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Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Caveolin-1 is a protein constituent of cell membranes. The caveolin-1 scaffolding region (residues 82-101) is a known inhibitor of protein kinase C. Inhibition of protein kinase C results in maintained nitric oxide (NO) release from the endothelium, which attenuates cardiac dysfunction after ischemia-reperfusion (I/R). Therefore, we hypothesized that the caveolin-1 scaffolding region of the molecule, termed caveolin-1 peptide, might attenuate postischemia polymorphonuclear neutrophil (PMN)-induced cardiac dysfunction. We examined the effects of caveolin-1 peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. Caveolin-1 peptide (165 or 330 µg) given intravenously 1 h before I/R significantly attenuated postischemic PMN-induced cardiac dysfunction, as exemplified by left ventricular developed pressure (LVDP) (P < 0.01) and the maximal rate of develped pressure (+dP/dtmax) (P < 0.01), compared with I/R hearts obtained from rats given 0.9% NaCl. In addition, caveolin-1 peptide significantly reduced cardiac PMN infiltration from 195 ± 5 PMNs/mm2 in untreated hearts to 103 ± 5 and 60 ± 5 PMNs/mm2 in hearts from 165 and 330 µg caveolin-1 peptide-treated rats, respectively (P < 0.01). PMN adherence to the rat coronary vasculature was also significantly reduced in rats given either 165 or 330 µg caveolin-1 peptide compared with rats given 0.9% NaCl (P < 0.01). Moreover, caveolin-1 peptide-treated rat aortas exhibited a 2.2-fold greater basal release of NO than vehicle-treated aortas (P < 0.01), and this was inhibited by NG-nitro-L-arginine methyl ester. These results provide evidence that caveolin-1 peptide significantly attenuated PMN-induced post-I/R cardiac contractile dysfunction in the isolated perfused rat heart, probably via enhanced release of endothelium-derived NO.
contractile dysfunction; polymorphonuclear leukocytes; polymorphonuclear neutrophil adherence
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MYOCARDIAL ISCHEMIA followed by reperfusion results in marked cardiac contractile dysfunction (4, 27, 28). The sequential events that produce this cardiac dysfunction are a very early reduction in nitric oxide (NO) release, followed by upregulation of adhesion molecules on the endothelial surface (e.g., P-selectin), leading to enhanced polymorphonuclear neutrophil (PMN) adherence to the endothelium. These events result in a marked infiltration of PMNs into the myocardium, contributing to cardiac dysfunction and enhanced myocardial necrosis (4, 27, 28). The time course of these events starts 2.5-5 min after the onset of reperfusion with reduced NO release, and PMNs begin to adhere to the coronary vasculature and infiltrate into cardiac tissue at 20 min after the onset of reperfusion (12, 28). PMNs contribute to endothelial and myocardial cell injury by releasing cytotoxic substances such as oxygen-derived free radicals, inflammatory cytokines, and proteolytic enzymes (1, 29). Oxygen free radicals can quench endogenous NO released from the endothelium and promote upregulation of endothelial cell adhesion molecules (2, 6, 22). Thus maintenance of basal NO release from the coronary endothelium minimizes PMN adherence to the coronary endothelium and preserves cardiac contractile function in ischemia-reperfusion (I/R) injury (5, 12, 30). Previous studies (20, 25) have shown that inhibition of superoxide release from the coronary endothelium also attenuates endothelial and cardiac contractile dysfunction. These findings suggest that compounds that either inhibit superoxide release or quench superoxide radicals may enhance NO production from the endothelium after I/R and exert cardioprotective effects in reperfusion injury (24, 25, 33).
Caveolae are invaginations within the plasma membrane of several cell types including endothelial cells, neurons, and cardiac myocytes. Caveolae consist of coat proteins, called caveolins, in close proximity to other proteins such as protein kinase C (PKC), endothelial NO synthase (eNOS), G proteins, and inositol trisphosphate receptors (3, 13, 21). Caveolins are a 21- to 24-kDa family of membrane proteins that consist of three members (i.e., caveolin-1, -2, and -3) (3, 21). Caveolin-1 is abundantly expressed in endothelial cells, and caveolin-3 is primarily expressed in muscle cells (3, 21). The NH2-domain (i.e., residues 1-101) contains a scaffolding region (i.e., residues 82-101) (9, 21) that interacts with other proteins such as PKC and eNOS via a discrete binding motif on each of these proteins (3, 13, 19, 26). Inhibition of PKC in endothelial cells results in inhibition of superoxide release (15, 33). In addition, PKC also inhibits eNOS, thereby attenuating NO release from endothelial cells (8). Therefore, substances that inhibit PKC, such as caveolin-1, tend to inhibit superoxide generation and augment NO release from endothelial cells. Enhanced NO release coupled with inhibition of superoxide release from the endothelium attenuate endothelial dysfunction and hence retard PMN infiltration into cardiac tissue, thereby preventing PMN-induced cardiac contractile dysfunction after I/R (10, 12, 20).
