Colonisation of prosthetic grafts by immunocompetent cells in a sheep model.

The present study examined the distribution of immunocompetent cells in synthetic vascular grafts in an experimental sheep model. Sixty-two adult Merino sheep underwent synthetic patch closure of a longitudinal arteriotomy in the left common carotid artery. The synthetic patch materials used were gelatin sealed Dacron (n=10), fluoropassivated Dacron (n=10), Fluoropassiv (n=12), polyurethane (n=10), expanded polytetrafluoroethylene (n=10) and carbon-lined expanded polytetrafluoroethylene (n=10).

Reduced potassium currents in old rat CA1 hippocampal neurons.

Potassium currents are an important factor in repolarizing the membrane potential and determining the level of neuronal excitability. We compared potassium currents in CA1 hippocampal neurons dissociated from young (2-3 months old) and old (26-30 months old) Sprague-Dawley rats. Whole-cell patch-clamp techniques were used to measure the delayed rectifier (sustained) and the A-type (transient) potassium currents.

An outbreak of multi-resistant Shigella sonnei in a long-stay geriatric nursing centre.

An outbreak of Shigella sonnei infection in a long-stay nursing centre was detected during routine surveillance of notifications in July 1999. Subsequent investigations identified 13 cases of multi-resistant S. sonnei infection affecting nine staff, three community members associated with the centre and one resident of the centre.

Electron-microscopic detection of apoptotic and necrotic cell death in non-atherosclerotic areas of stenotic aortocoronary saphenous vein bypass grafts.

Aortocoronary saphenous vein bypass grafts undergo structural alterations within the arterialized vein, resulting in graft stenosis and failure. Areas of the acellular intima contribute to fissuring, cracking and ulceration, while areas of the media become highly vascular but thinned. This study aimed to examine the ultrastructural features of cell death, including apoptosis and necrosis, in non-atherosclerotic areas of the stenotic aortocoronary saphenous vein bypass grafts.

Modulation of drug resistance by alpha-tubulin in paclitaxel-resistant human lung cancer cell lines.

Beta(beta)-tubulin isotype variation has recently been implicated in the modulation of resistance to paclitaxel in human lung cancer cells and in primary human ovarian tumour samples. Whether alpha-tubulin is involved in drug resistance has not been reported. We have generated a paclitaxel-resistant cell line (H460/T800) from the sensitive human lung carcinoma parental cell line NCI-H460.

Accumulation of lymphocytes, dendritic cells, and granulocytes in the aortic wall affected by Takayasu's disease.

The aim of this study was to analyze the cellular composition of the arterial wall in Takayasu's disease and to investigate the contribution of the various cell types to the immunoinflammatory processes and degenerative alterations of the vessel wall in this disease. Specimens of aorta were obtained at operation from 10 patients with Takayasu's arteritis. The duration of disease ranged from 2 months to 13 years.

Modulation of paclitaxel resistance by annexin IV in human cancer cell lines.

A recurring problem with cancer therapies is the development of drug resistance. While investigating the protein profile of cells resistant to a novel antimitotic compound (A204197), we discovered an increase in annexin IV expression. When we examined the annexin IV protein expression level in a paclitaxel-resistant cell line (H460/T800), we found that annexin IV was also overexpressed.

Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.

Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.

Identification of dendritic cells in ePTFE grafts explanted from humans.

Following implantation different cell types interact with synthetic vascular prostheses resulting in a complex immuno-inflammatory response. Dendritic cells are responsible for activating the primary T-lymphocyte immune response in various pathological conditions by their role as antigen-presenters. This study aimed at examining whether dendritic cells accumulate within small diameter expanded polytetrafluoroethylene (ePTFE, Goretex(R)) grafts explanted from humans.

Perioperative anticoagulation in patients with chronic atrial fibrillation who are undergoing elective surgery: results of a physician survey.

Objective: To survey physicians' anticoagulation preferences in patients with chronic atrial fibrillation who are undergoing elective surgery.

