only if it is lower than 400 Pa; above this value, a rigid-walled model gives a good estimate of the pressure drop in the system for the parameters studied.

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients.

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), > or =90 and < or =109 mm Hg; systolic blood pressure (SBP), > or =150 and < or =180 mm Hg). After a single-blind 2- to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n=62) or to active treatment (n=61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (-8.00 mm Hg, P=0.002) and DBP (-5.38 mm Hg, P=0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (P<0.001) reductions in serum ACE activity and significant (P<0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P=0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

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.

Bethanechol provocation testing does not predict symptom relief after cholecystectomy for acalculous biliary pain.

BACKGROUND: The currently accepted hypothesis to explain acalculous gallbladder pain is the lack of contractile co-ordination between the body and neck. We have previously shown that bethanechol, a muscarinic stimulant causes differential stimulation of these two regions. AIM: To evaluate the reliability of bethanechol-induced gallbladder contraction in predicting symptom relief after cholecystectomy in patients with acalculous gallbladder disease. METHODS: Fifty-one patients underwent a bethanechol provocation test together with serial ultrasound to determine gallbladder emptying. McGill pain questionnaires were completed, and patients positive for pain (bethanechol provocation test +ve) were offered cholecystectomy, and patients negative for pain (bethanechol provocation test -ve) were reassessed at 6 months and offered cholecystectomy if symptoms persisted. All patients answered pain questionnaires either 6 months after surgery or as follow-up. RESULTS: There was no difference in the percentage of gallbladder emptying between the bethanechol provocation test +ve and bethanechol provocation test -ve groups. Fifty-three percent of bethanechol provocation test +ve patients and 54% of bethanechol provocation test -ve patients still remained symptomatic 6 months after surgery. Conclusion. Gallbladder pain provoked by bethanechol does not predict symptom relief after cholecystectomy.

Management of acute cholecystitis in UK hospitals: time for a change.

Early cholecystectomy for patients with acute cholecystitis is safe, cost effective, and leads to less time off work compared with delayed surgery. This study was designed to assess current practice in the management of acute cholecystitis in the UK. A postal questionnaire was sent to 440 consultant general surgeons to ascertain their current management of patients with acute cholecystitis. Replies were received from 308 consultants who were involved in treating patients with acute cholecystitis of whom 18 transferred these patients on to another team for further management the day after admission. Thirty two consultants (11%) routinely treated patients by early cholecystectomy, with limiting factors stated to be the availability of surgical staff, theatre space, and radiological investigations. The remaining consultants (n = 258) routinely manage their patients conservatively with intravenous antibiotics and allow the inflammation to resolve before undertaking cholecystectomy at a later date. Indications for undertaking early cholecystectomy during the first admission by this latter group included the presence of spreading peritonitis due to bile leak, empyema, and unexpected space on theatre list. The commonest method for both elective and early cholecystectomy is laparoscopic, but the percentage of consultants using an open method rises from 8% in the elective situation to 47% for urgent early cholecystectomy. Despite evidence which strongly advocates early cholecystectomy, this practice is routinely carried out by only 11% of consultants in the UK at present.

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.

Acute cholecystitis--room for improvement?

AIMS: A recent survey of UK general surgeons showed that almost 90% prefer to manage patients with acute cholecystitis by initial conservative management and delayed cholecystectomy (DC). The aim of this study was to assess the effectiveness of this management policy in a large university hospital. PATIENTS AND METHODS: All patients admitted with acute cholecystitis between January 1997 and June 1999 who went on to have a cholecystectomy were identified. Patients were required to have right upper quadrant pain for > 12 h, a raised white cell count and findings consistent with acute cholecystitis on ultrasound to be included in the study. RESULTS: 109 patients were admitted with acute cholecystitis (76 female, 33 male) with a median age of 62 years (range, 22-88 years). Conservative management failed in 16 patients (14.7%) who underwent emergency cholecystectomy due to continuing symptoms (9), empyema (4) and peritonitis (3). Symptoms settled in 93 patients and delayed cholecystectomy was performed without further problems in 66 (60.6%). 27 patients were re-admitted with further symptoms before their elective surgery and, of these, 3 were admitted for a third time before surgical intervention. Ten of the 30 re-admission episodes (33%) occurred within 3 weeks of discharge but 15 (56%) occurred more than 2 months after discharge. Elective surgery was undertaken at a median of 10 weeks post-discharge with 67% of operations occurring within 3 months. Mean total hospital stay (days) +/- SEM, for the three groups were: emergency surgery group, 10.21 +/- 0.85; uncomplicated DC group, 12.48 +/- 0.37; re-admitted group, 14.75 +/- 0.71. CONCLUSIONS: The policy of conservative management and DC was successful in 60.6% of cases but 14.7% of patients required emergency surgery and 24.8% were re-admitted prior to elective surgery with a resultant increase in total hospital stay. Performing elective surgery within 2 months of discharge in all cases would have reduced the re-admission rate by 56% and this along with the increased use of early cholecystectomy during the first admission are areas where the treatment of acute cholecystitis could be significantly improved.

