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Biomedical subjects

T C Northfield

Publications and source records attributed to T C Northfield.

At least 73 records · Page 4Linked to original sources
PubMed1994

Hydrophobic/hydrophilic balance of proteins: a major determinant of cholesterol crystal formation in model bile.

Biliary proteins are speculated to play an important role in modulating nucleation of cholesterol crystals from supersaturated gallbladder bile, acting either as pro- or antinucleating agents. However, conflicting results have been obtained in attempts to isolate specifically active proteins. Our hypothesis, therefore, was that this may be a nonspecific effect of proteins, related to their secondary structure or to their overall hydrophobic/hydrophilic balance. We studied the effect of a number of "nonspecific" proteins with different secondary structures on cholesterol crystal formation in model bile. Their relative hydrophobic/hydrophilic indices were experimentally determined by measuring their retention time on a phenyl-agarose column (hydrophobic ligand). The potency of each protein in enhancing or inhibiting crystal formation was ranked according to the lowest protein concentration capable of significantly influencing crystal formation by comparison with control using model bile with cholesterol saturation index (SI) of 1.2 and 1.5. Some of these proteins (chymotrypsin, IgA, myoglobin) significantly enhanced crystal formation, while some (apolipoproteins A-I, A-II, and B) inhibited it, and others (IgG, chymotrypsinogen) showed no effect. The different effects were not related to their secondary structure but to their hydrophobic/hydrophilic index, with the most hydrophilic proteins showing maximal pronucleating potency and vice versa (r = 0.93; and 0.97, P < 0.005 for SI = 1.2 and 1.5, respectively). Pronucleating proteins enhanced, while antinucleating proteins inhibited, the transfer of cholesterol and phospholipid from micellar to vesicular forms. We conclude that the effect of proteins on cholesterol crystal formation in model bile is nonspecific and mainly related to their hydrophobic indices rather than to their secondary structures.

Bile↗
PubMed1993

Prevalence of Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter (H pylori) are both associated with an increased risk of peptic ulceration and gastropathy. It is not known, however, if there is an interaction between these two agents, and thus whether or not screening for H pylori before NSAID treatment is of value. The aim of this study was to find out if H pylori potentiates the damaging effects of NSAIDs. Fifty two patients with rheumatoid arthritis requiring longterm NSAID treatment were studied. Dyspeptic symptoms were assessed according to a standardised questionnaire. Gastroscopy was performed after a one week washout period during which NSAIDs were discontinued. Gastric and duodenal mucosal damage was graded endoscopically. H pylori was identified by biopsy urease test and by histological tests. Investigations were repeated after one month's treatment with an NSAID. Patients with H pylori infection (n = 26) had a higher dyspeptic symptom score (p < 0.05). One patient with duodenal ulcer (H pylori +ve) and two with endoscopic gastritis (both H pylori +ve) were excluded from further study. Forty two subjects completed the study. After treatment there was a rise in the gastric damage score both in the H pylori +ve (p = 0.06) and the H pylori -ve (p < 0.005) groups. There was no difference in the extent of increase in grade or the final grade at the end of the treatment period between the H pylori +ve and -ve patients. It is concluded that H pylori infection is associated with increased dyspeptic symptoms in patients receiving NSAIDs but that it does not potentiate NSAID gastropathy.

Adult↗
PubMed1993

Cholesterol nucleation time measurement in nasobiliary or nasoduodenal bile. Comparison with surgical bile.

The usual technique of collecting gallbladder bile at laparotomy is not suitable for sequential studies of cholesterol nucleation time (NT) in patients receiving therapy to prevent or dissolve cholesterol gallstones. Our aim was to study the feasibility of measuring NT in bile obtained by nasobiliary or nasoduodenal intubation. We studied a total of 10 cholesterol gallstone patients; in 8 bile was collected by nasobiliary drainage, in 7 it was collected by nasoduodenal intubation, and in 3 it was collected at laparotomy the next day. Three patients developed abdominal pain and increased serum amylase after endoscopic retrograde cannulation. All three biles obtained at operation nucleated quickly (NT, 1-4 days), whereas duodenal biles were all beyond the expected range (NT, > 21 days). Chymotrypsin activity, as a marker of pancreatic juice contamination, was detected in five of eight nasobiliary biles and in all seven duodenal biles but in none of the surgical biles. Free fatty acids (reflecting lipolysis) were significantly higher in duodenal than in surgical biles, with nasobiliary bile showing intermediate values. Nasobiliary bile showed either a rapid (median NT, 3 days) or a slow (median NT, 22 days) NT, depending on whether chymotrypsin activity was absent or present (p < 0.05). We conclude that duodenal bile is never suitable for NT determination because of contamination by pancreatic enzymes, and that nasobiliary bile, if not contaminated by pancreatic enzymes, may be suitable for NT determination but that its collection via a nasobiliary tube after cholecystokinin injection carries a risk of pancreatitis.

