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Biomedical subjects

T Gilat

Publications and source records attributed to T Gilat.

At least 91 records · Page 5Linked to original sources

Polyamines--potential nucleating factors in bile.

Lithogenicity of human bile is dependent not only on cholesterol saturation, but also on the presence of nucleating and antinucleating factors. Most of the research in this field is directed toward biliary proteins, particularly glycoproteins. In the present study we have shown that spermine, spermidine, cadaverine and putrescine have a nucleating effect in model bile as well as in native human bile. These findings are based on 183 mixing experiments using biles from 10 patients and model biles. The effect seems to be dose dependent at concentrations up to 10 mmol/l. It is not accompanied by a shift in cholesterol distribution between its vesicular and micellar carriers. It is at present uncertain whether these effects are pharmacologic or physiologic. These findings emphasize, however, the potential importance of non-protein compounds in the cholesterol nucleation process in bile.

Bile↗

Gel filtration and quasielastic light scattering studies of human bile.

Analyses of cholesterol carriers in the extremely variable biliary samples were performed by chromatography under standard conditions. Sephacryl columns were eluted with buffer containing 10 mmol/L sodium cholate, 150 mmol/L sodium chloride, 50 mmol/L Tris(hydroxymethyl)aminomethane-hydrochloride, pH 8.0, and 1.5 mmol/L ethylenediaminetetraacetate. Moderate changes in temperature, flow rate or sample size produced only minor differences in the results. Increments in bile salt concentration in the elution buffer caused progressive disappearance of vesicles and a rise in their cholesterol/phospholipid ratio. Using the standard chromatographic technique, analyses of the same bile gave reproducible results, and comparisons among various biles were possible. Quantitative light scattering measurements of bile showed that the amount of vesicular cholesterol in whole unprocessed bile was similar to that measured by Sephacryl chromatography. Analyses of human gallbladder biles using a high-resolution Sephacryl column showed four cholesterol-containing peaks: vesicles, lamellae, mixed micelles and an undefined carrier. This long chromatographic column separated the lamellar from the micellar peaks (which had merged on the short column). Phospholipid lamellae solubilized most of the biliary cholesterol. These findings were confirmed by ultracentrifugation of bile.

Bile↗

An evaluation of arbaprostil at multiple doses for the treatment of acute duodenal ulcer: a randomized double-blind placebo-controlled international trial.

Six hundred and thirty patients were enrolled in a randomized double-blind placebo-controlled trial evaluating two arbaprostil dosages (25 micrograms and 50 micrograms) qid for 4 wk for the treatment of acute duodenal ulcers. The healing rates in the placebo, 25-micrograms, and 50-micrograms treatment groups were 39%, 51%, and 60%, respectively. Smoking was found to adversely affect the healing rates in all the treatment groups. Pain severity was less with either arbaprostil treatment. The only side effect found was diarrhea: 10%, 14%, and 32% in the placebo, 25-micrograms, and 50-micrograms treatment groups, respectively. Severe diarrhea occurred in 1% of those patients who received the 50-micrograms dosage regimen, but in none of the other two groups. Arbaprostil at these two dosage levels, when given for 4 wk, appears to be a safe and efficacious agent for the treatment of acute duodenal ulcers.

Acute Disease↗

Biliary micellar cholesterol nucleates via the vesicular pathway.

Biliary cholesterol nucleates primarily from phospholipid vesicles. In this study, we investigated the mode of nucleation of micellar cholesterol. Ten biles (four human and six model) were examined. The vesicular and micellar fractions of each bile were separated by gel chromatography. The whole biles and their isolated carriers were incubated at 37 degrees C until nucleation time. In whole human biles, the proportion of total cholesterol in vesicles rose throughout the incubation (from zero time to nucleation time) from 15.5 +/- 8.6% to 28.0 +/- 12.5%, and in model biles from 46.8 +/- 22.4% to 75.5 +/- 8.2%. The vesicular isolated fraction remained unchanged throughout incubation. In isolated micelles devoid of vesicles at zero time, new vesicles formed during incubation, carrying increasing proportions of cholesterol. At nucleation time, these vesicles contained 11.0% of originally micellar cholesterol in human biles, and 41.2% in model biles. The new vesicles formed in whole bile and in the micellar fraction were chromatographically and chemically similar to the vesicles originally present in bile. These data suggest that micellar cholesterol nucleates via the neoformation of phospholipid vesicles, which seem to be the final common pathway for cholesterol nucleation in bile.

