Daniel Hollander

Increased Intestinal Permeability in Patients with Crohn's Disease and Their Relatives: A Possible Etiologic Factor

The cause of Crohns disease is unknown, although alterations in intestinal permeability may play a primary role. Because we were interested in permeability changes that occur before the onset of intestinal inflammation, we took advantage of the known genetic predisposition to this disease and studied not only patients with Crohns disease, but their clinically unaffected relatives as well. Intestinal permeability was assessed using the marker polyethylene glycol-400 ingested with a standard meal. We found that 17 normal volunteers absorbed 215 +/- 29.6 mg (mean +/- SE), whereas 11 patients with Crohns disease absorbed 514 +/- 94.7 mg and their 32 healthy relatives absorbed 566 +/- 62.4 mg. The twofold increase in permeability of patients and their relatives (p less than 0.005 compared with controls) indicates that the intestinal defect in the ability to exclude larger sized molecules is not secondary to clinically recognized intestinal inflammation, but is a primary defect that may be an etiologic factor in this disease.

The Use of Alkylating Agents in the Treatment of Wegener's Granulomatosis

Excerpt Wegeners granulomatosis, a rare disease of unknown etiology, was first described by Klinger (1) in 1931. Wegener (2), in 1936, reported three additional patients, recognizing the syndrome ...

Protective Effect of Sucralfate Against Alcohol-Induced Gastric Mucosal Injury in the Rat: Macroscopic, Histologic, Ultrastructural, and Functional Time Sequence Analysis

Histologic or ultrastructural evidence of the ability of sucralfate to protect the gastric mucosa against ethanol injury is lacking. Therefore we analyzed morphologic and functional changes in the mucosa of 120 rats receiving, intragastrically, 2 ml of either sucralfate 500 mg/kg body wt or a control solution and 1 h later 2 ml of 100% ethanol. At 15 min, 1, 4, 6, and 24 h after ethanol instillation, mucosal changes were assessed by macroscopic examination, quantitative histology, scanning electron microscopy, recordings of gastric potential difference, and measurements of volume, pH, and electrolytes in the gastric contents. Between 15 min and 24 h after ethanol instillation, macroscopic necrotic lesions in controls involved greater than 33% of mucosal area and in the sucralfate-treated group less than 4% (p less than 0.001 for each period). In controls, ethanol instillation produced surface epithelial cell disruption and deep (greater than 0.2 mm) mucosal necrosis involving greater than 55% +/- 3% of the mucosal length. In sucralfate-pretreated animals, disruption of the surface epithelium was present at 15 min, 1 h, and 4 h after ethanol instillation, but deep necrotic lesions were virtually absent (0%-2%; p less than 0.001 vs. controls) during the entire study period. The surface epithelium was mostly reestablished by 6 h after ethanol instillation in the sucralfate group but not in the controls. We concluded that sucralfate protects the gastric mucosa against ethanol-induced injury by preventing deep mucosal necrosis and as a consequence the mucosal proliferative zone cells rapidly restitute mucosal integrity.

Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: Prophylactic and therapeutic strategies

Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs in the Western world. Patients undergoing NSAID therapy often experience abdominal discomfort, and some of them develop serious complications, such as ulceration, perforation, or bleeding. Since serious complications of NSAID therapy can occur in relatively asymptomatic patients and abdominal symptoms do not serve as a signal of impending difficulties, there is a need for methods to identify those patients who may benefit from prophylactic therapy to prevent NSAID-induced injury. Therapy to prevent NSAID-associated gastrointestinal ulcerations is most effective when prostaglandins are used. H2-receptor antagonists prevent duodenal ulcerations but not gastric ulcerations. The role of omeprazole (hydrogen-potassium pump inhibitor) and sucralfate in the prevention of gastroduodenal ulcerations has not been firmly established. Healing of existing ulcerations in the face of continuing therapy with NSAIDs is marginally accelerated by H2-receptor antagonists, but the rate of healing in the presence of continued NSAID therapy is much slower than when NSAIDs are discontinued. Omeprazole may prove to accelerate the healing of NSAID-associated ulcerations even when NSAID therapy is continued, but more information is needed to substantiate this possibility. New methods are needed for early noninvasive detection of mucosal damage by NSAIDs and for the identification of individuals who should receive prophylactic therapy. New agents are also needed to provide cost-effective prophylaxis against the development of ulcerations and serious complications from NSAIDs.