Adolescent↗
PubMed1993

Oesophageal cancer in gastric surgery patients.

Oesophageal adenocarcinoma (which has been steadily increasing in incidence during the last 20 years) is thought to be promoted by gastric reflux. In a cohort of 5018 gastric surgery patients, 19 of whom developed oesophageal cancer, there was no increased proportion of adenocarcinomas. We conclude that the hypothesized aetiology was not supported.

Adenocarcinoma↗
PubMed1992

Childhood living conditions and Helicobacter pylori seropositivity in adult life.

Infection with Helicobacter pylori increases an individual's risk of peptic ulceration and gastric cancer. In the developed world, prevalence of infection rises with age and varies with social class. We used a cross-sectional study design to test the hypothesis that H pylori infection would be more closely associated with childhood living conditions than with current socioeconomic status. Prevalence of IgG antibodies against H pylori was determined with an enzyme-linked immunosorbent assay in 215 subjects (median age 46 years, range 18-82) attending a health-screening clinic in London. Seropositivity varied from 9% (age less than 30) to 67% (greater than or equal to 70). Subjects were asked about their living conditions at present and when they were aged 8 years. Absence of a fixed hot-water supply (p = 0.0005) and domestic crowding (p = 0.0005) in childhood were powerful independent risk factors for current infection with H pylori. Among current living conditions, only the number of children living in the household was independently associated with H pylori infection (p = 0.004). Most British adults infected with H pylori probably became infected by household contact in childhood.

Adult↗
PubMed1992

Surface hydrophobicity of gastric mucosa in Helicobacter pylori infection: effect of clearance and eradication.

Surface hydrophobicity of the gastric mucosa is reduced in peptic ulcer disease and Helicobacter pylori infection. This abnormality may be caused by H. pylori or may be an inherent defect. The aim of the present study was to clarify the relationship between H. pylori infection and mucosal hydrophobicity by examining the effect of eradication of the organism. H. pylori-positive patients with (n = 42) or without (n = 42) duodenal ulcer were randomized to receive ranitidine, bismuth, or bismuth plus antibiotics. Surface hydrophobicity of gastric mucosa was assessed by measurement of plateau-advancing contact angle. Measurements were performed at presentation, end of treatment, and 1 month later. Contact angle was unchanged after ranitidine (55 degrees vs. 56 degrees) but increased with bismuth (57 degrees-62 degrees; P < 0.05) and bismuth plus antibiotics (56 degrees-67 degrees; P < 0.0001). One month after treatment ended, contact angles in patients in whom H. pylori was not eradicated were not different from those before treatment (56 degrees vs. 56 degrees) but increased to a value similar to H. pylori-negative controls in patients in whom H. pylori was eradicated (56 degrees-69 degrees; P < 0.0001). It is concluded that reduced mucosal hydrophobicity in peptic ulcer disease is secondary to H. pylori infection and that this impaired mucosal defense provides a possible mechanism whereby H. pylori infection predisposes to acid/peptic digestion.

Adult↗
PubMed1992

Management of recurrent gallstones.

The risk of gallstone recurrence following non-surgical treatment has been overestimated in the past for two reasons: (1) diagnosis of primary gallstone dissolution was based on oral cholecystography; and (2) gallstone recurrence was expressed as a cumulative recurrence rate. Results based on better methodologies for diagnosis of gallstones (ultrasonography) and for calculation of results (life-table analysis) have indicated that gallstones recur in about 50% of patients, and that the risk of recurrence is confined mainly to the first 5 years after dissolution. Pretreatment gallstone characteristics, but not patient characteristics, are important risk factors for gallstone recurrence. Multiple stones are more likely to recur than solitary stones, a phenomenon attributable to the presence of a potent pronucleating factor in the bile of patients with multiple stones. This observation, and the finding that NSAID administration may reduce gallstone recurrence via inhibition of mucin secretion, suggests that the nucleation defect might be a key factor in the pathogenesis of recurrent gallstones. Prophylaxis with low-dose CDCA or UDCA has proven ineffective for preventing gallstone recurrence, although it may reduce it. Since the majority of recurrent gallstones are small when first seen because of regular ultrasonographic follow-up, multiple, radiolucent and in functioning gallbladders, they are amenable to bile acid retreatment, and intermittent bile acid therapy is probably a viable strategy for long-term management of cholesterol cholelithiasis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Increased intragastric acid-resistant lipase activity and lipolysis in pancreatic steatorrhoea due to cystic fibrosis.