Bile↗

Prostaglandin E2 in pyloric stenosis.

Prostaglandins are presumed to have many cytoprotective properties that play a role in the pathogenesis of duodenal ulcer and its complications where decreased levels of prostaglandin E2 (PGE2) impair gastric motility, oppose ionic membrane influx, and enhance obstructive changes. These are just some of the mechanisms that may cause pyloric obstruction and may result from decreased PGE2 levels. To evaluate this hypothesis, 17 patients with duodenal ulcer complicated by pyloric stenosis were examined. Biopsy specimens were obtained from the duodenal bulb, ulcer margins, gastric antrum, fundus, and gastric secretions. Prostaglandin E2 levels were measured and compared with those taken from the same areas during a second endoscopy in a later quiescent or exacerbated phase. During the active phase of pyloric stenosis, decreased levels of PGE2 were found in the gastroduodenal tissues and secretions were compared with levels found during convalescence. These level differences were statistically significant. A correlation between the severity of the clinical and endoscopic findings and the PGE2 levels was found. A further decrease in PGE2 levels in the second endoscopy were indicative of the presence of scar tissue, representing an irreversible obstructive peptic disease.

Aged↗

Acute left colonic obstruction: a new nonsurgical treatment.

Acute obstruction of the left side of the colon is traditionally treated by colostomy, which entails two or three surgical procedures usually in a high-risk group of patients. We present a new nonsurgical approach by which decompression of the bowel is achieved with a tube introduced proximal to the obstruction with the aid of a flexible sigmoidoscope. This procedure was successful in six of nine patients with left-sided large-bowel obstruction, thus avoiding staged surgery and allowing one definitive operation. No complications were encountered.

Aged↗

A comparison of metronidazole and sulfasalazine in the maintenance of remission in patients with ulcerative colitis.

In a double-blind, randomized trial, we tested the effectiveness of metronidazole (0.6 g/day) against sulfasalazine (2 g/day) in the maintenance of remission in patients with ulcerative colitis. The patients were in remission for 1-11 months at entry to trial, which lasted for 12 months. Forty patients entered the trial and 33 completed it. Metronidazole was found to be slightly more effective than sulfasalazine, a difference statistically significant only at 12 months. Six patients also completed a crossover trial. Remission was maintained for 12 months in 3 patients by metronidazole and in none of the 6 by sulfasalazine. No significant side effects were noted, and in particular, no paresthesias were reported. This trial, as well as our previous one, suggests that metronidazole may be useful in the maintenance of remission in patients with ulcerative colitis, but that it is ineffective in the therapy of the acute attack.

Clinical Trials as Topic↗

Intestinal cancer in patients with Crohn's disease. A population study in central Israel.

A population study of Crohn's disease (CD) during the years 1970-1980 was performed in a defined area in central Israel with 1,400,000 inhabitants. Three hundred and sixty-five patients with definite CD were identified, and a complete follow-up was obtained with particular attention to intestinal cancer. The mean follow-up time was 9.95 years (range, 1-49 years). Forty-four per cent of the patients were operated on, but only a few had total colectomy or bypass operations. Only one patient developed colorectal cancer after 7 years of disease. The observed to expected ratio for this cancer was 1.14 at 10 years of disease and 0.73 at 20 years of disease. The incidence of colorectal cancer was not significantly different from the expected in the population. None of the patients developed small-bowel cancer. At least five patients had extraintestinal malignancies. A review of the literature showed conflicting results with regard to cancer risk in CD. The risk was not significantly increased in the two existing population studies, including the present one.

Adolescent↗

Epidemiology of ulcerative colitis in the Jewish population of central Israel 1970-1980.

