Soluble Syndecan-1: A Novel Biomarker of Small Bowel Mucosal Damage in Children with Celiac Disease.

BACKGROUND: Syndecan-1 (SDC1) is essential for maintaining normal epithelial barrier. Shedding of SDC1 ectodomain, reflected by serum soluble syndecan-1 (SSDC1) levels, is regulated by inflammation. Increased intestinal permeability plays a central role in celiac disease (CD). The association between SSDC1 levels and mucosal damage in CD has not been evaluated. AIMS: To evaluate serum SSDC1 levels in children with CD and to determine its relationship with histological grading classified by modified Marsh criteria. METHODS: This is a cross-sectional, pilot study, in which serum SSDC1 was analyzed by ELISA in a cohort of 49 untreated children with CD and 15 children with nonspecific abdominal pain (AP). CD was diagnosed based on positive celiac serology and small intestinal biopsy. SSDC1 levels at the time of biopsy were correlated with Marsh grading. Controls were defined by AP, negative celiac serology, normal upper endoscopy, and small intestinal biopsies. RESULTS: SSDC1 levels were significantly higher in CD patients compared to AP controls (116.2 ± 161 vs. 41.3 ± 17.5 ng/ml, respectively, p < 0.01). SSDC1 levels were significantly higher in patients with Marsh 3c lesion compared to AP controls (170.6 ± 201 vs. 41.3 ± 17.5 ng/ml, respectively, p < 0.05). SSDC1 concentrations displayed a significant correlation with mucosal damage defined by Marsh (r = 0.39, p < 0.05). CONCLUSION: This is the first study demonstrating elevated levels of serum SSDC1 in children with CD. Our results suggest that SSDC1 is a potentially novel marker of intestinal mucosal damage in patients with CD. Its applicability as a surrogate biomarker in CD remains to be determined.

Dietary enrichment with alpha-linolenic acid during pregnancy attenuates insulin resistance in adult offspring in mice.

OBJECTIVE: Our objective was to test the contribution of dietary enrichment in essential or saturated fatty acids, in normocaloric diets, on the lipid accumulation and insulin resistance in the adult offspring in a C57Bl6/J mice model. METHODS: Pregnant mothers were fed normocaloric diets containing 6% fat enriched in essential fatty acids (EFA): alpha-linolenic (ALA-18:3, n-3), linoleic (LA-18:2, n-6), or saturated fatty acids (SFA). After a washing-out period with regular diet, the offspring received a high-fat diet before euthanization. RESULTS: Adult mice fed maternal ALA showed lower body weight gain and lower liver fat accumulation, lower HOMA index and lower stearoyl-CoA desaturase (SCD1) activity than those fed maternal SFA. CONCLUSION: The results observed using this novel model suggest that ALA in maternal diet may have the potential to inhibit insulin resistance in adult offspring.

Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer.

BC-819 is a DNA plasmid that was developed to target the expression of diphtheria-toxin gene under the control of H19 regulatory sequences. BC-819 has the potential to treat pancreatic cancer that overexpresses the H19 gene. The objectives were to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of BC-819 administered intratumorally in subjects with unresectable, locally advanced, non-metastatic pancreatic cancer. Nine patients with unresectable pancreatic adenocarcinoma were enrolled in an open-label, dose-escalation trial. Subjects were entered into one out of two cohorts with escalating doses of BC-819. Each cohort received 2 weeks of twice weekly intratumoral injection of BC-819 under computerized tomography (CT) (n = 3) or endoscopic ultrasound (EUS) (n = 6) guidance. Patients were assessed by CT or positron emission tomography (PET)/CT during week 4 for tumor response. The maximum tolerated dose of BC-819 was not reached in this study at the highest dose. Asymptomatic elevation of lipase, which was considered as an adverse event with dose-limiting toxicity, occurred in only one subject in the high-dose group and was resolved spontaneously. The tumors did not increase in size 4 weeks after initiating treatment. Two weeks after completing the treatment, the two subjects who went on to receive subsequent chemotherapy or chemoradiation therapy, pancreatic tumors were downstaged and considered surgically resectable. Remarkably, three of the six subjects in cohort no. 2 evaluated at month 3 had a partial response. BC-819 can be safely administered intratumorally via EUS- or CT-guided injection at a dose of at least 8 mg per injection weekly twice. BC-819 given locally in combination with systemic chemotherapy may provide an additional therapeutic benefit for the treatment of pancreatic cancer.

