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BACKGROUND Previous studies have shown the feasibility of peripheral arterial ultrasound angioplasty. METHODS AND RESULTS In this report, we describe the use of percutaneous therapeutic ultrasound for coronary angioplasty. In vitro, 11 postmortem, atherosclerotically occluded coronary arteries were obtained to assess catheter-delivered ultrasound for arterial recanalization as well as for assessment of the size of particulate debris. Clinically, coronary ultrasound angioplasty was performed in 19 patients (mean age, 56 years) to assess safety and feasibility for the treatment of obstructive coronary atherosclerosis. Three patients with unstable angina and 16 with exercise-induced myocardial ischemia were treated with a prototype 4.6F coronary catheter ultrasound ablation device with a 1.7-mm diameter ball tip. The ultrasound coronary catheter delivered ultrasound energy at 19.5 kHz, with a power output of 16 to 20 W at the transducer. Energy is delivered in a pulsed mode with a 50% duty cycle of 30 milliseconds. Patients were treated for a mean of 493 seconds (range, 130 to 890) with intracoronary ultrasound ablation. All lesions were treated with adjunctive balloon angioplasty. All 11 postmortem coronary occlusions were recanalized, and 99% of the particulates generated were < 10 microns in diameter. We found that after ultrasound, mean (+/- SD) coronary arterial stenosis fell from 80 +/- 12% to 60 +/- 18% (P < .001) and to 26 +/- 11% (P < .001) after adjunctive balloon angioplasty. Mean pressures required to achieve full balloon inflation were 2.7 atm (range, 1 to 5.5) with a median of 3.0-mm balloon size (2.5 to 3.5). No ultrasound-related complications were identified. CONCLUSIONS Intracoronary ultrasound plaque ablation appears to be safe. Our findings suggest that catheter-delivered high-intensity, low-frequency ultrasound may be useful for lesion debulking and enhancing arterial distensibility, allowing balloon dilation at relatively low pressures.

3Patherogenic and anti-inflammatory effects in monocyteshnacrophages, and binds thiazolidinedionesnovel antidiabetic agents with insulin-sensitising effects. However, there is no direct evidence to conclusively implicate this receptor in the regulation of mammalian glucose homeostasis. We have screened the PPARy gene in 85 unrelated subjects with severe insulin resistance. Two different heterozygous mutations (P467L, V290M) were identified within the ligand-binding domain in three affected individuals, all of whom exhibited a distinct clinical phenotype of severe early onset type 2 diabetes mellitus and hypertension. In the crystal structure, these mutations destabilise helix 12 which is critical for transactivation by the receptor. Consistent with this, both receptor mutants exhibit impaired ligand binding, coactivator recruitment and transcriptional activity. Moreover, they inhibit the action of coexpressed wild type PPARy in a dominant negative manner, an effect which correlates with their ability to silence basal gene transcription. These data provide compelling genetic evidence for a direct role of PPARy in the control of mammalian glucose homeostasis and blood pressure.To further investigate the mechanism of dominant negative inhibition, an artificial PPARy mutant (L468AE471A) was also generated. Both natural and artificial mutants recruit nuclear corepressors (SMRT and NCoR) in a 2-hybrid assay and exhibit delayed ligand-dependent corepressor release. Our studies indicate that, as in other mutant nuclear receptor contexts (acute promyelocytic leukaemia, resistance to thyroid hormone), such aberrant corepressor interaction is linked to dominant negative activity. To date, no complete, specific chemical PPARy antagonists exist. The artificial dominant negative PPARy mutant was therefore introduced into a recombinant adenovirus and used to specifically inhibit PPARy-mediated differentiation of primary cultured human preadipocytes. We plan to use this biological receptor antagonist to elucidate the mechanisms by which PPARy regulates insulin action and vascular tone. Edinburgh. EH8 9AG Introduction. We have previously reported our finding of significantly elevated levels of IL-8 within the alveolar airspaces of patients at risk of developing ARDS (Lancet 1993; 341: 643-647), and identified the macrophage as a potent source of this chemokine. Subsequent extended studies in multiple trauma patients confirm that raised lung IL-8 levels are strongly associated with ARDS progression (n=56, P=O.OOOl). The mechanism by which IL-8 is rapidly raised in these circumstances is unknown. A correlation between reduced Pa02Fi02 ratio on presentation to casualty and raised IL-8 levels was noted (r4.56, P=O.OOl). We postulated that acute hypoxia may upregulate IL-8 synthesis in human macrophages. Methods. Macrcphages cultured from peripheral blood mononuclear cells were exposed to hypoxia (Pa02-3.5Kpa) or normoxia (Pa02-20Kpa) for up to 2 hrs. Secreted IL-8 protein was measured by ELSA and mRNA expression by northem blotting. ...

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