The TRAPIST Study. A multicentre randomized placebo controlled clinical trial of trapidil for prevention of restenosis after coronary stenting, measured by 3-D intravascular ultrasound.

BACKGROUND: Studies have reported benefit of oral therapy with the phosphodiesterase inhibitor, trapidil, in reducing restenosis after coronary angioplasty. Coronary stenting is associated with improved late outcome compared with balloon angioplasty, but significant neointimal hyperplasia still occurs in a considerable proportion of patients. The aim of this study was to investigate the safety and efficacy of trapidil 200 mg in preventing in-stent restenosis. METHODS: Patients with a single native coronary lesion requiring revascularization were randomized to placebo or trapidil at least 1 h before, and continuing for 6 months after, successful implantation of a coronary Wallstent. The primary end-point was in-stent neointimal volume measured by three-dimensional reconstruction of intravascular ultrasound images recorded at the 6 month follow-up catheterization. RESULTS: Of 312 patients randomized at 21 centres in nine countries, 303 (148 trapidil, 155 placebo) underwent successful Wallstent implantation, and 139 patients (90%) in the placebo group and 130 (88%) in the trapidil group had repeat catheterization at 26+/-2 weeks. There was no significant difference between trapidil and placebo-treated patients regarding in-stent neointimal volume (108.6+/- 95.6 mm(3)vs 93.3+/-79.1 mm(3);P=0.16) or % obstruction volume (38+/-18% vs 36+/-21%;P=0.32), in angiographic minimal luminal diameter at follow-up (1.63+/-0.61 mm vs 1.74+/-0.69 mm;P=0.17), restenosis rate (31% vs 24%;P=0.24), cumulative incidence of major adverse cardiac events at 7 months (22% vs 20%;P=0.71) or anginal complaints (30% vs 24%;P=0.29). CONCLUSION: Oral trapidil 600 mg daily for 6 months did not reduce in-stent hyperplasia or improve clinical outcome after successful Wallstent implantation and is not indicated for this purpose.

The influence of stent length on clinical and angiographic outcome in patients undergoing elective stenting for native coronary artery lesions; final results of the Magic 5L Study.

AIMS: To prospectively evaluate the influence of stent length on 6 month clinical and angiographic outcome, in patients with native coronary lesions up to 45 mm in length, undergoing elective Magic Wallstent implantation. METHODS AND RESULTS: On the basis of pre-procedural angiography, 276 patients (aged 61.3+/-10.2 years; 78.6% male; 41.7% unstable angina) with a total of 302 lesions were prospectively assigned to one of five different length categories of Magic Wallstent. Angiography in multiple matched projections before and after implantation and at 6 months follow-up was analysed at the core laboratory. Primary end-points for the efficacy analysis were cumulative incidence of major adverse cardiac events and quantitative coronary angiography analysis 6 months after stent implantation. Magic Wallstent implantation was successful in 301 of 302 lesions and in 98.6% a residual stenosis <20% by online quantitative coronary angiography was achieved. At 30 days, 6.2% (1.8% subacute occlusion) of patients had experienced major adverse cardiac events, 27.5% at 6 months and 30.4% at 9 months. Angiographic restenosis occurred in 37%. Restenosis rates for the mini, extra-short, short, medium and long Wallstent groups were 25.9%, 25%, 22.6%, 36.2% and 67.5%, respectively. Multivariate analysis revealed stent length to be independently associated with greater angiographic restenosis and major adverse cardiac events. CONCLUSIONS: While shorter Magic Wallstents provided late outcomes comparable with short balloon-expandable stents, excessive restenosis with longer Wallstents should obviate their use in elective percutaneous intervention. Long coronary lesions provide a challenging substrate for emerging antirestenosis therapies, such as stent coatings and brachytherapy.

Different cardiovascular profiles of three melanocortins in conscious rats; evidence for antagonism between gamma 2-MSH and ACTH-(1-24).

1. We investigated the effects of [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH), adrenocorticotropin-(1-24) (ACTH-(1-24)) and gamma 2-MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration. 2. As was previously found by other investigators as well as by us gamma 2-MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC3 receptor, caused a dose-dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP-MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC1 receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg-1. 3. ACTH-(1-24) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in heart rate in a dose-range from 15 to 500 nmol kg-1. The cardiovascular effects of ACTH-(1-24) were independent of the presence of the adrenals. 4. Pretreatment with ACTH-(1-24) caused a pronounced, dose-dependent parallel shift to the right of the dose-response curve for the pressor and tachycardiac effects of gamma 2-MSH. The antagonistic effect of ACTH-(1-24) was already apparent following a dose of this peptide as low as 10 nmol kg-1, which when given alone had no intrinsic hypotensive activity. 5. These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that gamma-MSH-like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH-(1-24) seem not to be mediated by the adrenal melanocortin MC3 receptors, for which ACTH-(1-24) is a selective agonist, or by adrenal catecholamines. 6. There appears to be a functional antagonism between ACTH-(1-24) and gamma 2-MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown.