Nonspecific esophageal motility disorders may be an early stage of a specific disorder, particularly achalasia.

The clinical significance of nonspecific esophageal motility disorder (NEMD) is unclear. Our aim was to investigate the natural history of NEMD. All manometries performed at Meir Hospital from 1997 to 2004 and diagnosed as NEMD were reviewed. Manometric criteria for NEMD included either low-amplitude peristalsis, nonprogression of peristalsis, prolonged retrograde or triple-peaked waves, or incomplete relaxation of the lower sphincter. Patients determined to have NEMD were contacted and asked to complete a questionnaire and undergo a second manometry. NEMD had been diagnosed in 137 patients. Upon review of manometry results, 65 patients were eligible for the study (36 men and 29 women). The other 72 patients did not have NEMD when we reviewed their manometry tracing, applying strict criteria as specified in Table 1. The average age was 64 +/- 16 years (range 24-83 years). The average follow-up period was 7 +/- 2 years. All 65 patients were symptomatic at their initial prestudy visit. By the second visit, symptoms had resolved in 33 (51%) patients and improved in 13 (19%). Dysphagia, chest pain, and food regurgitation had improved, whereas heartburn and respiratory symptoms had not. Of 37 patients with triple-peaked waves, only 11 (30%) had improved clinically. Of the 65 study patients, 17 (26%) had a second manometry during the study, which was normal in 2 (12%), unchanged in 11 (69%), and revealed achalasia in 4 (23%), representing 6% of all study patients. NEMD is generally a benign disorder that improves clinically in most cases. Nevertheless, in about 6% of patients, NEMD may evolve into achalasia.

Low-dose heparin for the prevention of post-ERCP pancreatitis: a randomized placebo-controlled trial.

BACKGROUND: As suggested by observational and animal studies, heparin has antiinflammatory effects that could prevent acute post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Low-molecular-weight heparin did not reduce the incidence of post-ERCP pancreatitis in a controlled study. The current study aimed to determine whether prophylactic administration of low-dose unfractionated heparin, which has potentially more antiinflammatory capability, can prevent acute post-ERCP pancreatitis. METHODS: Patients scheduled for ERCP in the authors' department were randomized to receive unfractionated heparin (5,000 IU) or placebo (saline solution 0.5 ml) administered subcutaneously 20 to 30 min before the ERCP. Patients who had undergone endoscopic sphincterotomy in the past were excluded from the study. Post-ERCP pancreatitis was defined according to criteria established by Cotton: abdominal pain combined with a threefold elevation of blood amylase 24 h after the ERCP. RESULTS: The study enrolled 106 patients. One patient was excluded from the analysis due to inaccessible papilla of Vater, leaving 51 patients in the heparin group and 54 in the placebo group, for a total of 105 patients (62 women and 43 men) with a mean age of 64.6 years. The rate of post-ERCP pancreatitis was not different between the groups (heparin, 4 patients, 7.8%; placebo, 4 patients, 7.4%). Two patients in each group experienced mild bleeding. CONCLUSIONS: The study did not demonstrate a significant effect of low-dose unfractionated heparin in the prevention of post-ERCP pancreatitis. A multicenter trial with a larger number of patients is needed to demonstrate a benefit from this drug.

The clinical significance of bile duct sludge: is it different from bile duct stones?

BACKGROUND: Some patients with suspected common bile duct (CBD) stones are found to have sludge and no stones. Although sludge in the gallbladder is a precursor of gallbladder stones, the significance of bile duct sludge (BDS) is poorly defined. This study aimed to compare BDS with bile duct stones in terms of frequency, associated risk factors, and clinical outcome after endoscopic therapy. METHODS: The study enrolled 228 patients who underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for suspected choledocholithiasis. The patients were divided into two groups: patients with BDS but no stones on ERCP and patients with CBD stones. The presence of risk factors for bile duct stones (age, periampullary diverticulum, ductal dilation or angulation, previous open cholecystectomy) were assessed at ERCP. Follow-up data (36 +/- 19 months) were obtained from medical records and by patient questioning. RESULTS: Bile duct sludge occurred in 14% (31/228) of patients and was more common in females. After endoscopic clearance, CBD stones recurred in 17% (33/197) of the patients with CBD stones, and in 16% (5/31) of the patients with BDS (p = 0.99). Common bile duct dilation was less common in the sludge group. The other known risk factors for recurrent CBD stones (age, previous open cholecystectomy, bile duct angulation, and the presence of a peripampullary diverticulum) were not statistically different between the two groups. CONCLUSIONS: The findings indicate that the clinical significance of symptomatic BDS is similar to that of CBD stones. Bile duct sludge seems to be an early stage of choledocholithiasis.

