Effect of aging and caloric restriction on intestinal permeability.

Intestinal permeability is increased in several disorders such as Crohn's disease or rheumatoid arthritis. Since aging leads to alteration of many biological functions, the effect of aging on intestinal permeability was studied by measuring the intestinal permeability in aging rats gavaged with different size permeability probes--mannitol, polyethylene glycol (PEG) 400, and inulin. In rats fed with control diet, there was a significant increase in intestinal permeability to medium size probes PEG 400 (14.8 +/- 0.4 and 21.0 +/- 1.1% at 3 and 28 months respectively, p less than .01) and mannitol (3.41 +/- 0.4 and 5.3 +/- 0.5% at 3 and 28 months, respectively, p less than .01). Intestinal permeability of the large macromolecule inulin did not change (0.42 +/- 0.03 and 0.38 +/- 0.02% at 3 and 28 months, respectively) with aging. There was no correlation between weight of the rats and their intestinal permeability. Because dietary caloric restriction has been found to prolong the life span, retard deterioration of several biological functions, and affect intestinal absorptive functions, we examined the effect of lifelong calorie restriction on intestinal permeability changes. Lifelong calorie-restricted diet did not affect age-related change in intestinal permeability. We conclude that intestinal permeability of medium size probes increases with aging and that lifelong caloric restriction does not prevent this change. We speculate that age-associated deterioration in intestinal barrier functions could permit increased systemic absorption of lumenal antigens and could perhaps contribute to the genesis of antigen-related age-associated diseases.

[Screening for colorectal cancer and polyps].

Screening programs for the early detection of colorectal neoplasms may prevent cancer or improve its prognosis. We screened 1101 individuals (89% of whom were asymptomatic) using 3 methods. The fecal occult blood test, done in 96% of those screened, was positive in only 1.9% and was low in both sensitivity (2.1%) and positive predictive value (6.7%). However, flexible sigmoidoscopy, performed in 48%, gave positive results in 7.8% of those screened, revealing 41 cases of polyps and 1 of cancer. Colonoscopy was performed in 8% and 37 cases of polyps and 1 of cancer were detected. Of the 3 screening methods tested, sigmoidoscopy appeared to be the best because of its high diagnostic yield. The risk of colorectal neoplasm was shown for the first time to be equal in Jews of oriental and occidental origin.

[Ambulatory liver biopsy].

During 1992-1994 we performed 77 needle liver biopsies on ambulatory patients. 59 patients were observed for 6 hours and then released. 15 who lived more than 40 km away and 3 in whom complications were feared were hospitalized. All were released within 24 hours and there were no complications. We conclude that ambulatory needle biopsy of the liver is safe and cost-effective is selected patients.

Gastroesophageal obstruction from food in an epiphrenic esophageal diverticulum.

An epiphrenic diverticulum is usually accompanied by esophageal motor disorders, diaphragmatic hernia, or esophagitis. Symptoms are rarely attributable to the diverticulum except very rarely when no other explanation for dysphagia or chest pain is demonstrated. We describe acute esophageal obstruction from food accumulating in an epiphrenic diverticulum and compressing the gastroesophageal junction, and we confirm the mechanism with an artificial balloon.

PEG 400, a hydrophilic molecular probe for measuring intestinal permeability.

There is a widely held misconception that low-molecular-weight polyethylene glycols are "highly lipophilic" permeability probes and therefore are transported across lipid cell membranes. The relative lipophilicity of polyethylene glycols 400 and 600 were examined by determining their partition coefficients (Kd) in water and organic solvents of increasing relative polarity. The Kd of polyethylene glycol 414 between hexane and water was 0.000015, indicating that there are only 1.5 parts of polyethylene glycol 414 in hexane for 100,000 parts of polyethylene glycol 414 in water. When the Kd was determined in organic solvents with increasing relative polarity or "water character", there was a linear increase in Kd. The relative urinary recovery of individual molecular weight fractions of polyethylene glycol 400 in normal volunteers was analyzed. After oral ingestion, there was a progressive decrease in relative urinary recovery of increasing molecular weight fractions of polyethylene glycol 400 suggesting that increase in the molecular size limited polyethylene glycol intestinal permeability. There was excellent correlation between the relative urinary recovery and the hydrophilicity of the intravenously administered polyethylene glycol 400 fractions. It is concluded that polyethylene glycols 400 and 600 are strongly hydrophilic. Since partitioning of polyethylene glycol into lipid phase is negligible in lipid/water mixtures, they are unlikely to be transported via lipid pathways. The intestinal permeability of polyethylene glycols are governed by their molecular size, and once in circulation their urinary excretion appears to be governed in part by their plasma or water solubility.

Propofol versus midazolam for conscious sedation guided by processed EEG during endoscopic retrograde cholangiopancreatography: a prospective, randomized, double-blind study.

BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is a complex procedure, which requires appropriate sedation. The aim of this prospective, randomized, double-blind study was to compare the quality and characteristics of sedation with midazolam or propofol in patients undergoing ERCP. PATIENTS AND METHODS: A total of 32 patients undergoing ERCP were randomly allocated for sedation with propofol (n = 15) or midazolam (n = 17). Blood pressure, heart rate, and O2 saturation were monitored. Sedation was maintained at near constant levels by use of the spectral edge frequency (SEF) technique, an EEG-based method for measuring the depth of sedation. Clinical variables, patient cooperation, time to recovery, and amnesia served as outcome variables. RESULTS: There was no significant difference between the two study groups in patient characteristics. The "target SEF" was 13.6 +/- 0.7 Hz for the propofol group and 14.8 +/- 1.1 Hz for the midazolam group (n.s.). The only clinical parameter with a significant difference between the groups was the percent of time in which the heart rate deviated more than 20% from baseline for at least 2 minutes, i.e. 14.6 +/- 2.0 % for propofol and 48.2 +/- 38.0% for midazolam (P<0.01). Patient cooperation was better in the propofol group than in the midazolam group (full cooperation, 13/15 vs. 1/17, respectively; P<0.001). Patient recovery was significantly quicker in the propofol group (P<0.001). The degree of amnesia was similar in both groups; no patient in either group remembered details of the procedure. CONCLUSIONS: ERCP is better tolerated by patients sedated with propofol compared with midazolam, with a shorter recovery time and lesser hemodynamic side effects. Propofol should be considered to be the sedative drug of choice for ERCP.

Mechanism of colonic permeation of inulin: is rat colon more permeable than small intestine?

BACKGROUND/AIMS: Colonic epithelium is considered to be relatively tight. The colonic "pore" diameter is 6 A; therefore, colonic epithelium has generally been considered to be impermeable to hydrophilic probes with a cross-sectional diameter of > 6 A. This study examined whether rat colon is permeable to inulin, a large hydrophilic macromolecule having a molecular weight of 5000 g/mol and a cross-sectional diameter of 15 A (hydration diameter, 20 A). METHODS: The colonic permeation of inulin (10 mumol/L) in vivo was investigated by perfusion of rat colonic segments. RESULTS: There was significant colonic permeation of inulin, but tissue retention of inulin was low. The net colonic flux of inulin was strongly dependent on net water flux, showing a strong solvent drag effect. Addition of 16,16-dimethyl prostaglandin E2 decreased water flux with a corresponding decrease in inulin flux; this process seemed to be mediated by 5'-cyclic adenosine monophosphate because both the phosphodiesterase inhibitor aminophylline and dibutyryl adenosine 5'-cyclic adenosine monophosphate decreased water and inulin flux in a parallel manner. Chenodeoxycholic and taurocholic acids decreased net mucosal-to-serosal water flux but increased inulin flux. The net colonic permeation rate of inulin was higher than the small intestinal permeation rate. CONCLUSIONS: Rat colon is permeable to inulin. The higher net colonic permeability may be caused by differences in mucosal surface, permselectivity, solvent drag effect, and differences in net water fluxes of the colon and small intestine.

Oxygen free radical injury of IEC-18 small intestinal epithelial cell monolayers.

Oxygen radicals can cause endothelial and epithelial permeability changes and mucosal injury of the small intestine. There is no clear consensus concerning the relative injurious potential of individual oxygen radicals. In this study, the small intestinal cell line IEC-18 was used as an in vitro model to study the relative injurious effects of reactive oxygen metabolites. By introducing different combinations of oxygen metabolite-producing enzymes, xanthine oxidase, superoxide dismutase, and catalase, and an iron chelator, deferoxamine, to the fully confluent monolayers and to proliferating IEC-18 cells, the differential injurious effects of the oxygen metabolites O2-, H2O2, and OH. could be evaluated. The extent of cellular injury was assessed using [3H]thymidine uptake, 51Cr release, and morphological evaluations. Our results suggest that OH. produced as a by-product of O2- and H2O2 via the Haber-Weiss reaction was the most injurious oxygen species involved in cellular injury of IEC-18 monolayers induced by xanthine oxidase. O2- produced by xanthine oxidase appeared to be only minimally injurious, and H2O2 produced by xanthine oxidase and as a result of conversion of O2- by superoxide dismutase was moderately injurious. Superoxide dismutase and deferoxamine at appropriate concentrations were protective against xanthine/xanthine oxidase-induced monolayer injury. H2O2 added directly or produced indirectly by glucose oxidase was very injurious to the intestinal monolayers, and this injury was mitigated by catalase.

Is the small intestinal epithelium truly "tight" to inulin permeation?

