Search PubMed⌕ Search

Biomedical subjects

S Kaul

Publications and source records attributed to S Kaul.

At least 145 records · Page 8Linked to original sources
PubMed1998

Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage.

BACKGROUND: We hypothesized that the persistence of albumin microbubbles within the myocardium during crystalloid cardioplegia (CP) infusion and ischemia-reperfusion (I-R) occurs because of endothelial injury. METHODS AND RESULTS: The myocardial transit rate of albumin microbubbles was measured in 18 dogs perfused with different CP solutions and in 12 dogs undergoing I-R. Electron microscopy with cationized ferritin labeling of the glycocalyx was performed in 9 additional dogs after CP perfusion and in 3 additional dogs undergoing I-R. Microbubble transit was markedly prolonged during crystalloid CP perfusion. The addition of whole blood to the CP solution accelerated the transit rate in a dose-dependent fashion (P<0.05), which was greater with venous than with arterial blood (P<0.05). The addition of plasma or red blood cells to CP solutions was less effective in improving transit rate than addition of whole blood (P<0.05). Microbubble transit rate was independent of the temperature, K+ content, pH, PO2, osmolality, viscosity, and flow rate of the perfusate. Similarly, a proportion of microbubbles persisted in the myocardium after I-R, which was related to the duration of ischemia (P<0.01) but not of reflow. Crystalloid CP perfusion and I-R resulted in extensive loss of the endothelial glycocalyx without other ultrastructural changes. This effect was partially reversed in the case of crystalloid CP when it was followed by blood CP. CONCLUSIONS: Sonicated albumin microbubbles persist within the myocardium in situations in which the endothelial glycocalyx is damaged. The measurement of the myocardial transit rate of albumin microbubbles may provide an in vivo assessment of endothelial glycocalyx damage.

Animals↗
PubMed1998

Spontaneous redistribution after reperfusion: a unique property of AIP 201, an ultrasound contrast agent.

OBJECTIVES: We sought to determine the mechanism of spontaneous redistribution of AIP 201 microbubbles after reperfusion from a single left heart injection performed during coronary occlusion. BACKGROUND: AIP 201, an ultrasound contrast agent consisting of 10-microm sized microbubbles, has demonstrated spontaneous myocardial redistribution in preliminary studies. METHODS: Myocardial video intensity (VI) and radiolabeled microsphere-derived myocardial blood flow (MBF) were measured serially after reperfusion in seven dogs undergoing an AIP 201 injection during coronary occlusion. The behavior of these bubbles was also assessed in the rat spinotrapezius muscle using intravital microscopy (IM), both with and without ultrasound. The effect of ultrasound on these bubbles was also determined in vitro. RESULTS: A spontaneous and gradual increase in myocardial VI was noted after reperfusion, which was related to the magnitude of increase in MBF to that region (r=0.82, p < 0.001). On IM, most of the microbubbles were seen entrapped in small arterioles. Some larger arterioles had aggregates of microbubbles that periodically became dislodged and moved downstream. This behavior was not affected in vivo by ultrasound. In vitro, however, microbubble aggregation was noted only during ultrasound exposure. CONCLUSIONS: The magnitude of redistribution of AIP 201 microbubbles to the reperfused myocardium is related to changes in MBF and occurs from their dislodgement from microbubble aggregates entrapped in large arterioles. In vitro microbubble aggregation seen during ultrasound exposure was not reproduced in vivo. These results may have important implications for studying the effects of interventions in acute coronary syndromes and after coronary artery bypass graft surgery.

Animals↗
PubMed1998

Assessment of transmural distribution of myocardial perfusion with contrast echocardiography.