The epidemiology of ulcerative colitis (UC) was studied in the Jewish population of central Israel in a densely populated urban area of more than 1,400,000 inhabitants. The mean annual incidence for the years 1970-80 was 3.86/100,000, 3.94 in males, and 3.79 in females. The incidence rose from 2.67 in 1970 to 5.09 in 1979, the rise being similar in both sexes. This rise in incidence was found in 3 separate localities in the study area inhabited by communities of different extraction and age composition. The disease started most frequently between the ages of 25 and 29. The crude prevalence of UC in 1980 was 55.2/100,000. The age-adjusted prevalence in Israel-born Jews was 45.8, in Asia-Africa-born 48.5 and in Europe-America-born 52.7/100,000. Compared with our previous study in 1960-70 in the city of Tel Aviv-Yafo, the prevalence of UC was increased and the differences between the community groups have narrowed. This suggests an effect of environmental factors in the causation of ulcerative colitis.

Adolescent↗

Epidemiology of Crohn's disease in the Jewish population of central Israel, 1970-1980.

The epidemiology of Crohn's disease (CD) during the years 1970-80 was studied in the Jewish population in a defined area of central Israel with 1.4 million inhabitants. Three hundred sixty-five patients with definite CD were identified, and a complete follow-up was obtained. The incidence of CD rose from 0.33 (per 10(5)) in 1970 to 3.10 in 1979. This rise was noted in both sexes, in all age groups, in all major Jewish community groups, and was demonstrated in three different regions of the study area. It is thought to represent a true (10-fold) increase in incidence. The mean annual incidence was 1.55/10(5). The prevalence in 1970 was 7.08/10(5), and in 1980 it was 19.47/10(5). In 1970, the age-adjusted prevalence in immigrants from Europe-America was 13.27 and in immigrants from Asia-Africa it was 1.69. In 1980, the difference between the two groups narrowed and the prevalences were 26.05 and 12.37, respectively. This decrease in differences between original migrant groups, as well as the rapid changes in incidence, point to the effect of environmental factors in the pathogenesis of CD. Population studies worldwide have demonstrated an increased incidence of CD in Jews, with marked differences among Jews in different geographic areas. This suggests the coexistence of genetic and environmental factors in the pathogenesis of the disease.

Adult↗

Quantitation of phospholipid vesicles and their cholesterol content in human bile by quasi-elastic light scattering.

The proportion of biliary cholesterol carried by phospholipid vesicles may be an important determinant of the lithogenicity of bile. The distribution of biliary cholesterol between vesicles and other aggregational forms is often determined by gel filtration under standard conditions. The aim of this study was to measure the proportion of biliary cholesterol in vesicles in native unprocessed bile and to compare it with values obtained by chromatography. A modified quasi-elastic light-scattering method was used to measure vesicular cholesterol in whole bile. It was suitable only for lightly pigmented biles with a relatively monodisperse population of vesicles. In ten human biles examined, the proportion of cholesterol in vesicles by gel filtration was 40 +/- 8.1% (mean +/- S.D.) by chemical measurement, and 38 +/- 7.2% by [3H]cholesterol estimation. Quasi-elastic light-scattering measurements of these biles produced vesicular cholesterol values of 36 +/- 9.4%. Chromatography may affect lipid particles in bile. Nevertheless, it provides a relatively accurate measurement of biliary cholesterol in vesicles.

Bile↗

Vesicular cholesterol in bile. Relationship to protein concentration and nucleation time.

A study was done to determine whether the nucleation time was related to the amount of cholesterol carried in vesicles. Bile was obtained from cholesterol gallstone patients and controls. Gel-exclusion chromatography was used to separate vesicles and micelles in the native bile using an eluting buffer containing 10 mM sodium cholate. The percent of total cholesterol carried in vesicles in gallbladder bile of stone patients was significantly greater than that in control patients. Total cholesterol concentration in gallbladder bile of stone patients was significantly greater than in controls. This difference was due to the fact that vesicular cholesterol concentration was significantly greater in the gallbladder bile of stone patients compared to controls. Micellar cholesterol concentrations were similar in the two groups. Nucleation time was related significantly to vesicular cholesterol concentration in correlation analysis and, as previously shown, so was total protein concentration. This study supports the importance of vesicular cholesterol in solid crystal formation and demonstrates for the first time that the rate of cholesterol monohydrate crystal formation is directly related to the amount of cholesterol transported in vesicles.