Economics of surgery.

The time has come to subject surgery to the same rigours of economic assessment that other health-care sectors are already receiving--namely, the comparative assessment of costs and benefits. The surgical management of gallstones provides a good example of the role of economics in surgery. Gallstone disease is common and patients are usually referred to a surgeon, but the threshold for intervention is not agreed and varies widely, with considerable implications for resources. Gallstone removal has been subject to much innovation over the past 10 years, yet economic assessment of laparoscopic and "mini" cholecystectomy and of gallstone lithotripsy is rare, despite the fact that operation rates have increased by up to 50% in some countries. For surgery to compete with other interventions, economic assessment of new surgical techniques will be increasingly important. This assessment should be based on well-conducted clinical trials in which interventions are provided in a routine service setting, and in which benefits are assessed among other things on the basis of the patient's perceived quality of life. Economic assessment often needs data beyond those collected in a clinical trial, however pragmatic the trial design, so modelling will often be required, incorporating a range of sources of evidence. Finally, evidence alone will not be enough to promote cost-effective practices. The take-up of surgical techniques will always be affected by the way hospitals and surgeons are remunerated. Affecting practice requires a realistic system of reimbursement that reflects evidence on cost effectiveness.

Mismatch between general surgical trainees' sub-specialist interests and advertised jobs: a cause for concern?

The main aim of this study was to establish the primary sub-specialist interest of a group of senior general surgical trainees and compare these results with the required sub-specialist interests in consultant vacancies advertised in the British Medical Journal between 3.1.98 and 25.12.99. Colorectal surgery was the most popular sub-specialty amongst trainees (29.4%) followed by upper gastrointestinal/hepato-pancreato-biliary (UGI/HPB) (27.2%) and vascular surgery (24.3%). The least popular sub-specialties were breast/endocrine (11.4%) and transplant (2.9%). A total of 324 consultant jobs were advertised, with the sub-specialist interest required as follows: Colorectal (25.6%), breast/endocrine (23.5%), vascular (20.4%), UGI/HPB (12%) and transplant (5.6%). Although this study only covers a two-year period, there are obvious discrepancies between trainees' sub-specialist interests and consultant vacancies. Whilst the jobs to trainees ratios are well matched in colorectal and vascular surgery, it appears that there are not enough transplant or breast trainees and too many UGI/HPB trainees for the number of jobs available. This problem needs urgent attention to avoid service shortfalls in unpopular sub-specialties and to avoid training people for jobs that do not exist.

Blood pressure is linked to salt intake and modulated by the angiotensinogen gene in normotensive and hypertensive elderly subjects.

OBJECTIVES: To evaluate salt sensitivity in elderly subjects with different forms of hypertension and controls and to investigate any modulation by genotype DESIGN: Randomized, double-blinded, placebo-controlled latin-square SETTING: Tertiary referral hospital PARTICIPANTS: Community subjects (n = 46) aged > or = 60 years classified as isolated systolic hypertension [ISH; systolic blood pressure (SBP) > or = 160, diastolic blood pressure (DBP) < 90 mmHg, n = 19], diastolic +/- systolic hypertension (SDH; DBP > or = 90 mmHg, n = 10) and normotension (SBP < 160, DBP < 90 mmHg, n = 17). INTERVENTION: Four 14 day treatments, 50, 100, 200 and 300 mmol/day of sodium chloride supplementation interspersed with 14 day washout periods on a salt-restricted diet. MAIN OUTCOME MEASURES: The 24 h blood pressure, heart rate, weight, urinary sodium and creatinine clearance measured during baseline, treatment and washout periods and angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genotypes. RESULTS: For the entire cohort, the mean +/- standard error (SE) of change from baseline in SBP for 50, 100, 200 and 300 mmol/day salt was 7.7+/-2.4, 12.1+/-2.4, 16.6+/-3.0, 18.5+/-2.6 mmHg, respectively. For DBP, the respective changes were: -0.1+/-1.5, 2.4+/-1.6, 3.0+/-1.5, 5.8+/-1.7 mmHg. The increase in SBP among ISH subjects was significantly higher than among subjects in the SDH and normotensive groups (P < 0.05). AGT genotype influenced the effect of salt dose on the change in DBP (P = 0.006) but not SBP (P = 0.7). CONCLUSIONS: In healthy, older subjects, a linear increase in BP occurred with increasing salt dose, it appeared most pronounced in ISH subjects and could be modulated by AGT genotype.

Laparoscopic cholecystectomy: a good buy? A cost comparison with small-incision (mini) cholecystectomy.

