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CARDIOVASCULAR
Division of Cardiovascular Disease, Department of Medicine, University of Alabama, Birmingham, Alabama (P.W., S.G.L., J.C.C.); and Department of Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (H.F., J.J.M., L.B.)
Received for publication
October 13, 2006
Accepted
December 28, 2006.
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Abstract |
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7-fold with a concomitant increase in carbohydrate oxidation. At these same concentrations, although ranolazine significantly improved LV functional recovery following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine was not mediated by inhibition of fatty acid oxidation and conversely that inhibition of fatty acid oxidation with CVT-4325 was not associated with improved LV functional recovery.
), coronary heart disease still accounts for one in five deaths in the United States. During the past 30 years, numerous experimental interventions have been reported to limit ischemic injury in experimental animals; however, with the exception of timely reperfusion, none has translated into routine clinical practice (Bolli et al., 2004). Glucose-insulin-potassium therapy has yielded encouraging results (Fath-Ordoubadi and Beatt, 1997; Diaz et al., 1998; van der Horst et al., 2003; Bolli et al., 2004); however, despite its potential, glucose-insulin-potassium therapy has not been widely accepted. This is due, at least in part, to the complexity of the treatment regimen and the limitations associated with infusion of large volumes of fluid into patients with compromised cardiac function (van der Horst et al., 2003). An alternative approach that potentially avoids these complications is direct pharmacological modulation of cardiac fatty acid and carbohydrate metabolism (Stanley et al., 1997b). This has been the focus of many studies of putative fatty acid oxidation inhibitors, such as trimetazidine and ranolazine, for the treatment of ischemic disease (Fragasso et al., 2002; Chaitman et al., 2004a).
However, despite the considerable interest in metabolic modulation as a therapy for myocardial ischemia, there is little consensus regarding the mechanism(s) underlying its possible cardioprotective effects. Recently, we reported that, although increasing glucose and insulin levels improved left ventricular (LV) functional recovery following ischemia in the isolated perfused heart, this was not associated with a significant effect on glucose oxidation (Wang et al., 2005). In contrast, in the same study, stimulation of glucose oxidation with dichloroacetate did not improve LV functional recovery following ischemia. Furthermore, although there is substantial evidence that trimetazidine and ranolazine are protective against the deleterious effects of myocardial ischemia in experimental and clinical settings (Gralinski et al., 1994; Zacharowski et al., 2001; MacInnes et al., 2003; Belardinelli et al., 2006), the data supporting their effect to inhibit fatty acid oxidation are less clear. For example, Saeedi et al. (2005) demonstrated that although trimetazidine significantly improved LV functional recovery in hypertrophied hearts, it had no effect on either glucose or palmitate oxidation. Likewise, MacInnes et al. (2003) reported that trimetazidine did not inhibit 
-oxidation in cardiomyocytes, and although ranolazine did inhibit fatty acid oxidation, this was only by 12% at a concentration of 100 µM, which exceeds the human therapeutic range by 10-fold. More recent reports suggest that the protective effect of ranolazine could be mediated via alterations in Ca2+ homeostasis (Fraser et al., 2005, 2006; Belardinelli et al., 2006), thus providing an alternative mechanism of action.
The controversy regarding both the mechanism of action of ranolazine as well as the putative beneficial effects of inhibiting fatty acid oxidation may be attributed to several factors, including the use of different perfused heart models, such as isovolumic Langendorff perfused heart and ejecting "working" heart preparations; different types of ischemia, such as zero- versus low-flow ischemia; different exogenous fatty acid concentrations; and different methods for measuring substrate utilization. Furthermore, the effects of putative "partial fatty acid oxidation inhibitors" such as ranolazine have not been directly compared with the effects of more potent fatty acid oxidation inhibitors. Recently, we have developed a new potent fatty acid oxidation inhibitor, CVT-4325, which has an IC50 of 0.9 µM for inhibiting fatty acid oxidation in the presence of 1.2 mM palmitate (Fraser et al., 2003). Therefore, the goal of this study was to directly compare the metabolic effects of ranolazine with CVT-4325 in two different heart perfusion models and measure substrate utilization using both [13C]glutamate NMR isotopomer analysis and radioisotope techniques.
