One hundred and seventeen coded intestinal biopsies were examined by electron microscopy and evaluated for morphological evidence of mast cell and basophil secretion in situ. Sixty percent of the biopsies had evidence of secretion. Mast cell secretion was evident in control biopsies, many of which were obtained from uninvolved tissues of patients with inflammatory bowel disease. Biopsies of inflamed continent pouches from ulcerative colitis (UC) patients showed more mast cell secretion than noninflamed UC pouch biopsies. This evidence of mast cell secretion supports recent work that documents high constitutive levels of histamine in jejunal fluids of Crohn’s disease patients and suggests a proinflammatory role for mast cells in inflammation associated with pouchitis.

Conventional guinea pigs provided with a solution of 5% (wt/vol) degraded carrageenan as the sole source of oral fluids developed ulcerations of their ceca and large intestines within 30 days. Similar lesions were not detected in germfree guinea pigs treated in an identical manner, suggesting that an intestinal microflora was necessary for development of intestinal lesions. To simplify the bacterial flora required for production of cecal ulcerations, 10 pools consisting of 10 bacterial strains each were isolated from the cecal microflora of carrageenan-treated animals. Groups of germfree guinea pigs were associated with 2 of the 10 pools by orogastric intubation and observed for development of disease. One-half of each group was treated with carrageenan. The two bacterial pools were characterized by the presence of cytopathic effects for WI-38 and Vero cells, increased chemotactic activity, and increased concentrations of long-chain fatty acids. The results indicated that animals associated with these two pools developed cecal ulcerations during carrageenan treatment. Preliminary results also indicated that cecal ulcerations developed in germfree animals mono-associated with a strain of Bacteroides vulgatus isolated from one of the pools, regardless of whether carrageenan was administered, suggesting a bacterial involvement in disease development in the absence of carrageenan treatment.

essential for the growth of some neoplastic cells including melanoma and hepatocellular carcinoma among others.Where does this leave us and what does all this have to do with the study by Vadillo-Ortega et al? First and most importantly, the balance between the protective and adverse effects of NO seems to be determined by the relative amount of NO and reactive radicals, yet the effects of these vary by tissue in ways not well understood. Second, a relative L-arginine deficiency does uncouple NOS and arginase pathways. Arginase upregulation seems to dominate during L-arginine deficiency resulting in NO deficiency and enhanced production of reactive oxygen species by NOS. Peroxynitrite is formed in place of NO and this leads to microvascular damage and impairs cytotrophoblast invasion. In contrast, the angiogenic/vasculogenic properties of NO likely promote cytotrophoblast endovascular invasion of uterine spiral arterials. Vadillo-Ortega et al attacked this NO deficiency by increasing the substrate through dietary arginine and seemed to demonstrate a beneficial effect, which likely would have resulted from recoupling of the NOS and arginase pathways. That being said, arginine supplementation may be a shotgun approach to what needs to be a sniper shot and therefore could well be associated with significant collateral damage since excessive NO production is not necessarily benign. Recent studies would suggest that a better approach would include both prevention of arginine deficiency but also suppression of the upregulation of arginase. As yet, however, specific ways to block arginase are awaiting discovery. As stated by Braam and Vehaar (Curr Pharm Des 2007;13:1727-1740, "Ideally, eNOS is sufficiently expressed, produces NO sufficiently and not abundantly, does not produce superoxide and is not scavenged by ROS; the produced NO then reaches its signaling target, mainly soluble guanylyl cyclase (sGC) and elicits a cellular responsey there is a great challenge ahead."

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