An angulated common bile duct predisposes to recurrent symptomatic bile duct stones after endoscopic stone extraction.

BACKGROUND: Endoscopic sphincterotomy and stone extraction are standard procedures for the removal of bile duct stones. Stone recurrence can, however, occur in up to 25% of cases. Risk factors have been poorly defined, but are believed to be related to bile stasis. This study investigated whether an angulated common bile duct (CBD) that may predispose to bile stasis influences symptomatic stone recurrence after successful endoscopic therapy. METHODS: This study included 232 consecutive patients (mean age, 64.1 years; 86 men) who had undergone therapeutic endoscopic retrograde cholangiopancreatography for bile duct stones. Data from the follow-up period (36 +/- 17 months) were obtained from medical records and patient questioning. Common bile duct angulation and diameter were measured from the cholangiogram after stone removal. RESULTS: Symptomatic bile duct stones recurred in 16% of the patients (36/232). Three independent risk factors were identified by multivariate analysis: an angulated CBD (angle, < or = 145 degrees; relative risk [RR], 5.2; 95% confidence interval [CI], 2.2-12.5; p = 0.0002), a dilated CBD (diameter, > or = 13 mm; RR, 2.6; 95% CI, 1.2-5.7; p = 0.017), and a previous open cholecystectomy (RR, 2.7; 95% CI, 1.3-5.9; p = 0.0117). Gender, age, urgency of procedure, or a periampullary diverticulum did not influence the recurrence rate. CONCLUSIONS: Angulation of the CBD (< or = 145 degrees) on endoscopic cholangiography, a dilated CBD, and a previous open cholecystectomy are independent risk factors for symptomatic recurrence of bile duct stones. The findings support the role of bile stasis in stone recurrence. Further studies using these data prospectively to identify high-risk patients are warranted.

Endoscopic sphincterotomy and temporary internal stenting for bile leaks following complex hepatic trauma.

BACKGROUND: Biliary leak secondary to blunt or penetrating hepatic trauma and damage to the intrahepatic biliary tree remains a challenging problem. The role and safety of endoscopic retrograde cholangiopancreatography (ERCP) and stenting in this setting were studied. METHODS: All trauma victims who developed a bile leak secondary to hepatic trauma were included. Bile leak was defined as the appearance of bile in a surgical wound or intra-abdominal drain after surgery, following percutaneous drainage of a perihepatic bile collection, or evidence of a leak on hepatobiliary scintigraphy. ERCP was performed within 24 h of diagnosis and included biliary sphincterotomy and internal stenting. Recovery was defined as cessation of leakage. RESULTS: Between 1996 and 2004, six patients with penetrating injuries and five with blunt abdominal injuries were treated according to the study protocol. Eight underwent surgery to control bleeding or for additional intra-abdominal injuries. All bile leaks resolved completely within 10 days of ERCP. One patient died from pulmonary sepsis; ten recovered without hepatobiliary sequelae. CONCLUSION: ERCP, biliary sphincterotomy and temporary internal stenting, together with percutaneous drainage of intra-abdominal or intrahepatic bile collections, represent a safe and effective strategy for the management of bile leaks following both blunt and penetrating hepatic trauma.

Faecal sterol output is increased by arachidyl amido cholanoic acid (Aramchol) in rats.

