The relevance of kinin B1 receptor upregulation in a mouse model of colitis.

BACKGROUND AND PURPOSE: Kinins are implicated in many pathophysiological conditions, and recent evidence has suggested their involvement in colitis. This study assessed the role of the kinin B1 receptors in a mouse model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice by 2,4,6-trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B1 receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR. KEY RESULTS: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of colon B1 receptor-mediated contraction, with the maximal response observed at 72 h. The upregulation of the B1 receptor at this time point was also confirmed by means of binding studies. B1 receptor mRNA levels were elevated as early as 6 h after colitis induction and remained high for up to 48 h. TNBS-evoked tissue damage and neutrophil influx were reduced by the selective B1 receptor antagonist SSR240612, and in B1 receptor knockout mice. In vivo treatment with inhibitors of protein synthesis, nuclear factor-kappaB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor alpha (TNFalpha) significantly reduced B1 receptor agonist-induced contraction. Similar results were observed in iNOS and TNF receptor 1-knockout mice. CONCLUSIONS AND IMPLICATIONS: These results provide convincing evidence on the role of B1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B1 receptors might represent a new therapeutic option for treating inflammatory bowel diseases.

Effects of alcohol on pilot performance in simulated flight.

Ethyl alcohol's known ability to produce reliable decrements in pilot performance was used in a study designed to evaluate objective methods for assessing pilot performance. Four air carrier pilot volunteers were studied during eight simulated flights between San Francisco and Los Angeles in a Boeing 727-232 simulator. Two flights were conducted at each of four target blood alcohol levels, 0, 0.025, 0.050, and 0.075%. Each flight lasted about 1 h. Flights were conducted with full crews in a full simulated ATC environment. Data from direct observations and videotapes were used to examine discrete errors committed by the subjects. Total errors increased linearly and significantly with increasing blood alcohol. Planning and performance errors, procedural errors and failures of vigilance each increased significantly in one or more pilots and in the group as a whole. Failures of crew coordination were not associated with blood alcohol level. Serious errors increased significantly even at the lowest alcohol level studied, 0.025% (25 mg/dl), compared with control values.

Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, alpha- and beta-amyrin, in a mouse model of colitis.

BACKGROUND AND PURPOSE: alpha- and beta-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of alpha- and beta-amyrin (alpha,beta-amyrin) on an experimental model of colitis in mice. EXPERIMENTAL APPROACH: Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with alpha,beta-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-kappaB (NF-kappaB) and phospho-cyclic AMP response element-binding protein (CREB). KEY RESULTS: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with alpha,beta-amyrin (3 mg x kg(-1), i.p.) or dexamethasone (1 mg x kg(-1), s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. alpha,beta-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1beta levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only alpha,beta-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-kappaB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both alpha,beta-amyrin and dexamethasone. CONCLUSIONS AND IMPLICATIONS: Systemic administration of alpha,beta-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-kappaB and CREB-signalling pathways. Taken together, our data suggest a potential use of alpha,beta-amyrin to control inflammatory responses in bowel disease.

Split-thickness skin graft for treatment of oral benign mucous membrane pemphigoid. Report of a case.

The painful oral lesions of benign mucous membrane pemphigoid often make the wearing of complete dentures difficult or impossible. A mandibular split-thickness skin graft vestibuloplasty was performed on a patient with benign mucous membrane pemphigoid. This procedure may be indicated in those cases which do not respond to meticulous denture construction and steroid therapy.