Familial nesidioblastosis as the predominant manifestation of multiple endocrine adenomatosis

Abstract The incidence of endocrine abnormalities in eight members of a family with multiple endocrine adenomatosis was compared with that in five nonrelated subjects with islet cell tumors and in seven normal control subjects. Three members of the family had documented islet cell hyperplasia, adenoma and/or carcinoma associated with hypoglycemia or the Zollinger-Ellison syndrome, and all but one member of the family was found to have hypersecretion of insulin, often associated with elevated blood glucagon and/or gastrin levels. Five members had hyper-insulinism but were asymptomatic, although several demonstrated glucose intolerance. Asymptomatic hypercalcemia and abnormal adrenal function were noted in some subjects. There was no evidence of primary abnormalities in pituitary function or of catecholamine and 5-hydroxyindoleacetic acid levels in the family subjects. The nonfamily subjects with insulinoma had no other endocrine abnormalities. In one nonfamily subject, who may also have multiple endocrine adenomatosis, the Zollinger-Ellison syndrome was associated with high blood gastrin and insulin levels with glucose intolerance. It is proposed that the basic genetic defect in the family with multiple endocrine adenomatosis involves hyperplasia of the primordial cell of the islets of Langerhans (nesidioblastosis) with chronic oversecretion of one or more islet cell hormones. Secondary changes in other endocrine glands may then evolve as a consequence of the islet cell hormone excess(es). A high incidence of asymptomatic endocrine abnormalities was found in this and other studies. It is suggested that when abnormal growth or function of one endocrine gland is detected, a careful search for asymptomatic involvement of other glands should be made in the patient and his immediate relatives.

Mechanisms and sites of mannitol permeability of small and large intestine in the rat

Mannitol is commonly used as an intestinal permeability probe, yet the mechanisms of its penetration of the intestinal barrier are not entirely clear. Therefore, we studied mannitols permeability of different segments of the intestine and studied the kinetics and influence of intraluminal factors on mannitol permeabilityin vivo in perfused intestinal segments of rats. There was linear relationship between permeability rate of mannitol and its luminal concentration (y=7.2x+1.7;r=0.98), indicating that passive diffusion is involved in mannitols permeability. Increased luminal fluid osmolarity from 0.3 to 0.6 osmol/liter resulted in decreased net water flux with a corresponding decrease in mannitol permeability in both jejunum and colon (P<0.01), indicating the prominent influence of solvent drag on net mannitol permeability. The relationship between mannitol permeability and water absorption at different osmolarities was linear in the jejunum and colon. At luminal osmolarity of 0.3 osmol/liter, 34.6% of mannitol permeability was mediated by passive diffusion and 65.4% was mediated by solvent drag in the jejunum. Mannitol permeability was much more dependent on solvent drag in the colon (88.9%) than in the small intestine (65.4%). The net permeability rate of mannitol was similar in the jejunum and ileum but was much higher in the colon (P<0.01). Addition of chenodeoxycholate (5 mM) to the perfusate resulted in a significant decrease in absorption of water (P<0.01) with a corresponding decrease in mannitol permeability (P<0.01). These studies indicate that mannitol permeability of the intestinal barrier is mediated by passive diffusion and solvent drag, with the latter accounting for a greater fraction of the total permeability.

Does Sucralfate Affect the Normal Gastric Mucosa

Although the action of sucralfate on ulcerated mucosa has been demonstrated, its effect on the histology, ultrastructure, and function of normal gastric mucosa is unknown. We investigated the effect of acute administration of sucralfate on the gastric mucosal history, ultrastructure, mucosal potential difference, and luminal release of prostaglandin E2. At 15 min, 1 h, and 3 h after intragastric instillation of sucralfate, whitish incrustations of the drug were firmly adhering to the glandular mucosa. Mucosal histology after sucralfate administration demonstrated the following: disruption and exfoliation of some of the surface epithelial cells, mucosal hyperemia, prominent release of mucus from the surface epithelial cells, and edema of lamina propria and submucosa. These changes were most prominent in the areas where sucralfate was in contact with the mucosal surface. Scanning and transmission electron microscopy confirmed the above changes. Sucralfate produced a drop in gastric mucosal potential difference and a significant increase in luminal release of prostaglandin E2. Sucralfate produces distinct morphologic and functional changes in the normal gastric mucosa, which may account for its preventive and therapeutic efficacy.

