Abstract-Superoxide (O 2·Ϫ ) in arteries may contribute to atherosclerosis in part by inactivation of nitric oxide. We hypothesized that regression of atherosclerosis in nonhuman primates is associated with a decrease in vascular NAD(P)H oxidase, decreased O 2 ·Ϫ levels, and improved endothelium-dependent relaxation. Cynomolgus monkeys (nϭ28) were fed an atherogenic diet for 47Ϯ10 (meanϮSE) months. In carotid arteries (containing advanced lesions), femoral arteries (moderate lesions), and saphena arteries (minimal lesions), we examined O 2 ·Ϫ levels and vasomotor function. Compared with vessels from normal monkeys (nϭ8), O 2 ·Ϫ levels (measured by lucigenin-enhanced chemiluminescence) were 3.3-fold higher in carotid, 1.7-fold higher in femoral, and not different in saphena arteries from atherosclerotic monkeys. Dihydroethidium staining also demonstrated increased O 2 ·Ϫ levels throughout the vessel wall in femoral and carotid arteries from atherosclerotic monkeys. Components of the NAD(P)H oxidase (p22 phox and p47 phox ) were increased in atherosclerotic arteries, and immunohistochemistry demonstrated colocalization primarily to areas of macrophage infiltration. Relaxation to acetylcholine was impaired in carotid and femoral, but not saphena, arteries from atherosclerotic monkeys. After 8 months of regression diet (nϭ9), serum cholesterol decreased to normal, and O 2 ·Ϫ levels (basal and NAD(P)H-stimulated), as well as expression of NAD(P)H oxidase, returned toward normal. Relaxation to acetylcholine improved in femoral arteries, but not in the more diseased carotid arteries. We conclude that, in a primate model of moderately severe atherosclerosis and regression of atherosclerosis, changes in endothelial function are inversely related to O 2 ·Ϫ and NAD ( Key Words: oxidative stress Ⅲ vascular reactivity Ⅲ blood vessels Ⅲ macrophages Ⅲ endothelium V ascular levels of reactive oxygen species increase during hypercholesterolemia and may contribute to the pathophysiology of atherosclerosis. For example, reaction with superoxide (O 2 ·Ϫ ) reduces the bioavailability of nitric oxide (NO), which impairs vasomotor function, 1 and increases platelet aggregation and monocyte adhesion. Superoxide can also activate matrix metalloproteinases and produce apoptosis, which may contribute to instability of atherosclerotic lesions. [2][3][4] Reduction of cholesterol levels in patients with established coronary artery disease markedly reduces the risk of major coronary events. 5-8 Improvement in vasomotor function and clinical benefits, however, occur much more rapidly than structural improvement during regression, possibly through an increase in the bioavailability of NO. 8,9 This observation is compatible with the hypothesis that regression of atherosclerosis is associated with reduction of vascular reactive oxygen species (ROS) levels.Macrophages, smooth muscle, fibroblasts, and endothelium all are potential sources of O 2 ·Ϫ in blood vessels. 2,10 -12 Reduction of endothelial O 2 ·Ϫ by a gene transfer approach is not suffici...

The goal of this study was to examine the role of endogenous copper/zinc (CuZn)-superoxide dismutase (SOD) on superoxide levels and on responses of cerebral blood vessels to stimuli that are mediated by nitric oxide (acetylcholine) and cyclooxygenase-dependent mechanisms (bradykinin and arachidonic acid). Levels of superoxide in the rabbit basilar artery were measured using lucigenin-enhanced chemiluminescence (5 microM lucigenin). Diethyldithiocarbamate (DDC; 10 mM), an inhibitor of CuZn-SOD, increased superoxide levels by approximately 2.4-fold (P < 0.05) from a baseline value of 1.0 +/- 0.2 relative light units x min(-1) x mm(-2) (means +/- SE). The diameter of cerebral arterioles (baseline diameter, 99 +/- 3 microm) was also measured using a closed cranial window in anesthetized rabbits. Topical application of DDC attenuated responses to acetylcholine, bradykinin, and arachidonate, but not nitroprusside. For example, 10 microM arachidonic acid dilated cerebral arterioles by 40 +/- 5 and 2 +/- 2 microm under control conditions and after DDC, respectively (P < 0.05). These inhibitory effects of DDC were reversed by the superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (10 mM). Arachidonate increased superoxide levels in the basilar artery moderately under normal conditions and this increase was greatly augmented in the presence of DDC. These findings suggest that endogenous CuZn-SOD limits superoxide levels under basal conditions and has a marked influence on increases in superoxide in vessels exposed to arachidonic acid. The results also suggest that nitric oxide- and cyclooxygenase-mediated responses in the cerebral microcirculation are dependent on normal activity of CuZn-SOD.