Fatty acid-bile acid conjugates (FABACs) were shown recently to have important and multiple effects on cholesterol metabolism. In human fibroblasts, they were found to markedly enhance cholesterol efflux by an ATP-binding cassette transporter A1-dependent pathway. In C57L/J mice, they increased CYP7A1 activity and RNA expression, while decreasing moderately 3-hydroxy-3-methylglutaryl-CoA reductase activity. In C57L/J mice and in hamsters, they also decreased serum cholesterol levels, whereas in other animals, this effect was not seen in short-term experiments. In the present study, we investigated potential mechanisms of action of arachidyl amido cholanoic acid (Aramchol), with particular reference to biliary and faecal sterol outputs in rats. Supplementation with Aramchol at a dose of 150 mg x kg(-1) x day(-1) increased neutral sterol output by approx. 50%, while the faecal outputs of bile salts and total sterols increased by almost 2-fold. Biliary lipid outputs were not significantly different between the control and FABAC-supplemented animals. These findings indicate an overall catabolic effect of FABACs on body cholesterol.

Cytokine network in nonresponding chronic hepatitis C patients with genotype 1: role of triple therapy with interferon alpha, ribavirin, and ursodeoxycholate.

OBJECTIVE: (i) to characterize the profile of tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), IL 10, Fas-ligand and transforming growth factor beta (TGF beta), chronic hepatitis C (HCV) patients with genotype 1; (ii) to determine the influence of triple therapy (TT) with interferon alpha (IFN alpha) + ribavirin + ursodeoxycholic acid on these cytokines and (iii) to establish the relationship between the pro-inflammatory cytokines and the outcome of treatment. DESIGN AND METHODS: 22 patients infected with HCV-genotype 1 a/b and non responsive to IFN-alpha monotherapy were enrolled in the TT. The controls were 49 HCV naïve patients with genotype 1 a/b. Cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline TNF alpha values (pg/mL) in the sustained responders (SRs) (63+/-3) were significantly lower than non-responders (NRs) (140+/-16) (p < 0.001). Baseline Fas (ng/mL) levels were also lower in SRs (4.3+/-0.2) than NRs (5.4+/-0.4) (p < 0.05). CONCLUSIONS: Fas and TNF alpha may be used as serological markers of inflammation and effectiveness of therapy.

Arachidyl amido cholanoic acid (Aramchol) is a cholesterol solubilizer and prevents the formation of cholesterol gallstones in inbred mice.

We have recently synthesized fatty acid bile acid conjugates (FABAC) that were able to reduce and retard cholesterol crystallization in model and human biles. When given orally, they prevented the formation of cholesterol crystals in the bile of hamsters. The aim of the present study was to determine whether the FABAC are cholesterol solubilizers, whether they can dissolve pre-existing crystals, whether they can prevent the formation of cholesterol gallstones, and to investigate the optimal type of bond between the fatty acid and bile acid. The presence of cholesterol crystals was determined by light microscopy, and the total crystal mass of precipitated crystals was measured by chemical means. Inbred (C57J/L) mice on a lithogenic diet were used to evaluate cholesterol crystal formation, dissolution, and gallstone formation in vivo. Arachidyl amido cholanoic acid (Aramchol) was the FABAC used in the present experiments. At equimolar amounts, the cholesterol-solubilizing capacity of Aramchol was higher than that of taurocholate and similar to that of phosphatidylcholine. The addition of Aramchol dissolved approximately 50% of pre-existing crystals in model bile solutions. The same phenomenon was demonstrated in human bile ex vivo, with a dose-response effect. All inbred mice developed cholesterol crystals in bile after 10-14 d on the lithogenic diet. Thereafter, supplementation of the diet with Aramchol progressively reduced the proportion of mice with crystals to 25% after 28 d. On the lithogenic diet, 100% of inbred mice developed cholesterol gallstones in the gallbladder by day 21. None of the mice whose diet was supplemented with 0.5 mg or 1.0 mg of Aramchol/d developed stones or crystals. FABAC are a new class of molecules that are cholesterol solubilizers and which are able to dissolve cholesterol crystals in bile. Upon oral administration, they dissolve pre-existing cholesterol crystals and prevent the formation of gallstones in gallstone-susceptible mice.

Microstructural analysis of bile: relevance to cholesterol gallstone pathogenesis.