Vascular and Microvascular Changes—Key Factors in the Development of Acetic Acid-Induced Gastric Ulcers in Rats

The present study examined the time sequence and histologic and ultrastructural features of the formation and evolution of experimental, acetic acid-induced gastric ulcerations in rats. One hundred percent acetic acid was applied to the gastric serosa of 140 fasted male Sprague-Dawley rats through a polyethylene tube for 30 s. Gastric mucosal changes were evaluated at 1, 5, 15, and 30 min, 1 and 3 h, and 1, 2, 3, 5, 8, and 11 days after acetic acid application by visual inspection, by quantitative and qualitative light microscopy, and by transmission electron microscopy. Following exposure to acetic acid, the earliest morphologic changes occurred at 1 min and consisted of dilatation of large submucosal veins and arteries and mucosal collecting venules. Five to 15 minutes after injury, thrombi developed in submucosal veins and collecting venules, leading to microvascular stasis and mucosal necrosis. By 3 h, necrotic masses started to detach. By 24–48 h, necrotic changes penetrated the submucosa. By 72 h, most ulcers underwent transition into a “chronic” stage characterized histologically by the presence of granulation tissue at the bottom, and the appearance of a transitional healing zone at the margins. By 5 days, an increased amount of granulation tissue was observed and the gastric glands in transitional zones at the ulcer margin displayed cystic dilatation. Based on this study, we conclude that a key feature of acetic acid-induced ulcer formation is the early vascular and microvascular injury, which precedes glandular cell necrosis.

Mechanism and Site of Small Intestinal Absorption of α-Tocopherol in the Rat

Abstract The site and mechanism of α-[5- methyl - 3 H]tocopherol absorption was investigated using everted rat small bowel sacs incubated in a micellar medium. Mean ± se absorption rates of the vitamin at 300 μm incubation solution concentration by proximal, medial, and distal small bowel segments were 2.2 ± 0.17, 3.4 ± 0.21, and 2.0 ± 0.04 nmoles per min per 100 mg, respectively. Addition of 2,4-dinitrophenol, sodium azide, or potassium cyanide to the incubation medium in separate experiments did not change the rate of absorption ( P > 0.10). Stepwise increase in incubation solution tocopherol concentration up to 1200 μm resulted in a linear increase in the absorption rate. In all of the above described experiments the rate of absorption of the vitamin by the medial portion of the small bowel was significantly ( P

Mechanisms of polyethylene glycol 400 permeability of perfused rat intestine

Abnormal permeability to polyethylene glycol 400 (PEG 400) has been demonstrated in various disorders with defective intestinal barrier functions. To understand the basic mechanisms of PEG 400 permeability, we compared PEG 400 permeation in different segments of the intestine and studied the kinetics and influence of intraluminal factors on PEG 400 absorption in vivo in perfused intestinal segments of the rat. The permeation rate of PEG 400 was dependent on the luminal concentration (y = 12.99x + 3.5; r = 0.97), indicating that passive movement is the mechanism involved in PEG 400 absorption. Changing the perfusate pH from 6 to 7.4 or modifying the unstirred water layer resistance by changing luminal flow rate did not affect PEG 400 absorption. When luminal osmolarity was varied from 0.225 to 0.6 osmol/L, higher osmolarity decreased both water and PEG 400 absorption (p greater than 0.01). The relationship between PEG 400 and water absorption at different osmolarities was linear (y = 0.9x + 5.7; r = 0.98). At a luminal osmolarity of 0.3 osmol/L 43% of PEG 400 permeation was mediated by passive diffusion and 57% was mediated by solvent drag. Increasing water absorption by decreasing luminal osmolarity resulted in proportional increase of PEG 400 permeation through solvent drag or convection. The solvent drag reflection coefficient (sigma f) for PEG 400 permeation of the jejunum was 0.1. Taurocholic acid (10 mM) alone or with oleic acid (2.5 mM) did not affect PEG 400 absorption. Permeabilities of 1 mM PEG 400 and water were similar in jejunum and ileum but were markedly increased in the colon (p greater than 0.01). These studies demonstrate that PEG 400 is absorbed by both passive diffusion and by solvent drag, with the latter accounting for a greater fraction of the absorptive drive under normal conditions. Polyethylene glycol 400 uses aqueous pathways for its permeation across the intestinal epithelium.