Limitation of the Vitros dry-slide technique in measuring high concentrations of salicylate in plasma.

The linearity of the Vitros dry-slide method for plasma salicylate was assessed in two ways: serial concentrations of sodium salicylate were added to fresh lithium heparin plasma, and the salicylate was determined both neat and in dilution. Vitros salicylate results submitted to the Heathcontrol External Quality Assessment Scheme were compared to the spike value. Similar loss of linearity was observed in both cases. Serious salicylate overdosage requiring specific clinical treatment may have been underestimated.

Biphasic modulation of atherosclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit.

There has been considerable debate about how copper status may affect the biochemical and cellular processes associated with atherogenesis. We have investigated the effects of graded dietary copper supplementation on processes likely to contribute to atherogenesis, using the cholesterol-fed New Zealand White rabbit model. Rabbits (n = 40) were fed a 0.25-1% cholesterol diet deficient in copper. Animals received either 0, 1, 3 or 20 mg copper/day and were killed after 13 weeks. Plasma cholesterol levels were similar in each dietary group. Aortic concentrations of copper were higher in the 20 mg copper/day animals compared to those receiving 0 mg copper/day (3.70 +/- 0.78 vs. 1.33 +/- 0.46 microg/g wet tissue; P < 0.05). Aortic superoxide dismutase activity was higher in animals receiving 20 mg copper/day (323 +/- 21 IU/mg tissue) compared to the other groups (187 +/- 21; 239 +/- 53; 201 +/- 33 IU/mg tissue) (P > 0.05). En face staining of aortae with oil red O showed that both high copper supplementation (20 mg/day) (67.1 +/- 5.5%) and a deficient diet (0 mg/day) (63.1 +/- 4.8%) was associated with significantly larger lesions (P < 0.05) compared to moderately supplemented animals (1 mg/day and 3 mg/day) (51.3 +/- 6.3 and 42.8 +/- 7.9%). These data indicate that in the cholesterol-fed rabbit, there is an optimal dietary copper intake and that dietary copper deficiency or excess are associated with an increased susceptibility to aortic atherosclerosis. Many Western diets contain insufficient copper and these findings indicate that a moderate dietary copper content may confer a degree of cardiac protection to the human population.

Endogenous neutralizing antibodies against platelet-derived growth factor-aa inhibit atherogenesis in the cholesterol-fed rabbit.

Previous studies have shown that the B chain of platelet-derived growth factor (PDGF) has an important role in atherogenesis. In this study we have investigated the contribution of PDGF-A chain in cholesterol-induced atherogenesis in the New Zealand White rabbit. High titers of antibodies to PDGF-AA or to platelet cytosolic protein (PCP) were induced in these animals by immunization against recombinant human PDGF-AA or human PCP. Rabbits were then fed a 0.25% to 1% cholesterol-containing diet for 10 weeks to induce atherosclerotic lesions; the rabbits were then humanely killed and perfusion-fixed and their aortas were removed. The extent of atherosclerosis in the thoracic aortas was determined by quantitative morphometry after staining with oil red O. The intimal and medial areas in histological sections taken at the level of the first intercostal branch were quantified by image analysis. Immunization against PDGF-AA and PCP, but not against adjuvant alone, resulted in rising titers of antibodies within 2 weeks, the levels of which reached a plateau by 8 weeks. The antibodies to PDGF-AA were isoform-specific, recognized both human and rabbit PDGF-AA, and neutralized the biological activity of PDGF-AA in vitro. Integrated plasma cholesterol levels were similar in both groups. Compared with nonimmune rabbits (n=10), animals immunized against PDGF-AA (n=10) or PCP (n=10) had significantly smaller areas of the aorta covered by atherosclerotic lesions (24.6+/-5.1% and 18.7+/-4.2%, respectively, vs 34.4+/-4.3%; P<0.05). This was associated with a reduced aortic intimal-medial area ratio in PDGF-AA-immunized (0.009+/-0.006) and PCP-immunized (0.025+/-0.017) rabbits than in nonimmune animals (0.159+/-0.066; P<0.05). These data suggest that PDGF-AA is actively involved in cholesterol-induced atherosclerosis in the rabbit.

The mechanisms of coronary restenosis: insights from experimental models.

Since its introduction into clinical practice, more than 20 years ago, percutaneous transluminal coronary angioplasty (PTCA) has proven to be an effective, minimally invasive alternative to coronary artery bypass grafting (CABG). During this time there have been great improvements in the design of balloon catheters, operative procedures and adjuvant drug therapy, and this has resulted in low rates of primary failure and short-term complications. However, the potential benefits of angioplasty are diminished by the high rate of recurrent disease. Up to 40% of patients undergoing angioplasty develop clinically significant restenosis within a year of the procedure. Although the deployment of endovascular stents at the time of angioplasty improves the short-term outcome, 'in-stent' stenosis remains an enduring problem. In order to gain an insight into the mechanisms of restenosis, several experimental models of angioplasty have been developed. These have been used together with the tools provided by recent advances in molecular biology and catheter design to investigate restenosis in detail. It is now possible to deliver highly specific molecular antagonists, such as antisense gene sequences, to the site of injury. The knowledge provided by these studies may ultimately lead to novel forms of intervention. The present review is a synopsis of our current understanding of the pathological mechanisms of restenosis.