We found that, regardless of the perfusion technique, experimental conditions, and methods used to measure rates of substrate oxidation, ranolazine (10 µM) had no effect on glucose or fatty acid oxidation or glycolysis, whereas CVT-4325 (3 µM) reduced fatty acid oxidation by 7 fold with a concomitant increase in glucose oxidation. Furthermore, although ranolazine significantly improved recovery of LV function following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine cannot be attributed to inhibition of fatty acid oxidation. Moreover, these data also suggest that direct inhibition of fatty acid oxidation may not be an effective approach for improving functional recovery following ischemia/reperfusion.
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Materials and Methods |
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; Elzein et al., 2004). Both drugs were prepared as stock solutions of 10 and 3 mM, respectively, in DMSO. The resulting DMSO concentration in the perfusate was <0.1% and was the same for both drugs. In a series of normoxic perfusion experiments, this concentration of DMSO was found to have no adverse effects on function or metabolism. Animals. Animal experiments were approved either by the Institutional Animal Care and Use Committee at the University of Alabama at Birmingham or Institutional Animal Care and Use Committee of CV Therapeutics and followed the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, 1996). Male Sprague-Dawley rats (Charles River Laboratories, Inc., Wilmington, MA) weighing 300 to 350 g were used throughout.
Isovolumic Langendorff Heart Perfusion Experiments. Hearts were perfused at 37°C as described previously in isovolumic Langendorff mode (Wang et al., 2005) with a Krebs-Henseleit solution containing 5 mM glucose, 1.0 mM sodium lactate, 0.1 mM sodium pyruvate, 1.0 mM sodium palmitate, 3% bovine serum albumin, and 100 µU/ml insulin. Cardiac function was continuously recorded via a fluid-filled balloon placed into the LV, connected to a pressure transducer, and LV end diastolic pressure (EDP) was set to 5 mm Hg by adjusting balloon volume at the beginning of the experiments, and the balloon volume was subsequently left unchanged for the remainder of the experiment. To ensure consistency with previous studies using this model, hearts were paced at a constant rate of 320 beats/min throughout the experiment.
In all experiments, hearts were initially perfused in the absence of drug. After 30 min, hearts were randomly assigned to an untreated control group, a ranolazine (10 µM) group, or a CVT-4325 (3 µM) group, and drugs were present for the remainder of the experiments. Hearts were either perfused under aerobic conditions for 60 min or were subjected to low-flow ischemia (LFI; 0.3 ml/min) for 30 min followed by 60 min of reperfusion where flow was restored to achieve a perfusion pressure of 75 mm Hg as described previously (Wang et al., 2005).
In both the aerobic and LFI experiments, hearts were perfused with [U-13C]palmitate, [3-13C]lactate, and [2-13C]pyruvate for the final 30 to 45 min of the protocol, at which time hearts were freeze-clamped and acid-extracted and 13C NMR were spectra collected as described previously (Lloyd et al., 2004; Wang et al., 2005). 13C NMR isotopomer analyses of heart extracts as described previously in detail elsewhere (Lloyd et al., 2003; Wang et al., 2005) were performed to determine the relative contribution of substrates to total acetyl-CoA entering the tricarboxylic acid (TCA) cycle.
The concentration of ranolazine used here (i.e., 10 µM) reflects the upper end of the proposed therapeutic concentration range (Belardinelli et al., 2006). The concentration of CVT-4325 was chosen based on the results of preliminary experiments that showed that the maximal inhibition of palmitate oxidation under the conditions of these experiments was achieved at a concentration of 3 µM (Fraser et al., 2003). Additional studies showed that, at 3 µM, the predominant pharmacological activity of CVT-4325 in the presence of 1.2 mM palmitate was the inhibition of fatty acid oxidation (IC50 = 0.9 µM) and stimulation of glucose oxidation (IC50 = 5.8 µM) (data not shown). The concentrations of ranolazine and CVT-4325 in the perfusate were assayed at the end of the experiments, and the mean concentrations were determined to be 12.6 ± 1.3 and 2.6 ± 0.2 µM, respectively.