BACKGROUND: We hypothesized that by using our newly defined method of destroying microbubbles and measuring their rate of tissue replenishment, we could assess the transmural distribution of myocardial perfusion. METHODS AND RESULTS: We studied 12 dogs before and after creation of left anterior descending coronary artery stenoses both at rest and during hyperemia (n=62 stages). Microbubbles were administered as a constant infusion, and myocardial contrast echocardiography (MCE) was performed with the use of different pulsing intervals. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y=A(1-ebetat), where A reflects microvascular cross-sectional area (or myocardial blood volume), and beta reflects mean myocardial microbubble velocity. The product A . beta represents myocardial blood flow (MBF). Average values for these parameters were derived from the endocardial and epicardial regions of interest placed over the left anterior descending coronary artery bed. Radiolabeled microsphere-derived MBF was also measured from the same regions. There was poor correlation between radiolabeled microsphere-derived MBF and A-endocardial/epicardial ratios (EER) (r=0.46). The correlation with beta-EER was better (r=0. 69, P<0.01). The best correlation with radiolabeled microsphere-derived MBF-EER was noted with A . beta-EER (r=0.88, P<0. 01). CONCLUSIONS: The transmural distribution of myocardial perfusion can be accurately assessed with MCE with the use of our newly described method of tissue replenishment of microbubbles after their ultrasound-induced destruction. In the model studied, an uncoupling of the transmural distribution of MBF and myocardial blood volume was observed during reversal of the MBF-EER.

Air↗
PubMed1998

Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound.

BACKGROUND: We have previously shown that the application of ultrasound to thin-shelled microbubbles flowing through small microvessels (<7 microm in diameter) produces vessel wall ruptures in vivo. Because many intravascular drug- and gene-delivery vehicles are limited by the endothelial barrier, we hypothesized that this phenomenon could be used to deliver drug-bearing vehicles to tissue. METHODS AND RESULTS: An exteriorized rat spinotrapezius muscle preparation was used. Intravascular fluorescent red blood cells and polymer microspheres (PM) (205 and 503 nm in diameter) were delivered to the interstitium of rat skeletal muscle through microvessel ruptures created by insonifying microbubbles in vivo. On intravital microscopy, mean dispersion areas per rupture for red blood cells, 503-nm PM, and 205-nm PM were 14.5x10(3) microm2, 24. 2x10(3) microm2, and 27.2x10(3) microm2, respectively. PM dispersion areas were significantly larger than the mean dispersion area for red blood cells (P<0.05). CONCLUSIONS: Microvessel ruptures caused by insonification of microbubbles in vivo may provide a minimally invasive means for delivering colloidal particles and engineered red blood cells across the endothelial lining of a targeted tissue region.

Animals↗
PubMed1998

Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue.

BACKGROUND: Our aim was to observe ultrasound-induced intravascular microbubble destruction in vivo and to characterize any resultant bioeffects. METHODS AND RESULTS: Intravital microscopy was used to visualize the spinotrapezius muscle in 15 rats during ultrasound delivery. Microbubble destruction during ultrasound exposure caused rupture of < or = 7-microm microvessels (mostly capillaries) and the production of nonviable cells in adjacent tissue. The number of microvessels ruptured and cells damaged correlated linearly (P<0.001) with the amount of ultrasound energy delivered. CONCLUSIONS: Microbubbles can be destroyed by ultrasound, resulting in a bioeffect that could be used for local drug delivery, angiogenesis, and vascular remodeling, or for tumor destruction.

Air↗
PubMed1998

Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I(Milano)/phospholipid complex (A-I[Milano]/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I(Milano)/PC would inhibit aortic atherosclerosis in apo E-deficient mice. METHODS AND RESULTS: Thirty-five apo E-deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I(Milano)/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11 +/- 1% versus 17 +/- 5% of the aortic surface, P=.002), and lipid content increased by 45% (22 +/- 8% versus 32 +/- 6% of plaque area, P=.02) without a significant change in macrophage content (10.8 +/- 2% versus 13.2 +/- 6%). Compared with 20-week-old untreated control mice, PC only-treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11 +/- 1% versus 15 +/- 4%, P=.01) and an increase in lipid content (22 +/- 8% versus 47 +/- 3%, P<.0001) without a change in macrophage content (10.8 +/- 2% versus 11 +/- 2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I(Milano)/PC-treated mice demonstrated no increase in aortic atherosclerosis (11 +/- 1% versus 10 +/- 4%, P=NS), a 40% reduction in lipid content (22 +/- 8% versus 13 +/- 8%, P=.01), and a 46% reduction in macrophage content (10.8 +/- 2% versus 5.8 +/- 2.9%; P=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I(Milano)/PC or PC only. In vitro, apo A-I(Milano)/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I(Miano) had no effect. CONCLUSIONS: Recombinant A-I(Milano)/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E-deficient mice despite severe hypercholesterolemia. Thus, A-I(Milano)/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.