We measured gastric lipase activity and lipolysis in postprandial gastric samples from 10 adults with steatorrhoea due to cystic fibrosis (CF) and from 10 healthy volunteers of similar age and sex. Gastric samples were aspirated for 2 h following a meal consisting of emulsified long-chain triglyceride. Mean acid-resistant lipase activity was twice as high in CF patients as in controls (596 vs. 299 nmol/ml/min fatty acid released; p = 0.028 for area under the curve). Lipolysis rose from 5 to 10% during the postprandial period in CF patients, compared with a constant 5% in controls (p = 0.036 for area under the curve). We conclude that, in healthy adults, lipolysis of long-chain triglyceride starts in the stomach, while in adults with pancreatic steatorrhoea due to CF, gastric lipase activity and intragastric lipolysis are increased, perhaps in compensation for pancreatic insufficiency.

Adult↗
PubMed1992

Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhoea due to cystic fibrosis.

We investigated the therapeutic potential of an acid-resistant fungal lipase prepared from Aspergillus niger. We first demonstrated in vitro that it had a wide pH optimum of 2.5-5.5 and was resistant to pepsin and trypsin. We gave the enzyme or matching placebo in random order by mouth with a fatty meal to 10 adult patients with pancreatic steatorrhoea due to cystic fibrosis (CF) and sampled gastric contents for the following 2 h. Mean acid-resistant lipase activity was 330 nmol/ml/min free fatty acid released on placebo, compared with 896 nmol/ml/min on fungal lipase (p = 0.006 for area under the curve). We compared this lipase's clinical efficacy with that of two conventional pancreatin microsphere formulations in an open randomised crossover fat-balance study in 10 similar patients. Each preparation was given for 2 weeks, and a fat-balance study, using a faecal recovery marker, was performed on the final 3 days; a period without treatment was also included. The fungal lipase had no effect on faecal wet weight or on the coefficient of fat absorption (59.0% vs. 52.3%; NS) in comparison with placebo. The established enteric-coated microsphere preparation (Creon) produced a significant reduction in faecal wet weight and improvement in coefficient of fat absorption (81.4% vs. 52.3%; p less than 0.01) in comparison with placebo. The newer microsphere preparation (Pancrex M) was also effective, but perhaps less so than Creon; there were no significant differences between the two preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed1992

Optimum bile acid treatment for rapid gall stone dissolution.

To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.

Chenodeoxycholic Acid↗
PubMed1991

Direct measurement of first-pass ileal clearance of a bile acid in humans.

The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%), implying a possible wide variation in recycling frequency per day.

Adult↗
PubMed1991

Ursodeoxycholic acid in chronic liver disease.

The hydrophilic bile acid ursodeoxycholic acid has recently been shown to reduce biochemical markers of both cholestasis and hepatocellular damage in patients with chronic liver diseases. The most compelling evidence available is for chronic cholestatic liver diseases, in particular primary biliary cirrhosis, primary sclerosing cholangitis, and cholestasis associated with cystic fibrosis. The effects may be less beneficial in patients with advanced liver disease from these conditions. Data from placebo controlled trials are now available in support of earlier uncontrolled observations, but it is not yet clear whether short term benefit results in an improvement in longterm prognosis. The mechanism of action of the compound seems to reside in its displacement of toxic hydrophobic bile acids from both the bile acid pool and hepatocellular membranes. There may be an independent effect on bile flow, which could be of particular importance in cystic fibrosis, and possibly an effect on the immune system. Ursodeoxycholic acid should now be regarded as occupying a central place in the medical management of chronic cholestatic liver diseases, in particular primary biliary cirrhosis, because it improves cholestasis and reduces hepatocellular damage and it is not toxic. Research should now be targeted on whether treatment with ursodeoxycholic acid, initiated early in cholestatic liver conditions, improves the long-term outcome.

Animals↗
PubMed1991

A practical guide to the nonsurgical treatment of gallstones.