The study of physical-chemical factors and pathways leading to cholesterol crystallization in bile has important clinical relevance. The major processes in cholesterol gallstone formation can be subdivided into nucleation, formation and precipitation of solid crystals (crystallization), crystal growth, crystal agglomeration and stone growth. A clear understanding of the microstructural events occurring during the earliest stages of these processes in bile is crucial for the identification of factors possibly delaying or preventing precipitation of cholesterol crystals and, therefore, gallstone formation in bile. Detection and characterization of microstructures in native and model biles can be achieved by both direct and indirect techniques. Direct imaging techniques provide more readily interpretable information, but sample preparation problems, particularly for electron microscopy, are a source of artifacts. Moreover, microscopic techniques provide only qualitative data without the possibility to quantitate or to analyse the composition of microstructures. Several indirect techniques have been used to obtain additional microstructural information about nucleating bile. These techniques have the disadvantage of often being model dependent in addition to constraints specific for each method. The systematic, judicious use of a combination of complementary direct and indirect techniques have led to a comprehensive understanding of the various microstructural processes and interactions occurring during bile secretion, flow in the biliary tract and storage in the gallbladder. This forms the basis for our current understanding of cholesterol nucleation, crystallization and gallstone formation.

Microstructural evolution of lipid aggregates in nucleating model and human biles visualized by cryogenic transmission electron microscopy.

Obtaining reliable information on the physical state and ultrastructure of bile is difficult because of its mixed aqueous-lipid composition and thermodynamic metastability. We have used time-lapse cryogenic transmission electron microscopy (cryo-TEM) combined with video-enhanced light microscopy (VELM) to study microstructural evolution in nucleating bile. A well-characterized model bile and gallbladder biles from cholesterol and pigment gallstone patients were studied sequentially during cholesterol nucleation and precipitation. In model bile, cholesterol crystallization was preceded by the appearance of the following distinct microstructures: spheroidal micelles (3-5 nm), discoidal membrane patches (50-150 nm) often in multiple layers (2-10), discs (50-100 nm), and unilamellar (50-200 nm) and larger multilamellar vesicles (MLVs). The membrane patches and discs appeared to be short-lived intermediates in a micelle-to-vesicle transition. Vesicular structures formed by growth and closure of patches as well as by budding off from vesicles with fewer bilayers. MLVs became more abundant, uniform, and concentric as a function of time. In native bile, all the above microstructures, except discoidal membrane patches, were observed. However, native MLVs were more uniform and concentric from the beginning. When cholesterol crystals appeared by light microscopy, MLVs were always detected by cryo-TEM. Edges of early cholesterol crystals were lined up with micelles and MLVs in a way suggesting an active role in feeding crystal growth from these microstructures. These findings, for the first time documented by cryo-TEM in human bile, provide a microstructural framework that can serve as a basis for investigation of specific factors that influence biliary cholesterol nucleation and crystal formation.

Additive deleterious effect of smoking on gastroduodenal pathology and clinical course in Helicobacter pylori-positive dyspeptic patients.

BACKGROUND: Cigarette smoking has long been regarded as an important factor in the pathogenesis of peptic ulcer disease. OBJECTIVE: To investigate whether cigarette smoking has an additive effect on the clinical presentation and course of disease in Helicobacter pylori-positive dyspeptic patients. PATIENTS AND METHODS: The study group comprised 596 consecutive H. pylori-positive dyspeptic patients (334 males and 262 females, mean age 50.6, range 12-81 years). Following upper gastrointestinal endoscopy, patients were subdivided by diagnosis as follows: Non-ulcer patient group (n = 312: gastritis 193, duodenitis 119), gastric ulcer (n = 19), and duodenal ulcer (n = 265). H. pylori infection was confirmed by histology and/or rapid urease test. In addition, 244 patients had a positive 14C-urea breath test prior to antimicrobial treatment. The patients' medical history and smoking habits were obtained using a detailed questionnaire completed by the patients and their referring physicians. RESULTS: There were 337 non-smoking patients, 148 current smokers and 111 past smokers. Gastric and duodenal ulcers were significantly less prevalent in non-smokers than in current or past smokers (gastric 1.8%, 4.1%, 6.3%; duodenal 39.8%, 50%, 51.4%, respectively) (P < 0.05). The incidence of gastrointestinal bleeding was significantly lower in non-smokers than in current or past smokers (7.1%, 8.1% and 20.7%, respectively) (P < 0.05). Bacterial density, as assessed by the UBT value in 244 patients, was higher in non-smokers (mean 352.3 +/- 273 units) than in past smokers (mean 320.8 +/- 199) or current-smokers (mean 229.9 +/- 162) (P < 0.05). Logistic regression analysis revealed that male gender, current smoking, and immigration from developing countries were all significant independent risks for developing duodenal ulcer, while only past smoking was associated with a higher rate of upper gastrointestinal bleeding in the past. CONCLUSIONS: In H. pylori-positive dyspeptic patients, current smoking as well as male gender and immigration from developing countries are associated with an increased risk for duodenal ulcer. This effect does not seem to be related to the bacterial density or increased urease activity of H. pylori organisms.