Working Heart Perfusion Experiments. Hearts were perfused as described previously in an ejecting (i.e., "working heart") mode (Neely et al., 1967) at 37°C with a Krebs-Henseleit solution containing 5.5 mM glucose, 1.2 mM palmitate, 3% bovine serum albumin, and 100 µU/ml insulin and continuously equilibrated with a 95% CO2 and 5% O2 gas mixture. After 10 min of perfusion in Langendorff mode, hearts were switched to working mode, with a constant left atrial preload of 11.5 mm Hg and aortic afterload of 80 mm Hg, and paced at a constant rate of 300 beats/min to ensure consistency with previous studies using this model (Fraser et al., 1999). Aortic systolic and diastolic pressures were measured via a pressure transducer attached to the aortic outflow line and cardiac output and aortic flow were measured using in-line ultrasonic flow probes. Left ventricular minute work (LV work), calculated as (cardiac output) x [left ventricular developed pressure (LVDP)], with LVDP = aortic systolic pressure–preload pressure, was used as an index of mechanical function. LV work was measured continuously. Glucose and fatty acid oxidation rates were measured simultaneously using dual-labeled substrates ([14C]glucose and [3H]palmitate) as described previously (Lopaschuk and Barr, 1997). Rates of palmitate and glucose oxidation are expressed as micromoles of substrate metabolized per minute per gram dry weight.
For the aerobic experiments, ranolazine (10 µM, n = 3) and CVT-4325 (3 µM, n = 5) were added to the perfusate after 5 min of aerobic perfusion and recirculated for 60 min. Hearts were paced at a constant rate of 300 beats/min throughout the experiment.
In the ischemia/reperfusion experiments, hearts were perfused aerobically for 30 min, followed by 15-min global, zero-flow ischemia induced by clamping off both the preload and afterload lines. After 15 min of global zero-flow ischemia, coronary flow was restored by removing the clamps and reperfusion was continued for 60 min. It has already been shown using a very similar protocol that 10 µM ranolazine improved functional recovery on reperfusion (MacInnes et al., 2003); therefore, in these experiments, hearts were either untreated (n = 9) or treated with CVT-4325 (3 µM, n = 6) added after the first 5 min of preischemic aerobic perfusion. Pacing can alter the response to ischemia/reperfusion by potentially exacerbating ischemic injury as well as obscuring the incidence of arrhythmias on reperfusion; therefore, in these ischemia/reperfusion experiments, hearts were not paced.
Statistics. All data are presented as means ± S.E.M., with five to six replicates in each group unless stated otherwise. Unpaired Student's t tests and one-way and repeated measure ANOVA were used where appropriate followed by a Dunnett's multiple comparison test using Prism 4.0c (GraphPad Software Inc., San Diego CA). Statistically significant differences between groups were defined as p < 0.05.
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Results |
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30% and ±dP/dt by more than 40%, which was accompanied by a significant increase in coronary flow relative to baseline. However, despite the increase in RPP with CVT-4325, there was no increase in MVO2; consequently, there was a significant increase in efficiency as defined by the ratio of RPP/MVO2. Thirty minutes after perfusion with ranolazine, there were no differences in function between control and ranolazine groups; however, there was a significant increase in all functional parameters in the CVT-4325 group compared with controls.