Induction of an antibody response in mice against human papillomavirus (HPV) type 16 after immunization with HPV recombinant Salmonella strains.

Human papillomaviruses (HPV) are present in approximately 95% of all cervical carcinomas and the HPV E6 and E7 genes are continuously expressed in these lesions. There is also circumstantial evidence that often natural immunity against HPV is generated and that this is of influence on HPV-induced lesions. Stimulation of the immune system by proper presentation of relevant HPV antigens might, therefore, lead to a prophylactic or therapeutic immunological intervention for HPV-induced lesions. For this purpose we have expressed the E6 and E7 protein of HPV 16 in an attenuated strain of Salmonella typhimurium (SL3261, aroA mutation), which has been used extensively as a live vector. Live recombinant Salmonella vaccines have the ability to elicit humoral, secretory and cell-mediated immune responses, including cytotoxic T cells, against the heterologous antigens they express. This report describes the construction of recombinant Salmonella strains expressing the HPV 16 E6 and E7 proteins, and the induction of an HPV-16-specific immune response in mice after immunization with these live vectors.

Acid ethanol fixation and polyester wax embedding combines preservation of antigenic determinants with good morphology and enables simultaneous bromodeoxyuridine (BrdU) labeling.

Lymphoid tissue, and/or isolated peripheral mononuclear blood cells were fixed in acid ethanol and embedded in polyester wax (melting point 37 C). The excellent cytomorphology obtained allowed distinguishing different types of individual lymphoid and nonlymphoid cells. Furthermore, this procedure was satisfactory in the immunophenotyping of histiocytes, endothelial, mesenchymal, epithelial cells, different (sub-) types of lymphocytes and also of lymphokine activated killer (LAK) cells. The staining patterns obtained with the different poly- and monoclonal antibodies on polyester wax sections were not only analogous to those obtained on frozen sections, but cells which had incorporated bromodeoxyuridine could be double labeled with specific antiserum.

Characterization of fastidious adenovirus types 40 and 41 by DNA restriction enzyme analysis and by neutralizing monoclonal antibodies.

The DNA of 48 strains of adenovirus type 40 (Ad40) and of 128 strains of adenovirus type 41 (Ad41), isolated between 1971 and 1986 from various countries, was characterized by restriction enzyme analysis using nine and ten restriction endonucleases respectively. Five new DNA variants of Ad40 and 18 new DNA variants of Ad41 were detected. Most of the restriction sites which differed among the various DNA variants appeared to be distributed at random over the entire length of the viral genomes of the two serotypes. The number of restriction sites by which two DNA variants differed from each other was used as a measure of their relatedness. Several clusters of closely related DNA variants were observed for each of the two serotypes. The 35 DNA variants of Ad40 and Ad41 were used to test monoclonal antibody preparations for their range of reactivity in a neutralization assay. One monoclonal antibody (5-8), raised against Ad40 strain Dugan, showed type-specific neutralization of all 11 Ad40 DNA variants tested. Six monoclonal antibodies, raised against Ad41 strain Tak, neutralized different proportions of the variants of Ad41. Two of these preparations (1-21 and 3-19) neutralized all 24 Ad41 DNA variants, while a third (1-23) reacted with only 12 Ad41 variants. Three other monoclonal antibody preparations (3-10, 3-18, 7-14) reacted specifically with only 6 of these 12 variants. The patterns of reactivity with the monoclonal antibody preparations correlated with the presence or absence of a HindIII restriction site at 56 map units and of an EcoRI restriction site at 52 map units on the Ad41 DNA. This region of the adenovirus DNA codes for the hexon protein, which is known to contain the type-specific neutralizing antigenic determinants.

A study to analyze the origin of tumor cells in malignant fibrous histiocytomas. A multiparametric characterization.

To study the derivation of tumor cells of malignant fibrous histiocytomas (MFH), their phenotypical marker profile was investigated and compared with those of malignant histiocytosis (MH) and of different types of soft tissue tumors (STT). The presence of the following markers was investigated: on paraffin sections, alpha-1-antichymotrypsin (ACT); on frozen sections antigens associated with lymphocytes, macrophages and fibroblasts, the enzymes acid phosphatase, nonspecific esterase, and beta-glucuronidase; and, on isolated and cultured cells, the receptors for EA-gamma and complement. Furthermore, the capacity to phagocytose sensitized erythrocytes and carbon particles was studied in vitro. MFH tumor cells and a part of other types of STT shared the expression of ACT and lysosomal enzymes with MH. They differed, however, from MH by the absence of monocyte/macrophage-associated antigens and by the expression of fibroblast-associated antigens, which property they had in common with other STT. MFH tumor cells were not able to form rosettes or to phagocytose Ig-sensitized erythrocytes, but they showed phagocytosis of carbon particles. The results strongly indicate that MFH tumor cells originate from (primitive) fixed mesenchymal cells and are not related to monocyte-derived histiocytes.