The effects of short term lipid infusion on plasma and hepatic bile lipids in humans.

BACKGROUND: Patients on parenteral nutrition have an increased incidence of gall bladder sludge and gallstone disease, thought to be related to bile stasis. Intravenous lipid emulsions, especially those containing medium chain triglycerides, have also been shown to have a lithogenic effect on the composition of bile in the gall bladder. AIMS: To determine whether lipid infusion influences hepatic bile composition in patients with an indwelling T tube following cholecystectomy and choledochotomy. METHODS: In eight patients undergoing the above surgical procedure, the time at which effects of the interrupted enterohepatic circulation were minimal was determined. Twenty two cholesterol gallstone patients with bile fistula were then randomised to receive an infusion of a lipid emulsion containing either long chain triglycerides or a mixture of long and medium chain triglycerides. RESULTS: Lipid infusion resulted in a significant increase in plasma levels of triglycerides and phospholipids. Both lipid emulsions caused an increase in hepatic biliary cholesterol level and cholesterol saturation index, but this effect was more pronounced with medium chain triglycerides. The fatty acid composition of biliary phospholipids showed a significant enrichment of linoleic acid by both lipid infusions. CONCLUSIONS: Infusion of triglycerides causes lithogenic changes in hepatic bile composition in humans, the lithogenic effect of infusion of medium chain triglycerides being more pronounced than that of long chain triglycerides. This effect, coupled with gall bladder stasis, may be responsible for the increased risk of biliary sludge and gallstone formation in patients on long term lipid infusion.

The efficacy of omeprazole-based short-term triple therapy in Helicobacter pylori-positive older patients with dyspepsia.

OBJECTIVE: To evaluate the efficacy of 1-week triple therapy with omeprazole, clarithromycin,and tinidazole (OCT) in Helicobacter pylori-positive older patients with dyspepsia. DESIGN: A prospective, nonrandomized therapeutic study. SETTING: The primary care and referral center of a gastroenterological outpatient clinic at a central university hospital serving an urban population (>1 million) in Israel. PARTICIPANTS: The study group consisted of 134 patients (71 men, and 63 women) more than 60 years old who were referred for evaluation of symptoms of dyspepsia and were endoscopically diagnosed as H. pylori positive. The patients were divided into two groups: those who received their first course of anti-H. Pylori therapy during this study (Group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate the H. pylori (Group 2). MEASUREMENTS: All the patients underwent upper gastrointestinal endoscopy, and H. pylori infection was confirmed by a rapid urease test (CUTest) and/or histological staining. Therapeutic efficacy was assessed by a 13C-urea breath test 4 weeks after completion of treatment. RESULTS: The mean age of the study population was 68.8 years (range 60-87). There were 112 patients in Group 1 and 22 patients in Group 2. Endoscopic findings were: gastritis (in 46), gastric ulcer (8), duodenal ulcer (52), and duodenitis (28). The H. pylori eradication rate was significantly higher in Group 1 patients (104/112, 92.9%) than in patients of Group 2 (15/22, 68.2%). There was no difference in the eradication rate in relation to gender, endoscopic diagnosis, more advanced age, place of birth, or smoking habits. The compliance in both groups was equally good, and no major side effects were recorded. CONCLUSIONS: A 1-week OCT triple therapy is well tolerated and effective as first line therapy for H. pylori among older people. It is less effective in patients previously treated.

Decreased fecal bile acid output in patients with coronary atherosclerosis.