Adult↗

Colorectal cancer in patients with ulcerative colitis. A population study in central Israel.

The incidence of colorectal cancer was studied in an unselected group of 1035 patients (total group) with ulcerative colitis and in a subgroup of 822 who resided, at the time of diagnosis, within a defined area in central Israel (regional group). The operation rate was 5.2% and the follow-up period (mean +/- SD) was 11.5 +/- 8.3 yr, range 1-52 yr. The cumulative incidence of colorectal cancer in all patients was 0.2% at 10 yr, 2.8% at 15 yr, 5.5% at 20 yr, and 13.5% at 30 yr. The ratio of observed to expected cancer was 0.9 at 10 yr, 5.0 at 20 yr, and 6.4 at 30 yr. The cancer incidence was 1 case per 3895 patient-years in the first decade of disease, 1 case per 198 patient-years in the second decade, and 1 case per 100 patient-years in the third decade. All these figures were higher in patients with total colonic involvement. There were no significant differences between the total and regional patient groups. Onset of ulcerative colitis in the first and second decade of life was not associated with a higher cancer incidence when standardized for extent and duration of disease. The risk of colorectal cancer in patients with ulcerative colitis was more strongly expressed in population groups with a lower incidence of this cancer. The cumulative incidence of colorectal cancer in ulcerative colitis is much lower in population-based studies than that reported from major medical centers. Worldwide this incidence may also vary among different populations.

Adult↗

The relative value of fecal occult blood tests and flexible sigmoidoscopy in screening for large bowel neoplasia.

The secondary prevention of colorectal cancer is based on the early detection of noninvasive cancer and removal of adenomatous polyps. The two commonly used screening tests are flexible sigmoidoscopy and guaiac fecal occult blood testing. Both were performed simultaneously and independently on 1176 asymptomatic volunteers followed by colonoscopic examination if either occult blood or a neoplasm was detected. Neoplasia (adenomatous polyps or cancer) were found in 48 screenees. Only ten had positive stool occult blood while 45 were detected by sigmoidoscopy. Analysis of sensitivity for neoplasia was 93.8% for sigmoidoscopy but only 20.8% for the occult blood tests, while the positive predictive values for neoplasia were 100% and 23.8% respectively. The fecal occult blood test detected only 18% of screenees with adenomas and 60% with invasive cancer. Flexible sigmoidoscopy detected 95% and 80% respectively. Analysis (kappa statistic) demonstrated little agreement between the two tests (P greater than 0.05), indicating that they are diagnosing different neoplasia. Evaluation of expected gain in diagnosing neoplasia, by combining both tests, gave 18% for the fecal blood test and 94% for the endoscopic test. These results confirm the complementary value of performing both tests, but especially the high sensitivity and predictive value positive of flexible sigmoidoscopy for adenomas, including those with severe dysplasia, and the converse for the fecal occult blood test. This latter test must be recommended and used within a screening program with caution and full understanding of its limitations.

Adult↗

Nucleation of cholesterol from vesicles isolated from bile of patients with and without cholesterol gallstones.