In this study, we evaluated the "leakiness" of intestinal epithelium through examination of small intestinal absorption of inulin in vivo by perfusing rat jejunum with 10 microM inulin. In physiological conditions, we found significant absorption of inulin at a rate of 44.6 nmol.100 cm-1.h-1 or absorption of 14.7%.100 cm-1.h-1 of the amount perfused. Increasing water flux by changing the luminal osmolarity resulted in linear (y = 31.1 + 2.4x, r = 0.97) increase in absorption of inulin, indicating a significant convective component of inulin absorption. There was large permeation of inulin at net water secretion and at zero net water fluxes (31.1 nmol.100 cm-1.h-1), indicating significant absorption of inulin by diffusive movement as well. The small intestinal tissue retention of inulin occurred rapidly within the first 15 min of perfusion, and the total tissue retention remained unchanged thereafter at approximately 10.8 nmol/100 cm. 16,16-Dimethylprostaglandin E2 decreased water flux, whereas cyclooxygenase inhibitors, indomethacin and acetylsalicylate, increased water flux. Inulin absorption closely paralleled changes in water flux induced by these agents. Taurocholate also caused parallel decrease in water and inulin absorption. Varying the resistance of unstirred water layer with changing luminal flow rate, the addition of mucolytic agent acetylcysteine, or alterations of luminal pH did not affect water or inulin absorption. We conclude that inulin permeates the small intestinal epithelium in significant amounts under normal physiological conditions, presumably through the paracellular pathways utilizing aqueous channels.

Role of cyclic GMP in gastrin secretion from rat antral mucosae in organ culture.

Rat antral mucosae maintained for 6 h in organ culture responded to carbamylcholine with a significant increase in endogenous cyclic GMP production and gastrin secretion. The acetylcholine analogue exerted a stimulatory action within a defined concentration range: exposure of antral explants to carbachol concentrations greater than the optimal stimulatory dose was accompanied by a marked decrease in both cyclic GMP production and gastrin release. Exogenous 8-Br-cyclic GMP (1 mM) significantly augmented gastrin secretion into the culture media during 6-12 h culture periods. Cycloheximide (0.1 mM) and the Ca2+ channel-blocker verapamil (5 microM) prevented 8-Br-cyclic GMP from acting as a gastrin secretagogue. Addition of cyclic somatostatin-14 (0.1 mM) to culture media was attended by complete inhibition of 8-Br-cyclic GMP-stimulable gastrin secretion. These results provide evidence that cyclic GMP may play a mediatory role in the coupling of gastrin secretory processes to agonist stimulation. It would seem that the secretagogue action of 8-Br-cyclic GMP requires unabated Ca2+ transmembrane fluxes and protein biosynthesis. Since somatostatin-14 abrogates the stimulatory effect of 8-Br-cyclic GMP on antral gastrin secretion, it is surmised that the inhibitory tetradecapeptide acts at a locus (or loci) distal to domains involved in the actual generation of the cyclic nucleotide.

Pathogenetic aspects of persimmon bezoars. A case-control retrospective study.

To prove that ingestion of unpeeled persimmon is necessary for the development of a persimmon phytobezoar, we interviewed 15 patients, in most of whom this condition developed after peptic ulcer surgery. We compared the study group with a control group of 15 patients who had undergone peptic ulcer surgery but did not have a bezoar. In contrast with the control group, most patients with bezoars had ingested unpeeled fruits (p < 0.01). While ingestion of persimmon carried a 9.8-fold risk of bezoar development, ingestion of the unpeeled fruit increased the risk of this complication 56 times over that of age- and sex-matched controls. We recommend that patients who have undergone ulcer surgery be warned particularly against eating unpeeled persimmons.

Esophageal metastasis from breast carcinoma associated with pseudoepitheliomatous hyperplasia: an unusual endoscopic diagnosis.

The clinicopathologic findings in a patient who developed dysphagia and obstruction of the middle third of the esophagus 12 years after mastectomy for breast carcinoma are presented. Endoscopic biopsy revealed metastatic breast carcinoma with pseudoepitheliomatous hyperplasia of the overlying esophageal mucosa. To the best of our knowledge, the case represents the first reported association between esophageal metastasis and pseudoepitheliomatous hyperplasia of the esophageal squamous epithelium.

IEC-18, a nontransformed small intestinal cell line for studying epithelial permeability.

