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Biomedical subjects

R Kernoff

Publications and source records attributed to R Kernoff.

17 recordsLinked to original sources
PubMed2000

Purified hematopoietic stem cell grafts induce tolerance to alloantigens and can mediate positive and negative T cell selection.

Engraftment of allogeneic bone marrow (BM) has been shown to induce tolerance to organs genotypically matched with the BM donor. Immune reconstitution after BM transplantation therefore involves re-establishment of a T cell pool tolerant to antigens present on both donor and host tissues. However, how hematopoietic grafts exert their influence over the regenerating immune system is not completely understood. Prior studies suggest that education of the newly arising T cell pool involves distinct contributions from donor and host stromal elements. Specifically, negative selection is thought to be mediated primarily by donor BM-derived antigen-presenting cells, whereas positive selection is dictated by radio-resistant host-derived thymic stromal cells. In this report we studied the effect of highly purified allogeneic hematopoietic stem cells (HSCs) on organ transplantation tolerance induction and immune reconstitution. In contrast to engraftment of BM that results in near-complete donor T cell chimerism, HSC engraftment results in mixed T cell chimerism. Nonetheless we observed that HSC grafts induce tolerance to donor-matched neonatal heart grafts, and one way the HSC grafts alter host immune responses is via deletion of newly arising donor as well as radiation-resistant host T cells. Furthermore, using an in vivo assay of graft rejection to study positive selection we made the unexpected observation that T cells in chimeric mice rejected grafts only in the context of the donor MHC type. These latter findings conflict with the conventionally held view that radio-resistant host elements primarily dictate positive selection.

Animals↗
PubMed1998

Microwave catheter ablation using a clinical prototype system with a lateral firing antenna design.

Microwave has been considered a potentially more effective and more versatile form of energy than radiofrequency. Its feasibility has been tested using various prototype systems and catheter designs. This study assessed the safety and efficacy of a clinically-suitable prototype microwave power supply and catheter system with a lateral-firing antenna design for atrioventricular (AV) junction ablation in canines and to correlate with tissue histopathology. The system consisted of a deflectable catheter with a 6-mm antenna and a thermocouple; and a 2.45-GHz frequency generator with power, time, and temperature controls. AV junction ablations were performed using 75 W energy for up to 60 seconds. Effective heating was confirmed by a rise in catheter temperature to 69.3 +/- 8.8 degrees C. Complete AV nodal block was accomplished in all canines after an average of 4.1 +/- 2.8 applications at 66.8 +/- 7.7 degrees C, and persisted after 28 days in all chronic animals. Lesions were consistent with thermal necrosis, were hemispherical to semi linear in shape and have distinct borders. Acute lesions were 3.4 +/- 1.5 mm wide, 4.8 +/- 2.1 long, and 2.0 +/- 0.9 deep. Chronic lesions showed typical healing and were smaller in size. Ablations did not cause any transvalvular, vascular or other cardiac structural damage, and no coagulum formation was noted on the antenna or catheter tip. Microwave AV junction ablation using this clinical prototype system specifically designed for it was safe and effective. Lesion's depth was limited to 5 mm with 60-second heating while its shape corresponded to the antenna's length. Microwave energy may provide greater versatility for producing discrete or linear ablation.

Animals↗
PubMed1997

Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts.

We have recently shown that ex vivo gene therapy of rabbit autologous vein grafts with antisense oligodeoxynucleotides (AS ODN) blocking cell cycle regulatory gene expression inhibits not only neointimal hyperplasia, but also diet-induced, accelerated graft atherosclerosis. We observed that these grafts remained free of macrophage invasion and foam cell deposition. Since endothelial dysfunction plays an important role in vascular disease, the current study examined the effect of this genetic engineering strategy on graft endothelial function and its potential relationship to the engineered vessels' resistance to atherosclerosis. Rabbit vein grafts transfected with AS ODN against proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (cdc2) kinase elaborated significantly more nitric oxide and exhibited greater vasorelaxation to both calcium ionophore and acetylcholine than did untreated or control ODN-treated grafts. This preservation of endothelial function was associated with a reduction in superoxide radical generation, vascular cell adhesion molecule-1 (VCAM-1) expression, and monocyte binding activity in grafts in both normal and hypercholesterolemic rabbits. Our data demonstrate that AS ODN arrest of vascular cell cycle progression results in the preservation of normal endothelial phenotype and function, thereby influencing the biology of the vessel wall towards a reduction of its susceptibility to occlusive disease.