In most patients with atherosclerosis, the underlying metabolic derangement remains undefined. Animal experiments have suggested that the ability to produce and excrete large amounts of bile acids may be an adaptation mechanism to cholesterol overload protecting against the atherogenic effects of cholesterol. However, there are very few data on bile acid excretion in human atherosclerosis. In the present study, we have investigated fecal bile acid secretion in subjects with and without coronary artery disease. The target group consisted of 30 patients with proven coronary artery disease and the control group consisted of 27 matched subjects without clinical or laboratory evidence of coronary atherosclerosis. Fecal bile acids were measured by gas-liquid chromatography from 24-hr stool collections under a controlled diet. The patients excreted significantly less bile acids than the controls (325+/-135 vs. 592+/-223 mg/day, respectively, p < 0.0001). The difference was primarily due to a reduced excretion of secondary bile acids. Less than 50% of deoxycholate was excreted by patients (180+/-81 mg/day) as compared to controls (367+/-168 mg/day, p < 0.0002), while lithocholic acid excretion was 111+/-62 mg/day in patients vs. 190 +/-70 mg/day in controls (p < 0.005). The fecal output of the two primary bile acids, cholic and chenodeoxycholic acid, did not differ significantly between patients and controls. The fecal output of total bile acids correlated with that of both secondary bile acids in patients as well as in controls. These findings suggest that patients with coronary heart disease are unable to excrete adequate amounts of bile acids to rid themselves of excess cholesterol, even if they are able to maintain a plasma cholesterol level comparable to that of healthy controls.

The effects of phospholipid molecular species on cholesterol crystallization in model biles: the influence of phospholipid head groups.

BACKGROUND/AIMS: Variations in the molecular species of biliary phospholipids have been shown to exert major effects on cholesterol solubility and carriers in model and human biles. The aim of this study was to explore systematically the effects of various phospholipid head groups on the cholesterol crystallization process in model biles. METHODS: Three different control model biles were prepared using varying proportions of egg lecithin, cholesterol and Na taurocholate. In the test biles, 20% of the egg lecithin was replaced with synthetic phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol or phosphatidylcholine, keeping the phospholipid acyl chains and other biliary lipids constant in each experiment. RESULTS: Phosphatidylserine and phosphatidylglycerol significantly prolonged the crystal observation time, from 2 days to 10 and 6 days, respectively (p<0.02), while phosphatidylethanolamine had little and phosphatidylcholine no effect. The crystal growth rate was significantly slowed down with 20% phospholipid replacement in the following order: phosphatidylglycerol >phosphatidylserine >phosphatidylethanolamine. The total crystal mass after 14 days, as measured by chemical analysis, was reduced by 59% with phosphatidylserine (p<0.05), and by 73% with phosphatidylglycerol (p<0.05); while phosphatidylethanolamine had little effect. The precipitable cholesterol crystal fractions after 14 days were significantly reduced with phosphatidylserine (54%) and phosphatidylglycerol (37%), but not with phosphatidylethanolamine or phosphatidylcholine. CONCLUSIONS: Variations in the head groups of biliary phospholipids may markedly slow down the cholesterol crystallization process in model biles.

Increased saturation of the fatty acids in the sn-2 position of phospholipids reduces cholesterol crystallization in model biles.

Changes in the molecular structure of biliary phospholipids were shown to have major effects on cholesterol solubility, carriers and crystallization in human and model biles. This study investigated systematically the effects of varying saturation of the phosphatidylcholine (PC) sn-2 fatty acid on the cholesterol crystallization process in 3 different model biles. Twenty % of the egg PC (EPC) in these biles were replaced by synthetic PC's with 16:0-18:0, 16:0-18:1, or 16:0-18:2 fatty acyl chains. With 18:0 in the sn-2 position, the crystal observation time (COT) was prolonged from 2 days in the control EPC solution to 14 days (p<0.05). The crystal growth rate (CGR) was reduced from 0.1 OD/day to unmeasurable levels, and the total crystal mass on day 14 decreased by 86%. The introduction of one (18:1), and two (18:2) double bonds in the sn-2 fatty acid rapidly reversed these effects. Ultracentrifugal analysis showed precipitable cholesterol as monohydrate crystals. In the 16:0-18:0 test solution, most of the precipitable cholesterol remained in the supersaturated multilamellar vesicles. Saturation of the biliary PC sn-2 fatty acyl chain prolongs the COT, slows the CGR, reduces the crystal mass, and extends cholesterol solubility in multilamellar vesicles. Desaturation of the sn-2 fatty acid reverses these effects.