Until recently, cholecystectomy was the only treatment available for symptomatic gallstone disease. During the past 20 years, better understanding of the pathogenesis of cholesterol gallstone disease has led to alternative nonsurgical methods for treating gallstones in selected groups of patients. Use of 2 naturally occurring bile acids, chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), was reported in 1972 and 1975, respectively, for successful dissolution of cholesterol gallstones in humans. Both these bile acids act by reducing cholesterol secretion in bile, thus enabling it to solubilise more cholesterol from the stone surface. Micellar solubilisation is involved, together with liquid crystal formation in the case of UDCA. Having been extensively studied in clinical trials to assess efficacy and safety, both these compounds are now available for general use. The efficacy of CDCA can be enhanced by single bedtime dose administration and by taking a low cholesterol diet. Bedtime administration also enhances the effect of a suboptimal dose of UDCA. CDCA induces dose-related diarrhoea and hypertransaminaemia, and UDCA can induce calcification of gallstones, thus rendering them resistant to medical dissolution. A combination of the 2 bile acids at half the recommended dose for each has become an accepted practice for reducing adverse effects, and this may also enhance efficacy. One of the main problems of bile acid therapy is that dissolution of gallstones is a very slow process. Use of extracorporeal shockwave lithotripsy (ESWL) to break the stones into smaller fragments, with concurrent use of bile acids, has been shown to speed dissolution rate and to achieve complete gallstone dissolution in 78% of selected cases within 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Chenodeoxycholic Acid↗
PubMed1991

Factors affecting gastric mucosal hydrophobicity in man.

Contact angle measurements in animal studies have demonstrated that gastric mucosa has a relatively hydrophobic surface. We have developed and validated a technique for the measurement of this property on human endoscopic biopsy specimens. Mean contact angle of the gastric body (70 degrees) and antrum (70 degrees) was higher than the duodenal bulb (62 degrees; p less than 0.01) and distal duodenum (50 degrees; p less than 0.001). Subjects with duodenal ulcer and gastric ulcer had a lower contact angle than controls without ulcer (57 degrees, n = 49, and 59 degrees, n = 17 versus 66 degrees, n = 124, respectively). Helicobacter pylori infection was associated with reduced contact angle in subjects with gastritis (59 degrees versus 68 degrees). The contact angle was unchanged after treatment with ranitidine but increased to control values after clearance and eradication of H. pylori with bismuth and antibiotics. In postgastrectomy patients, the contact angle was reduced and correlated negatively with the bile acid content of gastric juice (r = 0.51, p less than 0.0001). We conclude that in man gastric mucosal hydrophobicity can be validly measured on endoscopic biopsy specimens and that it is high in health and reduced in bile reflux and in peptic ulcer disease, largely as a result of H. pylori infection.

Bile Reflux↗
PubMed1990

Relation between severity and extent of precancerous lesions in the postoperative stomach.

The relation between the severity and extent of precancerous lesions in a precancerous condition of the stomach was assessed, to find a means of reducing the endoscopic workload required for the detection of such lesions. 87 subjects who had had gastric surgery for peptic ulcer more than 20 years ago underwent gastric endoscopy and biopsy. Severity of dysplasia correlated with its extent. Severity of intestinal metaplasia correlated with its extent and with severity of dysplasia. Type of operation, but not sex or type of ulcer, was the factor most strongly associated with dysplasia. Previous Billroth II operations were more strongly associated with occurrence of dysplasia (85%) than were other operations. In patients with previous Billroth II operations, moderate and severe dysplasia were commoner around the stoma (37%) than in the body (10%). These findings indicate that there is a relation between the severity and extent of precancerous lesions, which suggests that patients with dysplasia have widespread gastric mucosal instability. They also indicate that, if endoscopic screening is limited to Bilroth II subjects and if biopsies are limited to the stoma, endoscopic workload can be reduced by 85%, with only a small reduction (15%) in detection of moderate and severe dysplasia.

Biopsy↗
PubMed1990

Randomized comparison of Nd YAG laser, heater probe, and no endoscopic therapy for bleeding peptic ulcers.

Of 550 patients admitted with acute upper gastrointestinal hemorrhage, 143 with peptic ulcers containing stigmata of recent hemorrhage accessible to endoscopic therapy were included in a randomized comparison of neodymium yttrium aluminum garnet laser, heater probe, and no endoscopic therapy. The rebleeding rate in laser-treated patients (20%) was significantly less than in controls (42%; p less than 0.05), but in heater probe-treated patients (28%) it was not significantly different from either of the other two groups. The mortality rate in the laser group (2%) was not significantly different from either the heater probe (10%) or the control (9%) group. This trial has confirmed the efficacy of the Nd YAG laser but not that of the heater probe in the prevention of rebleeding from recently bleeding peptic ulcers.

Duodenal Ulcer↗