Animals↗
PubMed1997

Percutaneous method of laser transmyocardial revascularization.

Laser transmyocardial revascularization (TMR) creates conduits from the left ventricular cavity into the myocardium and has been forwarded as a potential method of perfusing ischemic myocardium. The procedure typically employs a CO2 laser to produce transmyocardial channels from the epicardial to the endocardial surface via an open thoracotomy. Preliminary studies in animals and human subjects have yielded promising results, and clinical trials evaluating the long-term efficacy of the procedure are in progress. We now report the use of a percutaneous method of TMR using a laser delivered through a novel catheter system. To assess the feasibility of performing percutaneous TMR, studies were performed on 15 adult canine subjects utilizing a holmium:YAG laser. Via a femoral artery approach, novel laser catheters were introduced into the left ventricular cavity under fluoroscopic guidance. Biplane coronary angiography, ventriculography, and transesophageal echocardiography were employed to direct catheters to specific regions and assess the efficacy of creating transmyocardial channels. Multiple channels could be created in the anterior, lateral, inferoposterior, and septal regions as demonstrated by contrast ventriculography with confirmation by subsequent gross and histologic examination. The procedure was tolerated well without any ventricular dysfunction or sustained ventricular arrhythmias. We have demonstrated that laser transmyocardial revascularization via a percutaneous approach is feasible with creation of channels from the endocardial surface of the left ventricle into the myocardium. On gross and histological examination, these channels are similar in appearance to those created by the currently employed open chest, epicardial method of TMR.

Angioplasty, Balloon, Laser-Assisted↗
PubMed1996

In vitro and in vivo results of transcatheter microwave ablation using forward-firing tip antenna design.

This study was designed to test a microwave (MW) ablation system using approximately 2,450 MHz of energy and a deflectable catheter with forward-firing tip antenna, an early clinical prototype system. In vitro three-dimensional thermal mapping of single and double helix antenna designs was performed. Quantitative measurements of antenna radiation were recorded on tissue phantoms equipped with temperature sensors distributed radially and outwardly. In vivo testing consisted of closed-chest AV junction ablation in three dogs. Thermal mapping showed hemispherical heat distribution from the tip antenna. For the double helix design, this distribution was measured at 8.4-mm diameter with a maximum temperature of 61.62 degrees C. As expected, the single helix design produced less heating with a measured diameter of 6.4 mm and maximum temperature of 55.90 degrees C. The in vivo study produced lesions of geometry and size concordant with these heating patterns. MW ablation produced bundle branch block in one dog and complete AV nodal block in the remaining two, without transvalvular or other structural damage. The histopathology of the lesions was typical of a thermal burn showing hemorrhage and coagulative necrosis with clearly demarcated borders. We conclude that, using this early clinical prototype system with a deflectable catheter and a forward-firing tip antenna design, MW heating can produce a moderate-size lesion and is safe and effective for cardiac ablation.

Animals↗
PubMed1996

Does sequential balloon injury of an artery lead to a different outcome than a single injury? An experimental study of angioplasty.

BACKGROUND: Mechanisms of stenosis after angioplasty are often studied in experimental models created by injury of normal arteries. Sequential rather than single insult may provide the better model. We compared the response of arteries to these two types of injury. METHODS: Two groups of arteries of cholesterol-fed New Zealand white rabbits were compared: single balloon injury arteries and two sequential balloon injury arteries (14-day interval between injuries). At 1-49 days after the first injury lumen dimensions and number of cells and cell proliferation in the media and neointima were assessed. RESULTS: Single injury resulted in cell proliferation in the artery wall, formation of neointimal, and progressive loss of lumen diameter. In sequentially injured arteries, the second injury caused an immediate increase in angiographic lumen diameter from 1.6 +/- 0.1 mm to 2.0 +/- 0.1 mm but the lumen decreased to 1.3 +/- 0.3 mm by 28 days after the second injury, consistent with restenosis. At late time points after injury the lumen diameter was similar in the two groups of arteries. The sequential lesion neointimal area increased at the same rate as the primary lesion neointimal. The second of the sequential injuries stimulated cell proliferation activity in the vessel wall that was similar in magnitude to that seen after primary injury. CONCLUSIONS: These findings suggest that the primary injury process initiated mechanisms that determine the rate of neointimal area formation and lumen dimensions over the 5-6 week time interval studied here. The second of the sequential injuries initiated a cell proliferation response in the artery wall but did not alter the neointimal area or lumen caliber consequences of primary injury.