Animals↗
PubMed1998

Telomerase activity correlates with tumor aggressiveness and reflects therapy effect in breast cancer.

Telomerase appears to be an important factor for the control of cellular proliferation capacity and for tumorigenesis. Enzyme activity is highly increased in almost all human tumors and distinguishes them from benign lesions. Besides its diagnostic value, telomerase activity appears to be associated with tumor progression. The purpose of our study was to evaluate the significance of telomerase activity as a clinical marker in breast cancer. Twenty-five tumor samples from breast cancer patients were analyzed retrospectively for telomerase activity in chemotherapy-treated and untreated tumors. For each patient an identical number of cells was measured quantitatively for telomerase activity using the Telomerase-PCR-ELISA based on the TRAP (telomerase repeat amplification protocol) method. The findings were compared to clinical course, therapy and staging parameters. Telomerase activity was detected in all breast cancers. A significant correlation was found between enzyme activity and tumor size, lymph node status and stage: with ongoing tumor progression, telomerase activity appeared to increase in primary carcinomas. No correlation was seen between enzyme activity and the clinical course of patients. Without exception, telomerase activity was strongly decreased in all chemotherapy-treated tumors compared to untreated tumors. Our preliminary data indicate that telomerase activity is associated with aggressiveness of breast tumors and appears to mirror the anti-proliferative effects of chemotherapy.

Adult↗
PubMed1998

Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion.

BACKGROUND: Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbubble velocity. Conversely, measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow (MBF) can then be calculated from the product of the two. METHODS AND RESULTS: Ex vivo and in vitro experiments were performed in which either flow was held constant and pulsing interval (interval between microbubble destruction and replenishment) was altered, or vice versa. In vivo experiments were performed in 21 dogs. In group 1 dogs (n=7), MBF was mechanically altered in a model in which coronary blood volume was constant. In group 2 dogs (n=5), MBF was altered by direct coronary infusions of vasodilators. In group 3 dogs (n=9), non-flow-limiting coronary stenoses were created, and MBF was measured before and after the venous administration of a coronary vasodilator. In all experiments, microbubbles were delivered as a constant infusion, and myocardial contrast echocardiography was performed using different pulsing intervals. The myocardial video intensity versus pulsing interval plots were fitted to an exponential function: y=A(1-e[-betat]), where A is the plateau video intensity reflecting the microvascular cross-sectional area, and beta reflects the rate of rise of video intensity and, hence, microbubble velocity. Excellent correlations were found between flow and beta, as well as flow and the product of A and beta. CONCLUSIONS: MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles. This novel approach has potential for measuring tissue perfusion in any organ accessible to ultrasound.

Animals↗
PubMed1998

Perivascular delivery of a nitric oxide donor inhibits neointimal hyperplasia in vein grafts implanted in the arterial circulation.

