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Glutathione is a nonenzymatic antioxidant synthesized by most animal cells and is depleted in inflammatory bowel disease. The effects of glutathione depletion on intestinal histology and inhibitory neurochemicals was examined in a mouse model. Glutathione depletion in A/J mice involved inhibition of gamma-glutamylcysteine synthetase using L-buthionine-(S,R)-sulfoximine (BSO) for 10 days. Ileum and colon were obtained from saline-control mice, BSO-treated mice, and BSO-treated mice receiving ascorbate or glutathione monoethylester. Glutathione, lipid peroxides, and nicotineamide adenine dinucleotide phosphate diaphorase activity were measured by colorimetric assays. Vasoactive intestinal peptide was measured by radioimmunoassay. Glutathione depletion induced enlargement of mucosal-submucosal lymphoid aggregates without germinal centers in ileum and colon. These aggregates were prevented by supplementation with glutathione monoethylester but not ascorbate. Tissue levels of inhibitory neurochemicals were unchanged. Depletion of glutathione appears to induce enlarged lymphoid aggregates by recruitment of lymphocytes from the peripheral circulation. A component of the inflammation that develops in inflammatory bowel disease could be related to depletion of tissue levels of glutathione. [ABSTRACT FROM AUTHOR]

It has been proposed that oxidative stress is involved in the pathophysiology of ulcerative colitis. We have reported the depletion of the nonenzymatic antioxidant, glutathione, in colon from active and inactive ulcerative colitis. The colon contains several biochemically linked antioxidant systems. We hypothesized that diminished total antioxidant capacity in active ulcerative colitis would be associated with increased colonic lipid peroxidation. This study was designed to determine total antioxidant capacity and lipid hydroperoxide levels using colon obtained at surgery from controls (N = 16; 4 females, 12 males; mean age 70 years), and active and inactive ulcerative colitis (N = 15; 3 females, 12 males; mean age 39). Total antioxidant capacity of control colon was higher in muscularis externa compared to the mucosal-submucosal layer (P < 0.05). There were no differences in colonic total antioxidant capacity or lipid hydroperoxide levels comparing control colon to inactive and active ulcerative colitis. The results did not support depletion of tissue total antioxidant capacity by free radicals. Depletion of glutathione in ulcerative colitis may be a specific disorder rather than a secondary defect attributable to global oxidative stress. Nonspecific antioxidant supplements appear unlikely to be beneficial in the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]

Purpose: Nitric oxide modulates human colonic smooth muscle function. To determine whether nitric oxide production is altered in colon from acquired megacolon, we measured cholinergic nerve-mediated contractions in vitro before and after inhibition of nitric oxide synthase., Methods: Intramural nerves in circular smooth muscle from histologically normal colon (n = 12) and acquired megacolon (n = 3) were activated by electrical field stimulation., Results: In controls blockade of nitric oxide synthase by N(G)-Nitro-L-Arginine induced increases (P < 0.05) in amplitude of contractions; these increases in amplitudes were blocked by L-Arginine (analysis of variance; P < 0.05). By contrast, blockade of nitric oxide synthase did not increase amplitudes of contractions with circular smooth muscle from acquired megacolon. An immediate phasic contraction was blocked by atropine sulfate., Conclusions: The results support the concept that nitric oxide production modulates cholinergic nerve-mediated contractions in normal colonic circular muscle, whereas acquired megacolon is associated with altered release of this inhibitory neurochemical. Potential explanations include depletion of tissue L-Arginine, decreased capacity to recycle citrulline to arginine, or decreased release of vasoactive intestinal peptide from circular smooth muscle in acquired megacolon.

Clinical and epidemiological studies have supported the belief that human beings exposed to stressful life events are vulnerable to the symptomatology consistent with posttraumatic stress disorder (PTSD). However, early detection of symptoms consistent with PTSD oftentimes does not occur within the medicolegal arena. The importance of an early and accurate diagnosis is emphasized. Fortunately, the diagnosis of PTSD has become more clearly conceptualized in the DSM-IV criteria. Many of the characteristics consistent with this diagnosis are measured through the use of relatively recently developed and refined psychometric measures including the Posttraumatic Stress Diagnostic Scale, the Trauma Symptom Inventory, and the Personality Assessment Inventory-2. Additional measures including the Computerized Response Bias Test, the Word Memory Test, and the Validity Indicator Profile can detect exaggeration of symptoms without using specific tests for symptom validity. These measures, as well as biochemical determinations, are reviewed and presented along with the over-all structured clinical interviews and mental status examinations of two patients for a better understanding of the multimethod approach which establishes the reliability of the PTSD diagnosis.

Transplantation of the small intestine is a neural model that could include extrinsic denervation, loss of intrinsic enteric neurons, or loss of intrinsic neural pathways. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity was measured in normal rat ileum, ileum 3 months after resection of the jejunum, and ileum 3 months after isotransplantation of the ileum. The distribution of NADPH diaphorase activity and immunoreactive neuronal nitric oxide synthase were examined. Nicotinamide adenine dinucleotide phosphate diaphorase activity was increased in transplanted ileum (16.5+/-3.5 mU/mg protein) compared to normal controls (6.6+/-0.7) and resection controls (6.8+/-0.6) (P < 0.05, ANOVA). Histologically, NADPH diaphorase activity and immunoreactive nitric oxide synthase appeared increased within nerve cell bodies following transplantation. These findings may represent an adaptive response of the enteric nervous system to extrinsic denervation. Loss of intrinsic neural pathways was not supported as a mechanism.

Despite its great promise, small intestinal transplantation in some patients is complicated by difficult postoperative management. The reasons for this are complex. In a rat model of small intestinal transplantation, frequencies of migrating myoelectric complexes during fasting are reduced in ileal isografts and muscarinic receptor density is decreased. We hypothesized that the distribution of muscarinic 1 receptors localized to enteric neurons is altered after small intestinal transplantation. Distal small intestine was orthotopically transplanted in Lewis-to-Lewis donor-recipient combinations. At 3 months, transplanted and normal ileum was obtained to prepare membrane fractions. [N-methyl-3H]Scopolamine served as ligand, while scopolamine methylbromide, pirenzepine, and methoctramine were used in competitive homologous and heterologous displacement experiments. Receptor subtype models were examined by nonlinear regression analysis. In normal and transplanted ileum, heterologous displacement was consistent with three site models (P < 0.05). In normals, the muscarinic 1 receptor subtype was most abundant, with a relative distribution of 69 to 78%. There was a relative distribution of 13 to 16% for muscarinic 3 receptor subtype. After transplantation, the muscarinic 1 subtype decreased to a mean of 45% but the muscarinic 3 subtype increased to a mean of 42%. Using pirenzepine, mean pKD values were not different between the two groups. It is concluded that the decrease in muscarinic 1 receptor subtype after transplantation could be related to neuronal cell loss or to downregulation of the expression of muscarinic 1 receptors. The results did not support defective posttranslational processing of receptor proteins., (Copyright 1998 Academic Press.)