Angiography↗
PubMed1994

Cell proliferation after balloon injury of iliac arteries in the cholesterol-fed New Zealand White rabbit.

Acute mechanical injury of an artery results in neointimal hyperplasia that is due at least in part to cell proliferation within the vessel wall. The purpose of this study was to quantify cell proliferation activity in the iliac artery of New Zealand White rabbits after balloon injury and cholesterol feeding. Retrograde pullback balloon injury of iliac arteries was performed, and the animals were then fed a 2% cholesterol diet. At intervals from day 1 through day 35 postinjury, iliac arteries were obtained for histological analysis. Intimal and medial areas were measured morphometrically. Total number of cells within the intima and media was counted. Smooth muscle cell-predominant or macrophage-predominant regions of the intima and media were identified using HHF-35 and RAM-11 immunocytochemical markers, respectively. Number of cells in the proliferative phase of the cell cycle was measured by using the proliferating cell nuclear antigen and bromodeoxyuridine techniques. Thirty-one arteries from 16 rabbits were available for analysis. Total number of cells and number of cells per square millimeter within the media did not change significantly from day 1 through day 35 postinjury. Total number of cells within the intima increased significantly, but the number of cells per square millimeter of intima decreased significantly during the same time period. Proliferative activity was identified in the media between days 3 and 35 with peak activity at day 3 postinjury. Proliferative activity in the intima was present in all specimens from day 8 through day 35. Proliferative activity was present in both HHF-35- and RAM-11-predominant regions of the intima.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed1993

Local infusion balloon angioplasty to obviate restenosis compared with conventional balloon angioplasty in an experimental model of atherosclerosis.

Balloon angioplasty is an accepted treatment for arterial obstruction; however, a substantial percentage of initially successfully treated lesions recur in the first 4 to 6 months. There is increasing interest in local treatment of lesions undergoing angioplasty to prevent restenosis, and an infusion catheter has been developed for this purpose. This study compared infusion balloon angioplasty by means of saline solution with conventional balloon angioplasty in atherosclerotic iliac arteries of 18 cholesterol-fed New Zealand white rabbits. Values for minimum stenosis diameter assessed angiographically immediately after maximum infusion balloon angioplasty (2.1 +/- 0.6 mm) and after conventional balloon angioplasty (2.3 +/- 0.3 mm, p = NS) were similar. In follow-up studies up to 5 weeks after angioplasty, the angiographic minimum stenosis diameter remained similar in the two treatment groups, but the histologically assessed intimal area was greater after infusion angioplasty (1.54 +/- 0.92 mm vs 1.02 +/- 0.75 mm in conventionally treated arteries, p = 0.0001). Infusion balloon angioplasty merits further evaluation as a treatment strategy for the simultaneous dilatation of atherosclerotic lesions with delivery of therapeutic agents to minimize restenosis.

Animals↗
PubMed1992

Time course and cellular characteristics of the iliac artery response to acute balloon injury. An angiographic, morphometric, and immunocytochemical analysis in the cholesterol-fed New Zealand white rabbit.