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The relative contributions of glucose, palmitate, lactate, and pyruvate to total TCA cycle flux from 13C NMR glutamate isotopomer analysis during aerobic perfusion are summarized in Fig. 1. Consistent with previous reports with similar substrate mixtures (Chatham et al., 1999), palmitate contributed 85% of acetyl-CoA entry into the TCA cycle, lactate 10%, and the remainder was from glucose and pyruvate. Ranolazine had no effect on the relative contributions of any of the substrates to the TCA cycle; however, CVT-4325 inhibited palmitate oxidation by 80%, which was accompanied by a more than 4-fold increase in lactate and pyruvate oxidation and approximately 9-fold increase in glucose oxidation.
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10 mm Hg, was significantly delayed in the ranolazine group (Fig. 2B), and the EDP averaged over the duration of LFI was significantly lower with ranolazine treatment (Fig. 2C).
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LV function at the end of reperfusion is summarized in Fig. 4 and Table 1. After 60 min of reperfusion, ranolazine treatment improved functional recovery compared with the control group; in contrast, despite the marked reduction in fatty acid oxidation, CVT-4325 did not improve recovery of LV function postischemia; indeed, relative to preischemic values, recovery of LV function was significantly lower than that observed in the control group. During reperfusion, oxygen consumption in the CVT-4325 group was significantly lower; however, in contrast to normoxic perfusion, efficiency (RPP/MVO2) was not significantly different between groups. At the end of reperfusion, LV EDP was significantly lower in the ranolazine group compared with the control group (20 ± 4 versus 35 ± 4 mm Hg; p < 0.05); CVT-4325 had no effect on end reperfusion EDP (33 ± 5 mm Hg; p > 0.05 versus control).
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Working Heart Experiments. To ensure that the results above were not specific to the isovolumic perfused heart preparation, fatty acid and carbohydrate oxidation rates were also determined in isolated perfused working hearts (Fig. 6). Similar to the results of experiments using the isovolumic Langendorff heart preparation, ranolazine had no effect on the rates of either glucose or fatty acid oxidation; however, CVT-4325 decreased fatty acid oxidation by 4- to 5-fold, with a concomitant increase in glucose oxidation.
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); however, the effect of CVT-4325 on the response of LV function to ischemia in this model has not been reported previously. Therefore, to determine whether the lack of protection seen with CVT-4325 in response to LFI in the isovolumic perfused heart was specific to that model, we examined the response of the working heart to zero-flow ischemia and reperfusion with and without CVT-4325. Similar to the isovolumic perfused heart experiments preischemic cardiac work was increased in the CVT-4325 group compared with controls (9.2 ± 0.2 versus 7.9 ± 0.4 mm Hg l/min; p < 0.025). Following ischemia/reperfusion, cardiac work was 40% of preischemic levels in both control and CVT-4325 groups; however, there were no differences in cardiac function between these two groups (Fig. 7).
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Discussion |
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Ranolazine has been shown to be protective against myocardial ischemic injury in a number of experimental settings (Clarke et al., 1996; McCormack et al., 1996; MacInnes et al., 2003) and has also been found to be efficacious as an antianginal agent in patients with coronary artery disease (Chaitman et al., 2004b). Early studies with ranolazine suggested that its protection was mediated by stimulation of glucose oxidation, secondary to partial inhibition of fatty acid oxidation (Clarke et al., 1996; McCormack et al., 1996). However, more recent findings that have shown that ranolazine improved cardiac function in response to various stressors, including ischemia/reperfusion and heart failure, in the absence of any changes in fatty acid or glucose metabolism (Gralinski et al., 1994; Matsumura et al., 1998; Maruyama et al., 2000; Chandler et al., 2002; MacInnes et al., 2003). Our observations that ranolazine had no effect on fatty acid or glucose oxidation are entirely consistent with these recent studies. The reason for the discrepancies between the earlier reports and our study regarding the metabolic effect of ranolazine is unclear; however, it may be related to the concentration of the drug used since high concentrations of ranolazine outside the therapeutic range have been reported to inhibit fatty acid oxidation (MacInnes et al., 2003).
