The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection

In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule-1 (VCAM-1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen-specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T-cell activation via the direct and/or the indirect pathways of allorecognition.     

Survival enhancing indications for coronary artery bypass graft surgery in California

Background  

Coronary artery bypass graft (CABG) surgery is performed because of anticipated survival benefit, improvement in quality of life, or both. We performed this study to explore variations in clinical indications for CABG surgery among California hospitals and surgeons.     

Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.      

Structural basis of the antagonism between inorganic mercury and selenium in mammals

Mercuric chloride toxicity in mammals can be overcome by co-administration of sodium selenite. We report a study of the mutual detoxification product in rabbit plasma, and of a Hg-Se-S-containing species synthesized by addition of equimolar mercuric chloride and sodium selenite to aqueous, buffered glutathione. Chromatographic purification of this Hg-Se-S species and subsequent structural analysis by Se and Hg extended X-ray absorption fine structure (EXAFS) spectroscopy revealed the presence of four-coordinate Se and Hg entities separated by 2.61 A. Hg and Se near-edge X-ray absorption spectroscopy of erythrocytes, plasma, and bile of rabbits that had been injected with solutions of sodium selenite and mercuric chloride showed that Hg and Se in plasma samples exhibited X-ray absorption spectra that were essentially identical to those of the synthetic Hg-Se-S species. Thus, the molecular detoxification product of sodium selenite and mercuric chloride in rabbits exhibits similarities to the synthetic Hg-Se-S species. The underlying molecular mechanism for the formation of the Hg-Se-S species is discussed.     

DEMONSTRATION OF α-ADRENOCEPTOR ANTAGONISM BY THE 5HT2 ANTAGONIST, KETANSERIN (R49945), IN SHEEP

Serotonin causes a dose related (0.1-20 micrograms/kg i.v.) increase in mean arterial blood pressure (MAP) and heart rate in conscious sheep. Ketanserin (0.1 mg/kg per h i.v.) causes a decrease in blood pressure, and an increase in heart rate. In the presence of ketanserin, serotonin induced increases in MAP are attenuated, or abolished, but the increases in heart rate are enhanced. Ketanserin (10 mg/kg per h i.v.) attenuates or abolishes the increase in blood pressure induced by the alpha-adrenoceptor agonist phenylephrine in conscious sheep. When administered in the presence of the alpha-adrenoceptor antagonist prazosin, ketanserin (0.1 mg/kg per h i.v.) fails to induce a further hypotensive response. These data suggest that in the conscious sheep ketanserin exhibits predominantly alpha-adrenoceptor antagonism.     

Carrier detection in X-pigmentary retinal dystrophy (X-linked retinitis pigmentosa) by DNA restriction fragment length polymorphism studies

As part of a patient care and DNA research programme commenced in 1985, a number of DNA markers on the short arm of the X chromosome have been used to demonstrate restriction fragment length polymorphisms (RFLPs) segregating with the X-pigmentary retinal dystrophy (X-linked retinitis pigmentosa) gene. The analysis of the segregation of the RFLPs in 3 kindreds enables carrier detection, to a high degree of probability, in females at risk who are not manifesting symptoms and signs.