OBJECTIVE: Nitric oxide has been reported to reduce intimal hyperplasia as a response to arterial injury. This study was designed to assess the possible effect of perivascular application of a nitric oxide donor on neointimal proliferation occurring in veins exposed to the dynamics of the arterial circulation in a hypercholesterolemic rabbit model. METHODS: Autologous jugular vein grafts were implanted in the carotid circulation of 20 hypercholesterolemic rabbits. A mixture of a biodegradable polymer and the nitric oxide donor, spermine/nitric oxide, which releases nitric oxide with a half-life of 39 minutes, was applied periadventitially at the time of implantation. Controls were veins bathed in saline solution, polymer alone, and polymer plus the carrier vehicle spermine without nitric oxide. Animals (n = 5 in each group) were put to death on day 28 for morphometric analysis, cell count, and immunohistochemical staining. RESULTS: Treatment with perivascular nitric oxide donor significantly decreased wall thickness (126 +/- 24 microm vs 208 +/- 45 microm, p = 0.0017) and area (124 +/- 22 microm2/microm vs 211 +/- 37 microm2/microm, p = 0.005). With the carrier vehicle spermine alone, there was a trend toward reduced intimal thickness, but the change was not statistically significant. In the grafts treated with nitric oxide donor, expression of insulin-like growth factor, fibroblast growth factor, thrombospondins, fibronectin, and tenascin was reduced. CONCLUSION: The periadventitial delivery of nitric oxide donor produces a reduction of neointimal hyperplasia in veins implanted in the arterial circulation. The mechanism of action is not entirely clear, but the reduction cannot be explained on the basis of decreased cell proliferation alone. Other possibilities are modulation of protein synthesis of vascular smooth muscle cells and production of extracellular matrix components.

Animals↗
PubMed1998

Basis for detection of stenosis using venous administration of microbubbles during myocardial contrast echocardiography: bolus or continuous infusion?

OBJECTIVES: This study sought to determine the basis of detection of stenosis by myocardial contrast echocardiography using venous administration of microbubbles and to define the relative merits of bolus injection versus continuous infusion. BACKGROUND: The degree of video intensity (VI) disparity in myocardial beds supplied by stenosed and normal coronary arteries can be used to quantify stenosis severity after venous administration of microbubbles. However, the comparative merits of administering microbubbles as a bolus injection or continuous infusion has not been studied. METHODS: Coronary stenoses of varying severity were created in either the left anterior descending or the left circumflex coronary artery in 18 dogs. Imagent US (AF0150) was given as a bolus injection in 10 dogs (Group I) and as both a bolus injection and a continuous infusion in 8 dogs (Group II). For bolus injections, peak VI was derived from time-intensity plots. During continuous infusion, microbubble velocity and microvascular cross-sectional area were derived from pulsing interval versus VI plots. Myocardial blood flow (MBF) was determined using radiolabeled microspheres. RESULTS: During hyperemia, VI ratios from the stenosed versus normal beds correlated with radiolabeled microsphere-derived MBF ratios from those beds for both bolus injections (r = 0.81) and continuous infusion (r = 0.79). The basis for detection of stenosis common to both techniques was the decrease in myocardial blood volume distal to the stenosis during hyperemia. The advantage of continuous infusion over bolus injection was the abolition of posterior wall attenuation and the ability to quantify MBF. CONCLUSIONS: Both bolus injection and continuous infusion provide quantitative assessment of relative stenosis severity. Compared with bolus injection, continuous infusion also allows quantification of MBF and data acquisition without attenuation of any myocardial bed.

Animals↗
PubMed1998

Myocardial perfusion characteristics and hemodynamic profile of MRX-115, a venous echocardiographic contrast agent, during acute myocardial infarction.

We sought to determine whether MRX-115, a new venous echocardiographic contrast agent, could accurately assess risk area during coronary occlusion and infarct size after reperfusion by using novel imaging modalities meant to selectively enhance contrast signals. In 12 open-chest dogs, venous injections of 0.5 ml of MRX-115 were performed during baseline and coronary occlusion and after reperfusion in the presence of exogenous hyperemia. Ultrasound was transmitted at 2 MHz and received at both 2 MHz (fundamental) and 4 MHz (harmonic) frequencies during continuous and intermittent (end-systolic only) imaging. The risk area during coronary occlusion was compared with technetium autoradiography, and the infarct size after reperfusion was compared with postmortem tissue staining. MRX-115 produced no alterations in hemodynamic or pulmonary gas exchange at any stage. During continuous (both fundamental and harmonic) and intermittent fundamental imaging, measurements of perfusion defects were precluded in many dogs by either poor signal enhancement or posterior wall attenuation. By comparison, these measurements were possible during intermittent harmonic imaging in all dogs except one, which had a very small infarction during reflow. Correlation analysis between perfusion defect size on intermittent harmonic imaging and either autoradiographic risk area or postmortem infarct size gave r values of 0.83 and 0.92, respectively. We conclude that MRX-115 is hemodynamically well tolerated and, when imaging is performed after venous injection, can accurately assess regions of hypoperfusion when combined with intermittent harmonic imaging. These results are promising for the use of this approach in patients with acute myocardial infarction.