The major purpose of the present study was to examine the effect of systemic administration of caveolin-1 peptide on cardiac contractile function in the isolated perfused rat heart after PMN-induced I/R injury and to ascertain the mechanisms of any such effect. To this end, we assessed 1) the number of PMNs adhering to the coronary vasculature and infiltrating into the cardiac tissue and 2) the NO release from the rat aortic endothelium. These studies thus enabled us to determine that caveolin-1 peptide is able to modulate endothelial NO release and PMN adherence to the endothelium in a manner that could significantly account for its cardioprotective effect.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolated Rat Heart Preparation
Male Sprague-Dawley rats (275-325 g) were anesthetized with 60 mg/kg pentobarbital sodium injected intraperitoneally. Sodium heparin (1,000 units) was also administered intraperitoneally. Hearts were rapidly excised, the ascending aortas were cannulated, and retrograde perfusion of the heart was initiated with a modified Krebs-Henseleit (K-H) buffer maintained at 37°C at a constant pressure of 80 mmHg. The K-H buffer had the following composition (in mmol/l): 17 dextrose, 120 NaCl, 25 NaHCO3, 2.5 CaCl2, 0.5 EDTA, 5.9 KCl, and 1.2 MgCl2. The perfusate was aerated with 95% O2-5% CO2 and equilibrated at a pH of 7.3-7.4. Two side arms in the perfusion line proximal to the heart inflow cannula allowed for infusion of PMNs and plasma directly into the coronary inflow line. Coronary flow was monitored by a flowmeter (model T106, Transonic Systems). Left ventricular developed pressure (LVDP) and the maximal rate of developed pressure (+dP/dtmax) were monitored using a pressure transducer (model SPR-524, 2.5-Fr, Millar Instruments), which was positioned in the left ventricular cavity. Coronary flow, LVDP, and +dP/dtmax were recorded using a MacLab data acquisition system (ADI Diagnostics) in conjunction with a Power Macintosh 7600 computer (Apple Computers). LVDP, +dP/dtmax, and coronary flow were measured every 5 min for 15 min to equilibrate the hearts and obtain a baseline measurement. LVDP was defined as left ventricular end-systolic pressure minus left ventricular end-diastolic pressure. After 15 min, the flow of K-H buffer was reduced to zero to induce global ischemia for 20 min. After ischemia, hearts were perfused for 5 min with 200 × 106 PMNs resuspended in 5 ml of K-H buffer plus 5 ml of plasma at a rate of 1 ml/min.Groups of Isolated Perfused Hearts
The following groups of isolated perfused rat hearts were used.Group 1: sham I/R. Hearts not subjected to ischemia and not perfused with PMNs (n = 6).
Group 2: sham I/R + caveolin-1 peptide. Hearts treated with caveolin-1 peptide (330 µg) not subjected to ischemia and not perfused with PMNs (n = 6).
Group 3: I/R. Hearts subjected to ischemia but reperfused without PMNs (n = 6).
Group 4: I/R + caveolin-1 peptide. Hearts treated with caveolin-1 peptide (330 µg) and subjected to ischemia but reperfused without PMNs (n = 6).
Group 5: I/R + PMNs. Hearts subjected to ischemia and reperfused with PMNs (n = 7).
Group 6: I/R + PMNs + caveolin-1 peptide (165 µg). Hearts treated with caveolin-1 peptide (165 µg) and subjected to ischemia and reperfused with PMNs (n = 7).
Group 7: I/R + PMNs + caveolin-1 peptide (330 µg). Hearts treated with caveolin-1 peptide (330 µg) and subjected to ischemia and reperfused with PMNs (n = 6).
Group 8: I/R + PMNs + caveolin-1 peptide (330 µg) + L-NAME. Hearts treated with caveolin-1 peptide (330 µg) and subjected to ischemia and reperfused with PMNs and NG-nitro-L-arginine methyl ester (L-NAME; 50 µM) (n = 5).
