Ulcer disease and duodenogastric reflux

The intragastric concentrations of lysolecithin and bile acids were determined in 44 chronic peptic ulcer patients and 35 healthy volunteers. Normal reflux values were found in the prepyloric ulcer (Johnson type III) (n = 15) Elevated reflux amounts could be observed in the type I gastric ulcer (n = 15), there was a three-to fourfold increase compared to the controls. - Slightly elevated reflux concentrations were found in the duodenal ulcer patients (n = 14), but only under fasting conditions. The increase of reflux concentration in chronic gastric ulcer type I is shown to be in the same range as in acute stress ulcer. Compared to the three-to four times higher reflux concentrations of the resected stomach, the duodenogastric reflux in ulcer disease is very moderate. It's role in ulcerogenesis has to be analyzed further.     

A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes

BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high in untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1- associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression. (Gastroenterology 1997 Dec;113(6):1892-900)     

Expression of chicken liver cell adhesion molecule fusion genes in transgenic mice.

The tissue-specific expression of the chicken liver cell adhesion molecule (L-CAM) was studied by generating transgenic mice. The rat insulin II promoter was fused to a chicken L-CAM cDNA or to chicken genomic L-CAM sequences. Mice carrying the cDNA showed no expression of L-CAM. Mice carrying L-CAM genomic sequences showed expression in the beta cells of the pancreas, suggesting that sequences in introns or in flanking regions are required for expression. Murine L-CAM was undetectable in the beta cells of the pancreas of those transgenic mice expressing chicken L-CAM and thus appeared to be down-regulated, but expression of the mouse protein was not altered at other sites. Chicken L-CAM was also found in extrapancreatic tissues such as skin, kidney, liver, lung, intestine, blood vessels, and the choroid plexus and leptomeninges of the central nervous system. These findings raised the possibility that the chicken L-CAM gene contains cis regulatory elements that interfere with the specificity of a tissue-specific promoter such as the rat insulin promoter. To test this hypothesis, transgenic mice were produced with a construct containing the murine neurofilament promoter fused to genomic chicken L-CAM sequences. Chicken L-CAM was expressed in the brain and spinal cord, where L-CAM is not normally found, but it was also found in some nonneural tissues (kidney, liver, intestine, lung) in which L-CAM is normally expressed. The combined results suggest that tissue-specific cis-acting elements in the chicken L-CAM gene, when combined with heterologous promoters/enhancers, can generate novel patterns of gene expression.     

Simvastatin Augmentation for Patients With Early-Phase Schizophrenia-Spectrum Disorders: A Double-Blind,Randomized Placebo-Controlled Trial

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X²(1) = 0.01, P = .90). Group differences varied over time (treatment*time X²(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = −4.8; P = .021; 95% CI: −8.8 to −0.7) and at 24 months follow-up (mean difference = −4.7; P = .040; 95% CI: −9.3 to −0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.