Evaluation of the response of the arterial vessel wall to acute arterial injury in experimental models has taken on substantial importance because of an increasing interest in angioplasty treatment of human atherosclerotic lesions. In this study, the response of normal arterial vessels to acute balloon injury was studied in 45 iliac artery segments from 24 New Zealand White rabbits fed a 2% cholesterol diet. At specified time points between 1 and 41 days after the initial balloon pullback injury, the iliac arteries were analyzed by angiographic, morphometric, and immunocytochemical techniques. Angiographic measurements indicated progressive compromise of the iliac artery lumen with increasing duration of time from injury. Morphometric measurements showed that intimal area increased from 0.004 +/- 0.01 mm2 3 days after injury to 1.15 +/- 0.30 mm2 34-41 days after injury. Cell line-specific immunocytochemical analysis identified the macrophage as a prominent component of the earliest intimal cellular infiltrate. Smooth muscle cells appeared within the intima 7-9 days after injury. As the intima increased in area, macrophages predominated along the internal elastic lamina aspect of the intimal lesion while smooth muscle cells occupied the portion of the intima adjacent to the lumen. In summary, retrograde balloon pullback injury followed by cholesterol feeding results in progressive arterial luminal narrowing due to a progressively enlarging intimal cellular infiltrate. The temporal and spatial contributions of smooth muscle cell and macrophage components of the developing intimal cellular infiltrate have been characterized.

Actins↗
PubMed1985

A new method for assessing right-sided heart pressures using encapsulated microbubbles--a preliminary report.

A new noncatheter method for measuring pressures of the right side of the heart uses specially manufactured microbubbles of carbon dioxide injected into the peripheral venous system. Sudden expansion of these bubbles in the cardiac chambers causes bubble oscillations at a frequency that is primarily a function of surrounding pressure. The oscillations are recordable by a microphone on the chest wall. The preliminary experience has been in dogs and further development is needed before we can begin clinical testing of the method. In its current form, the potential for measuring higher systolic pressures seems better than that for lower diastolic pressures.

Animals↗
PubMed1980

Non-invasive quantification of experimental canine myocardial infarct size using two-dimensional echocardiography.

In order to study whether wall motion abnormalities detected by two-dimensional (2D) echocardiography can be quantified and correlated with infarct size, we compared wall motion abnormalities viewed by 2D echocardiography in experimental canine infarction with post-mortem infarct size. Nineteen mongrel dogs underwent left anterior descending coronary artery snare occlusion. They were sacrificed 6 h later. Infarct sizing was done by technetium 99-m stannous pyrophosphate scintigraphy of the excised, sliced left ventricles. Fourteen dogs had both 2D echo wall motion abnormalities and infarctions. Four dogs failed to develop infarction and had no or minimal wall motion abnormalities. Inter-observer variation in 2D echocardiographic measurements was small. Wall motion abnormalities correlated with infarct size both in the 14-dog subgroup with infarction (r = 0.75, P less than 0.003) and all the 18 dogs that completed the protocol (r = 0.87, P less than 0.001). Thus, wall motion abnormalities in experimental canine myocardial infraction can be roughly quantified by 2D echocardiography and correlated with post-mortem infarct size measured by scintigraphy.

Animals↗
PubMed1979

Cardiac damage produced by direct current countershock applied to the heart.

This study examined the pathophysiology of the myocaridal damage produced by direct current shock over a dose range of 10 to 90 watt-seconds, applied directly to the heart in 26 dosgs. The extent of injury produced was assessed with creatine kinase depletion and light and electron microscopy, and was correlated with in vivo imaging and tissue distributions of the isotopes technetium-99m pyrophosphate and thallium-201. Changes in intramyocardial temperature and regional myocardial blood flow were also measured. Uptake of technetium-99m pyrophosphate occurred exponentially with graded increases in shocks, and this agent was more sensitive than thallium-201 in detecting injury both on imaging and at tissue level. The threshold for significant injury was approximately 30 watt-seconds, and on electron microscopy a characteristic feature was marked dehiscence of the intercalated disks between the damaged myocytes. The use of different-size paddles did not appear to affect the total number of cells damaged. However, with large paddles the injury was more superficial and spread over a wider area. With short time intervals between successive shocks, a greater amount of injury occurred, in part because of a compounding of the thermal component of the damage. Hypothermia can reduce the degree of injury.

Animals↗
PubMed1976

Normal myocardial contractile state in the presence of quinidine.