Materials And Methods: A survey was performed that asked physicians to provide pre- and postoperative anticoagulation preferences for two clinical scenarios of patients with chronic atrial fibrillation (high stroke risk, low stroke risk) undergoing elective surgery. In addition to the interruption of warfarin therapy, perioperative anticoagulation options were as follows: a) in-hospital full dose intravenous heparin; b) outpatient full dose subcutaneous unfractionated heparin or low molecular weight heparin (LMWH); c) low dose unfractionated heparin or LMWH (postoperative only); d) nothing other than stopping warfarin preoperatively and restarting it postoperatively; or e) another anticoagulant strategy.

Immunophenotypic analysis of the aortic wall in Takayasu's arteritis: involvement of lymphocytes, dendritic cells and granulocytes in immuno-inflammatory reactions.

The present study was undertaken to examine the cellular composition of the aortic wall in Takayasu's arteritis and to investigate the association of different cell types in the immuno-inflammatory reactions of this disease. Specimens of aortic wall affected by Takayasu's arteritis were obtained from 10 patients (five male, five female), aged 32 to 68 years (mean 49.5 years) at elective operation.

Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo.

Ras oncogenes can contribute to tumour development by stimulating vascular endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since farnesylation of Ras is required for its biological activity. In this paper we evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis.

Structural features of cell death in atherosclerotic lesions affecting long-term aortocoronary saphenous vein bypass grafts.

Aortocoronary saphenous vein bypass grafts fail because of structural pathologies (thrombosis, intimal hyperplasia and atherosclerosis) within the 'arterialized' vein leading to graft stenosis. This study examined structural characteristics of atherosclerotic alterations in long-term aortocoronary artery saphenous vein bypass grafts with particular attention to the features of cell death in atherosclerotic lesions. Stenotic vein grafts were obtained from 10 patients at redo coronary artery bypass grafting operations.

Neovascular expression of VE-cadherin in human atherosclerotic arteries and its relation to intimal inflammation.

Objective: The present work aimed to investigate how the Ca(2+)-dependent cell adhesion molecule vascular endothelial (VE)-cadherin might be involved in atherogenesis.

Methods: Specimens of human carotid artery and aorta were obtained at operation. An immunohistochemical approach using cell-type specific antibodies examined how VE-cadherin expression in areas of neovascularisation related to the accumulation of immunocompetent and inflammatory cells within atherosclerotic plaque.

Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.

Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.

Physician preferences for perioperative anticoagulation in patients with a mechanical heart valve who are undergoing elective noncardiac surgery.

Study Objective: To determine physicians' anticoagulation preferences in patients with a mechanical heart valve who are undergoing elective surgery, and to determine the effect of different risks of thromboembolism (TE) and postoperative bleeding on anticoagulation preferences.

Design: Mail survey of physicians who prescribe anticoagulant therapy.

Methods And Results: Physicians were asked to provide anticoagulation preferences in four clinical scenarios of patients with a mechanical heart valve who are undergoing elective surgery.

Involvement of dendritic cells in long-term aortocoronary saphenous vein bypass graft failure.

Antigen-presenting dendritic cells are present in atherosclerotic lesions in human arterial intima, but have not been investigated in atherosclerotic and hyperplastic stenotic lesions that affect vein grafts used as arterial conduits. This study was undertaken to examine whether dendritic cells are present in aortocoronary artery saphenous vein bypass grafts affected by high-grade atheromatous stenosis. Stenotic saphenous vein coronary artery bypass grafts (angiographic luminal stenosis > 75%) were harvested from 10 patients (nine male, one female), aged 4271 years (mean 56.

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile.

Clinical and angiographic features in patients under 35 years with a first Q wave acute myocardial infarction.

Sixty patients less than 35 years with a first Q wave acute myocardial infarction were prospectively studied to evaluate their features, risk factors and evidence of any viral infection. Typical chest pain was present in 98.3% with Q waves and ST segment elevation in all.

Dendritic cells in venous pathologies.

Dendritic cells are potent antigen-presenting cells responsible for the activation of T-lymphocytes in various immune responses. Their role in the initiation of immune reactions in allergies, autoimmune diseases, tumors, transplantation, and, more recently, in atherosclerosis has been well established, but their involvement in venous pathologies has not been previously investigated. The aim of this study was to determine whether dendritic cells are present in veins affected by varicosity and thrombophlebitis.

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4.

Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements.

Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity.

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29.