Previous studies have shown that sham I/R hearts given PMNs exhibited no changes from initial control values (11). Data were recorded every 5 min for the first 30 min after reperfusion and at the 45-min time point. Rats were anesthetized with ethyl ether and then given either caveolin-1 peptide (165 µg, approximating 2.5 µM in the blood, or 330 µg, approximating 5 µM in the blood) or 0.9% NaCl intravenously 1 h before the experiments. Caveolin-1 peptide (molecular weight = 2,518; amino acid residues 82-101, Genemed Synthesis) was prepared in 0.9% NaCl, pipetted into 0.5-ml aliquots, and stored at
20°C. Aliquots were thawed once just before intraveous injection. In an additional series, 50 µM
L-NAME (Sigma), a NO synthase inhibitor, was added to the
perfusate at the start of reperfusion of five I/R hearts perfused with
PMNs given caveolin-1 peptide (330 µg). After each experiment (i.e., at 45 min of reperfusion or the equivalent time in control hearts), hearts were placed in 4% paraformaldehyde and stored at 4°C for later histological analysis.
Isolation of Plasma
Blood was collected from the aorta in citrate phosphate buffer (Sigma) over a period of 1 min just before isolation of the rat heart. The blood was centrifuged at 10,000 g for 10 min. Thereafter, the plasma was decanted and used for infusion to I/R hearts. Five milliliters of plasma collected from a single rat were used for each perfused heart.Isolation of PMNs
Sprague-Dawley rats (350-400 g) were anesthetized with ethyl ether and given glycogen intraperitoneally (14 ml of 0.5% glycogen dissolved in PBS). Sixteen to eighteen hours later, the rats were anesthetized with ethyl ether, and the neutrophils were harvested from these donor rats by peritoneal lavage in 30 ml of 0.9% NaCl as previously described (17). The peritoneal lavage fluid was centrifuged at 250 g for 20 min at 4°C. The PMNs were then washed in 15 ml of PBS. Thereafter, the PMNs were resuspended in 2.5 ml of PBS, and a total of 10-12 samples was pooled before use in cardiac perfusion experiments. The neutrophil preparations were >90% pure and >95% viable according to microscopic analysis and exclusion of 0.3% trypan blue, respectively.Determination of PMN Infiltration of Cardiac Tissue
Three rat hearts from each of the eight experimental groups were used for histological analysis. Ten areas of each rat heart were counted for PMN infiltration. Hearts were dehydrated in graded ice-cold acetone washes (50-100%). The heart tissue was then embedded in plastic and sectioned into 4-µm serial sections and placed onto glass slides. Sections were then placed in 100% ethanol for 5 min to remove the plastic and rehydrated in tap water for 1 min. Thereafter, hematoxylin was applied to the sections for 7 min, and the sections were rinsed in running tap water for 30 s. Eosin stain was then applied to the sections for 2 min, followed by a second running tap water rinse for 30 s. The number of infiltrated PMNs was counted by light microscopy. We also counted intravascular PMNs that adhered to the vascular endothelium in cardiac tissue to determine the effect of caveolin-1 on PMN adherence to the coronary vascular endothelium. These results are expressed as intravascular and infiltrated PMNs per millimeter square area of cardiac tissue.Measurement of NO Release from Rat Aortic Segments
Rats were given either 330 µg of caveolin-1 peptide intravenously in the systemic circulation or an equal volume of 0.9% NaCl, as described above. One hour later, the aortas were isolated after pentobarbital sodium anesthesia, and the excised aortas were immersed in warm oxygenated K-H solution. Aortas were cleaned of adherent fat and connective tissue, and rings 6-7 mm in length (i.e., ~5-7 mg of tissue) were carefully prepared. Aortic rings were cut, opened, and fixed by small pins, with the endothelial surface facing up, in 24-well culture dishes containing 1 ml of K-H solution. After equilibration at 37°C, NO released into the K-H solution was measured. NO was measured according to the method of Guo et al. (7) using a calibrated NO meter (Iso-NO; World Precision Instruments; Sarasota, FL) connected to a polarographic internally shielded NO electrode. NO released into the medium was reported as picomoles per milligram of aortic tissue. After the basal NO release was determined, 200 µM L-NAME was added to the K-H bathing solution, and basal NO release was reassessed 30 min later.Statistical Analysis
All data are presented as means ± SE. The data for LVDP and +dP/dtmax were analyzed by ANOVA using post hoc analysis with the Scheffé's test. Probability values of <0.05 were considered to be statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To determine whether systemic administration of caveolin-1 peptide
exerted direct effects on cardiac contractile function in acute
myocardial I/R, we perfused nonischemic control rat hearts isolated from rats that received 330 µg caveolin-1 peptide 1 h before constant pressure perfusion for 80 min at 80 mmHg. Perfusion of
caveolin-1 peptide-treated sham I/R hearts without PMNs did not result
in any significant change in LVDP (Fig.