Frequently in biomedical literature, measurements are considered "not statistically different" if a statistical test fails to achieve a P value that is < or = 0.05. This conclusion may be misleading because the size of each group is too small or the variability is large, and a type II error (false negative) is committed. In this study, we examined the probabilities of detecting a real difference (power) and type II errors in unpaired t-tests in Volumes 246 and 266 of the American Journal of Physiology: Heart and Circulatory Physiology. In addition, we examined all articles for other statistical errors. The median power of the t-tests was similar in these volumes (approximately 0.55 and approximately 0.92 to detect a 20% and a 50% change, respectively). In both volumes, approximately 80% of the studies with nonsignificant unpaired t-tests contained at least one t-test with a type II error probability > 0.30. Our findings suggest that low power and a high incidence of type II errors are common problems in this journal. In addition, the presentation of statistics was often vague, t-tests were misused frequently, and assumptions for inferential statistics usually were not mentioned or examined.

Extraintestinal manifestations of inflammatory bowel disease are numerous. This study examined the effects of two models of acute colitis on cerebral blood flow (CBF) and permeability of the blood-brain barrier in rabbits. CBF (measured with radiolabeled microspheres), or the extraction ratio or permeability-surface area (PS) product of the blood-brain barrier to fluorescein and FITC-dextran, was measured 48 h after colitis induction with acetic acid (HAc) or trinitrobenzene sulfonic acid (TNBS). PS product for fluorescein increased ( P < 0.05) in TNBS colitis (1.33 × 10−5 ± 0.52 × 10−5 ml/s and 0.48 × 10−5 ± 0.13 × 10−5ml/s (mean ± SE) for treated ( n = 14) and untreated ( n = 10) animals, respectively. PS product for the larger FITC-dextran was not different in TNBS colitis (0.24 × 10−5 ± 0.09 × 10−5ml/s, n = 7) compared with untreated controls (0.19 × 10−5 ± 0.04 × 10−5 ml/s, n = 8). PS product for fluorescein increased ( P < 0.01) in HAc colitis compared with vehicle (2.66 × 10−5 ± 1.46 × 10−5 ml/s and 0.33 × 10−5 ± 0.05 × 10−5ml/s, respectively; n = 6 in each group). The extraction of fluorescein from the blood to the brain increased by 75% during TNBS colitis when compared with vehicle ( P < 0.05). CBF and cerebrovascular resistance did not change from the untreated control after TNBS colitis. Our data suggest that, irrespective of induction method, acute colitis increases the permeability of the blood-brain barrier to small molecules without changing CBF.

Laparoscopy requires the development of technical skills distinct from those used in open procedures. Several factors extending the learning curve of laparoscopy include ergonomic and technical difficulties, such as the fulcrum effect and limited degrees of freedom. This study aimed to establish the impact of four variables on performance of two simulated laparoscopic tasks.Methods:Six subjects including novice (n=2), intermediate (n=2) and expert surgeons completed two tasks: 1) four running sutures, 2) simple suture followed by surgeon's knot plus four square knots. Task variables were suturing angle (left/right), needle holder type (standard/articulating) and visualisation (2D/3D). Each task with a given set of variables was completed twice in random order. The endpoints included suturing task completion time, average and maximum distance from marks and knot tying task completion time.Results:Suturing task completion time was prolonged by 45-degree right angle suturing, articulating needle holder use and lower skill levels (all P < 0.0001). Accuracy also decreased with articulating needle holder use (both P < 0.0001). 3D vision affected only maximum distance (P=0.0108). For the knot tying task, completion time was greater with 45-degree right angle suturing (P=0.0015), articulating needle holder use (P < 0.0001), 3D vision (P=0.0014) and novice skill level (P=0.0003). Participants felt that 3D visualisation offered subjective advantages during training.Conclusions:Results suggest construct validity. A 3D personal head display and articulating needle holder do not immediately improve task completion times or accuracy and may increase the training burden of laparoscopic suturing and knot tying.