Since quinidine is one of the few agents available to treat and prevent ventricular arrhythmias in ambulatory patients, its hemodynamic effects have been reevaluated. When given in therapeutic doses to anesthetized mongrel dogs, quinidine significantly reduced heart rate, aortic pressure and flow, but it did not significantly change the first derivative of the left ventricular pressure curve (left ventricular dp/dt) in nine dogs. A subsequent group of dogs was studied after vagotomy and practolol administration to block cardiac reflexes. This group showed significant reductions in heart rate, aortic pressure and left ventricular dp/dt, with the latter returning to predrug control values when preload, afterload and heart rate were maintained constant. These studies suggest that quinidine does not directly affect myocardial contractility when given in therapeutic doses. Furthermore, the reduction in heart rate in these animals provides support for a direct depressant effect of quinidine on the sinus node. The adverse effects of quinidine on cardiac function previously reported may be due to the use of toxic doses or are secondary to quinidine peripheral circulatory effects, rather than due to a direct reduction in cardiac contractile state.

Animals↗
PubMed1976

Age-related changes in ouabain pharmacology. Ouabain exhibits a different volume of distribution in adult and young dogs.

To better understand why one must administer much higher doeses of digitalis glycosides to immature than to mature humans and animals, we studied ouabain pharmacokinetics in adult and young dogs. Consistent with reported observations that ouabain-binding, metabolism, and excretion do not change with age, we found no significant differences in the transfer coefficients in a linear two-compartment open model for ouabain pharmacokinetics following a bolus of 0.05 mg/kg. We did find, however, that young dogs had nearly twice the ouabain volumes of distribution per kilogram of body weight as adults (155.4 +/- 1.2 (SE) ml/kg vs. 80 +/- 0.6, P less than 0.0005) and that one could account for this difference with the fact that young dogs had nearly twice the plasma volume 108 +/- 9.8, vs. 68 +/- 7.3, P = 0.001) and interstitial fluid space (318 +/- 35 vs. 190 +/- 6.5, P = 0.006) as the adults. For the same dose per kilogram, left and right ventricular ouabain concentrations were inversely related to the volume of distribution, with the adults having significantly higher tissue levels and incidence of arrhythmias. One must give more ouabain to a young dog to get the same plasma concentration as in an adult because the mass of ouabain in rapid equilibrium with the plasma is diluted in a larger volume of distribution.

Aging↗
PubMed1976

Problems in assessing infarction size by epicardial mapping: preliminary studies with quinidine.

Some of the laboratory difficulties in assessing infarction size produced by intermittent coronary artery occlusion were demonstrated by using an epicardial mapping technique in anesthetized open-chest dogs. Intermittent occlusion of a left anterior descending coronary artery branch resulted in a marked elevation of the ST segment above the baseline in the areas of the myocardium supplied by this vessel. Repeated occlusions after administration of normal saline as a control produced less ST-segment elevation thn that noted during control occlusions; however, repeated occlusions after infusion of quinidine produced a further lessening in ST-segment elevation. The problems encountered in interpreting these results are emphasized. Long-term coronary occlusion studies were performed in order to correlate epicardial electrograms with histological findings of ischemia or myocardial necrosis. Our investigations show that epicardial mapping tended to underestimate the area of injury, and this limits the interpretation of drug intervention studies such as those in which quinidine is administered. Therefore, caution should be exerted when using epicardial mapping techniques to assess the effect of various pharmacological interventions on infarction size in open-chest dogs.

Animals↗
PubMedDate not supplied

Effects of equipotent blocking doses of acebutolol, acebutolol's primary metabolite, and propranolol on left ventricular hemodynamics in conscious awake dogs.

In six conscious dogs we compared the hemodynamic effects of propranolol, acebutolol, and acebutolol's primary metabolite at equipotent beta-blocking doses. Aortic pressure, heart rate, left ventricular end-diastolic pressure, dP/dt, and aortic flow velocity were measured 3 weeks after sterile surgery during three infusions of each drug. Only one drug was given on each day. The equipotent beta-blocking dose of each drug was obtained by comparing isoproterenol dose-response curves. All three drugs produced a fall in dP/dt. Left ventricular end-diastolic pressure increased in most dogs, but this was only significant for acebutolol. The heart rate tended to fall and the blood pressure rise, but this was variable and not significant. The concentration of the equipotent blocking dose of acebutolol was 44 times that of propranolol, and while the concentration of acebutolol's metabolite was 1.6 times that of acebutolol. In conclusion, at a concentration similar to acebutolol, acebutolol's metabolite has heart rate blocking and myocardial depressive effects similar to those of propranolol and acebutolol.

Acebutolol↗