Small intestinal epithelium is leaky and allows permeation of hydrophilic molecules of various sizes. Passively absorbed hydrophilic permeability probes have been shown to permeate across intestinal epithelium mainly through the paracellular pathways. In this study we introduce microporous filter-grown IEC-18 epithelial cells, a nontransformed small intestinal cell line, as a in vitro model of intestinal epithelium for the study of epithelial permeability. IEC-18 cells, originally derived from native rat ileal crypts, form confluent epithelium when grown on hydrated collagen-coated Millicell-CM permeable inserts (Millipore Corp., Bedford, Mass.). With scanning and transmission electron microscopy, the presence of tight junctions and desmosomes between cells and the development of microvilli at the apical surface were confirmed. Immunofluorescent labeling of ZO-1 proteins and desmoplakins verified the presence of tight-junctional proteins (ZO-1) and desmosomes in the intercellular junctions of confluent IEC-18 epithelium. The net electrical resistance of IEC-18 epithelium (28 omega-cm2) was similar to resistance values obtained from small intestinal tissue with (50 to 100 omega-cm2) or without (20 to 45 omega-cm2) muscularis and serosal layers. Assessment of mannitol and dextran permeation revealed early "maturation" of paracellular pathway, with increasing restriction of permeation to both probes through day 4. Resistance across IEC-18 epithelium also reached plateau levels between 4 and 7 days. Permeability studies with various probes indicate that cross-sectional diameter rather than molecular weight of the probe is the important determinant of permeation rate. IEC-18 epithelium selectively restricted the permeation of probes proportional to probe size; permeation of larger probes such as albumin was negligible. We conclude that cultured IEC-18 epithelial cells, because of their native crypt origin, similarity in resistance to small intestinal epithelia, retention of ability to differentiate into villus-like enterocytes, and permeability characteristics, are a useful model of intestinal epithelium for the study of permeability and paracellular transport.

Aspects of the epidemiology of Crohn's disease in the Jewish population in Beer Sheva, Israel.

The epidemiology of Crohn's disease in Jews in the Beer Sheva district of Israel was studied. The mean annual incidence per 10(5) population was 1.1 for the period 1961-80 and 1.8 for the period 1976-80. The crude prevalence rate on 31 December 1980 was 14.0 per 10(5) population. The unadjusted prevalence rates by place of birth were: Israeli-born 6.9, European/American-born 24.6 and Asian/African-born 19.4 per 10(5) population. The age-adjusted prevalence rates were: Israeli-born 9.7, European/American-born 15.8 and Asian/African-born 12.5 per 10(5) population. The study has demonstrated: 1) that Crohn's disease has a low prevalence in Jews in this district; 2) that Crohn's disease is not as uncommon in Asian/African-born Jews as was previously thought; 3) that the low crude rate of Crohn's disease in Israeli-born Jews in this district is partially accounted for by the age distribution of the population; and 4) that environmental rather than genetic factors appear to determine the incidence of Crohn's disease in this district.

Granular cell myoblastoma of the sigmoid colon.

A granular cell myoblastoma of the upper sigmoid colon is reported in a 53-year-old male. The tumor was detected during investigation of abdominal pain and was removed by colonoscopic polypectomy. Colonoscopy provides a new method of treatment for these unusual colonic lesions and avoids the need for surgery. To our knowledge the tumor has not been reported previously in the sigmoid colon.

Regulation of polyethylene glycol 400 intestinal permeability by endogenous and exogenous prostanoids. Influence of non-steroidal anti-inflammatory drugs.

Polyethylene glycol 400 (PEG 400) is a clinically useful intestinal permeability probe whose rate of intestinal permeation is influenced in part by solvent drag. As mucosal prostanoids are increased in inflammatory bowel disease and affect water transport we examined the possible relationship between prostaglandin E2 (PGE2) and the inhibitors of endogenous prostaglandins--the non-steroidal anti-inflammatory drugs (NSAIDS)--on PEG 400 absorption in vivo using segmental perfusion of rat small intestine. We found that the addition of exogenous PGE2 in concentrations of 0.5, 1.0, and 1.5 micrograms/ml significantly (p less than 0.01) decreased PEG 400 and water absorption. Addition of 5 mmol/l of the cyclooxygenase inhibitors acetylsalicylic acid (ASA) or indomethacin in concentrations 2.5 or 5.0 mmol/l to the perfusate significantly (p less than 0.01) increased PEG 400 and water absorption. The simultaneous addition of 1.0 micrograms/ml of exogenous PGE2 to the perfusate with 5 mmol/l of ASA or with 2.5 mmol/l of indomethacin reversed the increase of PEG 400 and water transport (p less than 0.01). There were no differences in PEG 400 and water absorption when PGE2 was given alone or in combination with ASA or indomethacin. This study suggests that endogenous or exogenous prostanoids play an important role in the regulation of PEG 400 permeation. PGE2 and NSAIDS modify PEG 400 permeation in parallel with changes in water transport indicating that their effect on permeability is through changes in solvent drag. These findings provide a mechanism which might explain the increase in PEG 400 intestinal permeability in Crohn's disease patients and the increase in intestinal permeability found in patients receiving NSAIDS.