1) or +dP/dtmax (Fig. 2) over the entire 80-min
observation period, indicating that caveolin-1 peptide did not exert
any direct effect on cardiac contractile function. Moreover, perfusion
of untreated I/R hearts without PMNs did not result in any significant
sustained attenuation in any of the cardiac function variables measured
at the end of the observation period, indicating that global
ischemia did not provoke a sustained cardiac dysfunction in
this model of I/R. LVDP did decrease to 50% of initial control at 15 min after the onset of reperfusion but by 45 min after the onset of
reperfusion had recovered to 88 ± 6% of initial control in I/R
hearts not given PMNs at reperfusion.
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However, I/R rat hearts perfused with PMNs experienced a marked and sustained reduction in cardiac contractile function compared with the first six groups. A decrease in LVDP and +dP/dtmax of >50% was observed at 45 min after the onset of reperfusion. In contrast, I/R rat hearts that received caveolin-1 peptide and were reperfused with PMNs exhibited a significant attenuation of cardiac contractile dysfunction (i.e., markedly higher LVDP and +dP/dtmax; Figs. 1 and 2). The 330-µg caveolin-1 peptide-treated group exhibited a significant improvement in final LVDP and +dP/dtmax compared with the I/R + PMN group (P < 0.01; Figs. 1 and 2). The 165 µg caveolin-1 peptide-treated group also exhibited a significant but less dramatic improvement in final LVDP compared with the I/R + PMN group (Figs. 1 and 2). However, the cardioprotective effects of caveolin-1 peptide (330 µg) were significantly blocked by L-NAME after the onset of reperfusion (Figs. 1 and 2).
The significant deficit in cardiac contractile performance in I/R
hearts we observed is closely correlated to the presence of infiltrated
PMNs after ischemia. We observed a 47 ± 5 and 69 ± 8% attenuation of PMN infiltration into postreperfused cardiac tissue
in the 165- and 330-µg caveolin-1 peptide-treated groups compared
with 0.9% NaCl-treated I/R + PMN rats (P < 0.01)
(Fig. 3A). A significant
reduction in PMN adherence (46 ± 7 and 70 ± 10%) was also
observed in the coronary vascular endothelium from 165- and 330-µg
caveolin-1 peptide-treated rat hearts, respectively, compared with
those isolated from untreated rats (P < 0.01) (Fig. 3B). The significant attenuation of PMN infiltration into
cardiac tissue and adherence to the coronary vascular endothelium in
caveolin-1 peptide-treated hearts was significantly blocked by
L-NAME (Fig. 3, A and B).
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Basal release of NO from caveolin-1 peptide-treated rat aortic segments
was significantly increased compared with control rat aortic segments
(P < 0.01) (Fig. 4).
Basal NO release was enhanced by more than twofold in
caveolin-1-treated aortic segments compared with control aortic
segments (26 ± 1 vs. 12 ± 1 pmol NO/mg aortic tissue) (Fig.
4). The addition of L-NAME totally inhibited NO release in
these rat aortic segments. These findings point toward a significant
NO-enhancing effect of caveolin-1 peptide on rat endothelium.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that the caveolin-1 peptide exerts
significant cardioprotective effects against PMN-mediated reperfusion
injury in the isolated perfused rat heart. These cardioprotective effects of the caveolin-1 peptide were characterized by a significant restoration of LVDP and +dP/dtmax compared with
PMN perfused I/R hearts obtained from rats receiving only 0.9% NaCl as
a vehicle. The cardioprotective effects of the caveolin-1 peptide are
most likely due to significantly reduced adherence of PMNs to the
vascular endothelium, thereby resulting in a significant reduction in
PMN infiltration into postischemic cardiac tissue (10,
12). Regarding the accessibility of the caveolin-1 peptide we
employed, we utilized a 20 amino acid portion of the caveolin-1 protein
(molecular weight = 2,518; residues 82-101). This small
peptide can be better understood to inhibit PKC in intact cells,
because it inhibits PKC activity in cell membrane caveolae
(19). A significant fraction of PKC-
is known to
colocalize with caveolin-1 within the caveolae of plasma membranes
(26). Therefore, it is not necessary for the caveolin-1
peptide to gain access to the cytoplasm to inhibit PKC. Moreover, the
caveolin-1 peptide may exert its antineutrophil and cardioprotective
effects by enhancing physiological amounts of NO production from the
vascular endothelium, because the cardioprotective effects of
caveolin-1 peptide-treated hearts were significantly blocked by
L-NAME (7, 12).