Bile was obtained from patients with and without cholesterol gallstones at surgery. Biliary vesicles were separated from micelles by gel filtration. The cholesterol/phospholipid ratio in vesicles was much higher than in micelles. Cholesterol crystals nucleated from vesicular fractions, but nucleation from the micellar fractions was slow or did not occur at all. Cholesterol nucleated from vesicles obtained from bile of control patients as rapidly (2.4 days +/- 0.7) as from patients with stones (2.4 days +/- 0.9) and there was no difference in the vesicular cholesterol/phospholipid ratio. The effect of alteration of the bile salt environment was studied by changing the concentration of sodium cholate in the eluting buffer. At low concentrations (5 mM) only vesicles were eluted from the column. These vesicles had a relatively low cholesterol/phospholipid ratio and cholesterol nucleated slowly from these vesicles. At higher concentrations the proportion of micelles increased. The proportion of vesicles decreased progressively but their cholesterol/phospholipid ratio increased and the nucleation time fell. These studies demonstrate that cholesterol nucleates from vesicles in the absence of micelles, that control vesicles are not protected by tightly bound antinucleating substances and that exposure of vesicles to micelles strips relatively more phospholipid than cholesterol from the vesicular fraction, resulting in vesicles with higher cholesterol/phospholipid ratios and shorter nucleation times.

Bile↗

Factors affecting methane production in humans. Gastrointestinal diseases and alterations of colonic flora.

Breath methane was studied in 394 subjects. Among 152 controls, 50.0% produced methane--42.1% of males and 57.9% of females. One hundred sixteen patients with gastrointestinal diseases were studied. Among 32 with Crohn's disease, only 2 (6.1%) produced methane, as well as 16 of 51 ulcerative colitis patients (31.4%) and 11 of 32 patients with the irritable bowel syndrome (34.4%). Breath methane is thus unusual in Crohn's disease. After bowel cleansing for colonoscopy or surgery, 15 of 18 methane producers became nonproducers, whereas after antibiotic treatment, 24 of 30 producers sustained their methane-producing status. After gentamycin and cephazolin therapy, methane production was abolished in three of eight patients. Slight spontaneous variations in methane production were also noticed with two of 23 control subjects, becoming nonproducers on restudy after 10-25 months. Thus gastrointestinal diseases, bowel cleansing and, to a much lesser degree, antibiotic therapy, affect methane production.

Adolescent↗

Prolonged administration of bile salts for gallstone dissolution and its effect on rectal epithelial cell proliferation.

Bile acids and cholesterol metabolites may play a role in large bowel carcinogenesis. Currently, the bile acids chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) are being used for dissolution of cholesterol gallstones in surgical high-risk patients. The effect of prolonged exogenous bile acid intake on rectal epithelial cell proliferation, as a marker for preneoplasia, was evaluated in 19 patients selected for treatment. They were divided into two groups: nine patients received CDCA, 15 mg/kg/day for a mean duration of 11.0 months, while 11 patients received UDCA, 10 mg/kg/day for a mean duration of 9.2 months. Rectal biopsies taken before treatment and at one, three, six, and 12 months of treatment were analyzed and evaluated by three proliferative parameters including labeling index (LI), distribution of labeled cells, and total cells per crypt column. No significant alterations in epithelial cell proliferation were observed among patients treated with UDCA or CDCA with the exception of the number of cells per crypt column which, in the latter instance, deviated only slightly from the predicted values. The lack of major persistent alterations in the proliferative behavior of rectal epithelial cells does not justify any change in the selection of patients for gallstone therapy, but cannot exclude the potentially deleterious long-term effects of bile acid treatment.

Autoradiography↗

A modified, solid phase radioimmunoassay for the differential diagnosis of acute and convalescent phases of hepatitis A infection.

The commercial assays for diagnosing the presence of hepatitis A antibodies (HAVAB; Abbott Laboratories, North Chicago, IL) or the presence of IgM class anti-hepatitis A virus antibodies (HAVAB-M; Abbott) do not provide precise information as to the timing of the acute infection. IgM class antibodies are detected as late as six months after the acute infection. In this study the authors describe a modified HAVAB test that inactivates the IgM class antibodies. It thus measures the proportion of IgG antibodies out of the total anti-hepatitis A virus antibodies. In a study of 139 patients with impaired liver function, the available and modified tests showed good agreement except for the convalescent phase of hepatitis A. During serial testing for three months after the acute infection, the commercial tests continuously detected IgM class antibodies. The modified test detected predominantly IgG class antibodies from four weeks on. By six weeks, 85% of the patients had predominantly IgG class antibodies. The modified test thus provides information on the timing of recent hepatitis A infection.

Acute Disease↗