Animals↗
PubMed1998

Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis.

AIMS: Use of ticlopidine in coronary stenting is limited by delayed onset of action. We studied the effects of clopidogrel, a rapidly acting analog of ticlopidine alone, and in combination with aspirin, in inhibiting stent thrombosis. METHODS: Unpolished nitinol stents were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood at a shear rate of approximately 1500. s-1. Stent thrombus, platelet aggregation and bleeding times were measured at baseline and after treatment. RESULTS: Intravenous clopidogrel produced a rapid (within 30 min) and dose-dependent inhibition of stent thrombosis, with 87% reduction at a dose of 10 mg.kg-1 (P < 0.001). Aspirin alone (10 mg.kg-1) was minimally effective (20% inhibition P > 0.05) in inhibiting stent thrombosis. Combined treatment with clopidogrel and aspirin produced 95-98% inhibition of stent thrombosis, even at low doses of clopidogrel (2.5-5.0 mg.kg-1) (P < 0.0001). At effective doses both clopidogrel and combined therapy produced significant prolongation of bleeding time (P < 0.05) and inhibition of platelet aggregation (P < 0.05). CONCLUSION: Clopidogrel, either alone or combined with aspirin, may have a potential role in preventing stent thrombosis in high-risk clinical situations.

Animals↗
PubMed1998

Effect of food on the bioavailability of stavudine in subjects with human immunodeficiency virus infection.

A randomized, three-way crossover study was carried out to determine the effects of food ingestion on the pharmacokinetics of stavudine (d4T). Fifteen subjects with human immunodeficiency virus (HIV) infection and CD4(+) cell counts of >/=200/microliter received 70 mg of d4T in a fasting state or 1 h before or 5 min after a standardized high-fat breakfast. A 7- to 15-day washout period was included between treatments. Blood and urine were collected before and for 10 h after dosing, and plasma and urine d4T concentrations were determined with a validated radioimmunoassay. Plasma drug concentration-time data were analyzed with a noncompartmental model. The mean maximum plasma drug concentration (Cmax) and the time to Cmax (Tmax) for administration of d4T after a meal were significantly lower and longer (P = 0.0001 for both measures) than those observed in the fasting state, although the area under the concentration-time curve from time zero to infinity (AUC0-infinity) was not significantly different. Neither of these parameters was significantly altered when d4T was taken 1 h before a meal. The bioavailability of d4T taken after a meal was 95% of that observed in the fasting state, and it was 97% when d4T was administered before a meal (P > 0.05 for both comparisons with the fasting state). The results of this study indicate that (i) ingestion of food does not affect the bioavailability of d4T and that patients with HIV infection can take it without regard to meals, and (ii) absorption is essentially complete within 1 h when d4T is administered in the fasted state.

Adolescent↗
PubMed1998

Therapeutic Concentrations of Heparin Augment Platelet Activation at the Time of Coronary Angiography.

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess the platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 +/- 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 +/- 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 +/- 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 +/- 86 seconds (8 +/- 9 v -1 +/- 4% change in resulting PLTs, P =.01, and 11 +/- 12 v 1 +/- 6% increase in adenosine diphosphate (ADP) [5 µM]-stimulated PLTs, P =.02). Heparin produced a slight increase in PA in group 1 patients (1.4 +/- 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 +/- 5.3 ohms, P.05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients (r = -.5, P =.05, -ADP; r = -.65, P =.006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients (r = -0.4, P =.2, -ADP; r =.11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (<0.7 U/mL). These findings may have implications for optimal dosing strategy for heparin as an antithrombotic agent in clinical situations characterized by platelet-dependent thrombotic events.

Journal Article↗