OBJECTIVES: To compare inpatient costs for laparoscopic and small-incision cholecystectomy. DESIGN: Retrospective analysis using results of a single blind prospective randomised trial. SETTING: Teaching hospital, UK. SUBJECTS: 200 patients having elective cholecystectomy. INTERVENTIONS: Standard laparoscopic cholecystectomy with conversion to open cholecystectomy if necessary. Small-incision cholecystectomy using high right transverse epigastric incision, enlarged if necessary for safe exposure. MAIN OUTCOME MEASURES: Providers inpatient costs. RESULTS: Small-incision cholecystectomy cost Pound Sterling 995 and was 29% less expensive than the laparoscopic procedure which cost Pound Sterling 1397. Costs of equipment and operations themselves accounted for most of the difference. Results also suggest that costs to patients and society from time lost away from work may be lower for mini-cholecystectomy. CONCLUSIONS: The national health service could be spending over Pound Sterling 10m a year by encouraging laparoscopic rather than small-incision operations for cholecystectomy. Commissioners of health care should question whether the benefits of laparoscopic surgery justify the additional costs.

Photodynamic therapy for dysplastic Barrett's oesophagus: a prospective, double blind, randomised, placebo controlled trial.

BACKGROUND AND AIMS: Photodynamic therapy (PDT) is a treatment in which cell damage is achieved by the action of light on a photosensitizing agent. We have assessed the potential use of PDT in the ablation of Barrett's oesophagus. METHODS: Thirty six patients with dysplastic Barrett's oesophagus receiving acid suppression medication with omeprazole were randomised to receive oral 5-aminolaevulinic acid (ALA) 30 mg/kg or placebo, followed four hours later by laser endoscopy. Follow up endoscopy was performed at one, six, 12, and 24 months. RESULTS: Of 18 patients in the ALA group, a response was seen in 16 (median decrease in area in the treated region 30%; range 0-60%). In the placebo group, a decrease in area of 10% was observed in two patients with no change in 16 (median 0%; range 0-10%; treatment v placebo, p<0.001). No dysplasia was seen in the columnar epithelium within the treatment area of any patient in the PDT group. However, in the placebo group, persistent low grade dysplasia was found in 12 patients (p<0.001). There were no short or long term major side effects. The effects of treatment were maintained for up to 24 months. CONCLUSIONS: This is the first randomised controlled trial of PDT for Barrett's oesophagus. It demonstrates that ALA induced PDT can provide safe and effective ablation of low grade dysplastic epithelium.

The serotonin transporter gene and Parkinson's disease.

Dysfunction in the serotonin (5-hydroxytryptamine) system and reduced serotonin concentrations have been reported in patients with Parkinson's disease (PD). Serotonin concentrations in neural tissue are controlled by a presynaptic serotonin transporter protein that is encoded by a single gene. Therefore, we investigated whether a polymorphic region in the serotonin transporter gene is associated with PD. Three variable-number tandem repeat (VNTR) elements of the serotonin transporter gene were detected by polymerase chain reaction, those with 9, 10, 11 and 12 copies of the repeat element. The 10-copy VNTR element was significantly less common in patients with PD than controls in the univariate analysis (p < 0.05). Logistic regression analysis revealed no significant differences between patients (n = 198) and controls (n = 200) in the distribution frequencies of 9- and 12-copy alleles and combined genotypes (odds ratio = 1.20; p = 1.71). A positive family history of PD was a strong predictor of disease risk (odds ratio = 2.98; 95% confidence interval 1.51-5.87; p = 0.001). Although slight differences were observed between patient and control groups, these data suggest that defects in serotonin concentrations in patients with PD are unlikely to be due to polymorphisms in the serotonin transporter gene in this large Australian cohort; however, the inverse association observed with the 10-copy allele warrants further investigation.

Long term response to gallstone treatment--problems and surprises.

OBJECTIVE: To re-evaluate after 5 years the results of a randomised trial of cholecystectomy and lithotripsy for the treatment of symptomatic gallstones. DESIGN: Late follow-up of a randomised controlled trial. SETTING: Teaching hospital, UK. SUBJECTS: 144 of the 179 patients originally randomised. INTERVENTIONS: Either elective open cholecystectomy under general anaesthesia or a maximum of 4 sessions of lithotripsy (up to 3000 shocks/session) on consecutive days with no anaesthesia or analgesia. RESULTS: Of the original 87 patients randomised to be treated by lithotripsy, 39 (45%) subsequently underwent cholecystectomy, most of them within 32 months of treatment ("crossover" group). Patients in both main groups had a pronounced reduction in the number of episodes of pain at 5 years and significant reductions in the mean severity scores both on VAS and the McGill rating. Those in the crossover group had the worst scores. Gastrointestinal symptoms improved in the two main groups, but again the crossover group did least well. Quality of life improved significantly over baseline in the two main groups, but was much poorer in the crossover group. CONCLUSIONS: Patients who had primary cholecystectomy were more likely to be free of pain than those treated by lithotripsy. Lithotripsy gave good symptomatic results in 55% of patients, and this was not dependent on clearance of stones. Patients who had a cholecystectomy after lithotripsy had the worst symptomatic results. It is difficult to identify patients who will not benefit from lithotripsy, but the presence of many coexisting symptoms may be an important predictor.

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.