Physiological concentrations of NO are known to attenuate PMN adherence to the vascular endothelium (2, 10, 12), thus reducing PMN infiltration into cardiac tissue. In this regard, NO has been shown to be a physiological inhibitor of leukocyte-endothelial cell interaction by suppressing upregulation of endothelial cell adhesion molecules (e.g., P-selectin) (2, 10-12). In contrast, ischemia followed by reperfusion results in a release of reactive oxygen species, particularly superoxide (28), via activation of NADPH oxidase activity from endothelial cells (15, 33). In this setting, superoxide released from the endothelium and from PMNs adhered to the endothelium can quench endogenous NO release and potentiate endothelial dysfunction, leading to further increased PMN adherence and infiltration into the coronary vasculature and surrounding tissue resulting in aggravated cardiac contractile dysfunction (14, 22).
Recently, Oka et al. (19) has shown that the caveolin-1 peptide was able to dose dependently inhibit the classic and atypical PKC isozymes at concentrations of 1-10 µM. PKC inhibition results in enhanced NO release from the endothelium by at least two mechanisms. First, PKC downregulates eNOS activity, leading to reduced endothelium-derived NO production from endothelial cells (8, 23). Inhibition of PKC will therefore counteract this downregulation of eNOS and enhance NO release (8). Second, PKC is required for stimulating NADPH oxidase activity and thus enhances superoxide production in endothelial cells (15, 33). Inhibition of PKC therefore suppresses superoxide production from endothelial cells and minimizes the quenching of NO by superoxide radicals in these cells. The combination of superoxide inhibition and enhanced NO release in the coronary vasculature could account for the cardioprotective effect of caveolin-1 peptide in myocardial I/R in the presence of PMNs. Inhibition of PKC also inhibits P-selectin expression (18). P-selectin is rapidly upregulated (i.e., 10 min after the onset of reperfusion) (30) and promotes PMN adhesion to the vascular endothelium (12). It is highly unlikely that the caveolin-1 peptide exerts its cardioprotective effects by directly increasing cardiac contractility, because we observed no increases in LVDP or +dP/dtmax in nonischemic perfused rat hearts given caveolin-1 peptide.
In contrast to our results, other investigators (9, 16) have shown that endogenous caveolin-1 inhibits eNOS activity. The nature of the inhibition by caveolin-1 peptide on eNOS activity is reversible and antagonized by Ca2+-calmodulin (9, 16). When intracellular Ca2+ concentration rises via receptor stimulation, caveolin-1 binding to eNOS dissociates and can be replaced by calmodulin binding (16). Calmodulin binding to eNOS then stimulates NO release (16). It is possible that the caveolin-1 peptide did not have an appreciable degree of inhibition of eNOS when given intravascularly or that the effects of PKC inhibition were sufficient to compensate for the negative regulation of caveolin-1 on eNOS activity. Alternatively, Xia et al. (32) have shown that caveolin-1 peptide suppresses eNOS production of reactive oxygen species when L-arginine is not available as a substrate for NO synthesis, so that caveolin-1 peptide may shift the product profile of eNOS away from superoxide radicals toward NO production in I/R. Consistent with this possibility, acute infusion of L-arginine at reperfusion has been shown to attenuate reperfusion injury (31).
In summary, our results are the first to show a cardioprotective effect of caveolin-1 peptide in myocardial I/R injury. Caveolin-1 peptide was able to significantly attenuate cardiac contractile dysfunction in isolated perfused I/R rat hearts compared with similarly perfused hearts isolated from 0.9% NaCl-treated rats. These cardioprotective effects appear to be closely related to inhibition of PMN adherence to the vascular endothelium, resulting in fewer PMNs infiltrating the cardiac tissue. Caveolin-1 peptide also appears to stimulate endothelium-derived NO release, which significantly contributes to these effects via downregulation of leukocyte-endothelium interaction.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institute of General Medical Sciences Research Grant GM-45434. L. H. Young was supported by National Heart, Lung, and Blood Institute Training Grant HL-07599. Y. Ikeda is a Postdoctoral Fellow of the Japanese Society of Clinical Pharmacology and Therapeutics.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. M. Lefer, Dept. of Physiology, Jefferson Medical College, Thomas Jefferson Univ., 1020 Locust St., Philadelphia, PA 19107-6799 (E-mail: Allan.M.Lefer{at}mail.tju.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 October 2000; accepted in final form 23 January 2001.
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RESULTS
DISCUSSION
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