It is noteworthy that the lack of effect of ranolazine on fatty acid and carbohydrate oxidation seen here was observed using two different techniques for evaluating substrate utilization and in two different isolated heart models. We cannot rule out the possibility that in vivo administration of ranolazine could lead to systemic metabolic effects, which could contribute to its cardioprotection; however, Chandler et al. (2002) showed in vivo in a canine model of heart failure that, although ranolazine improved cardiac function, it had no effect on the myocardial uptake of fatty acids or carbohydrates. Thus, there is consistent evidence demonstrating that ranolazine is cardioprotective in a number of experimental and clinical settings; however, on balance, recent evidence suggests that the mechanism of action is unlikely to be a consequence of alterations in carbohydrate and fatty acid oxidation.
Recent studies have suggested that the mechanism underlying the cardioprotection seen with ranolazine may be due at least in part to reduced intracellular sodium-dependent calcium overload secondary to inhibition of the late sodium current (Fraser et al., 2005, 2006; Belardinelli et al., 2006). Consistent with this hypothesis, the present study showed that ranolazine treatment delayed the onset of ischemic contracture, reduced the average LV EDP during ischemia, and lowered LV EDP at the end of reperfusion. The recovery of coronary flow at the end of reperfusion was also greater in the ranolazine group compared with either the control- or CVT-4325-treated hearts, which could also be a consequence of reduced contracture (i.e., lower LV EDP).
The fact that CVT-4325 did not improve functional recovery despite its marked inhibition of fatty acid oxidation and concomitant increase in glucose oxidation is consistent with our earlier study where we showed that increasing glucose oxidation with dichloroacetate also did not improve functional recovery following ischemia/reperfusion despite a 5-fold reduction in palmitate oxidation (Wang et al., 2005). One potential criticism of our earlier study was that we used 0.32 mM palmitate, whereas many studies demonstrating protection associated with increasing glucose oxidation used fatty acid concentrations in the 1 to 1.2 mM range (Lopaschuk et al., 1993). We also used low-flow ischemia in an isovolumic Langendorff preparation rather than zero-flow ischemia in an ejecting heart preparation, which are also more common in such studies. Here, we show that inhibition of fatty acid oxidation in hearts perfused with 1 to 1.2 mM palmitate afforded no protection regardless of whether the hearts were perfused in an isovolumic or working mode preparation. Furthermore, the lack of myocardial protection accompanying marked inhibition of fatty acid oxidation (4- to 7-fold) with CVT-4325 was also independent of whether low- or zero-flow ischemia was used. However, it is important to note that here and in our earlier study (Wang et al., 2005), metabolic interventions were initiated before ischemia; therefore, we cannot completely rule out the possibility that inhibition of fatty acid oxidation during reperfusion might afford some benefit as previously suggested (Finegan et al., 1996).
One frequently cited explanation for the beneficial effect of increasing glucose oxidation relative to fatty acid oxidation is that it improves efficiency because the amount of ATP produced per unit oxygen consumed is 12% greater when glucose is oxidized compared with palmitate (Stanley et al., 1997a). Interestingly, we found that CVT-4325 did improve efficiency (Table 1); however, the magnitude of this change was greater than can be attributed to the decrease in palmitate oxidation. Furthermore, despite this increase in efficiency, functional recovery was not improved. However, it should be noted that this increase in efficiency was associated with a significant increase in RPP, which could adversely affect the response to ischemia. The mechanisms underlying the increase in contractility and efficiency associated with CVT-4325 are unknown at this time and warrant further study.
A potential limitation associated the use of any pharmacological inhibitors is their specificity. Therefore, CVT-4325 was tested for potential pharmacological activity (using the MDS-Pharma SpectrumScreen; MDS Pharma Services, King of Prussia, PA) at 169 targets that included G-protein-coupled receptors (e.g., -adrenergic receptors), nuclear hormone receptors (e.g., estrogen receptor-
), and transporters (e.g., serotonin). CVT-4325 at 10 µM inhibited (70%) serotonin, histamine, L-type calcium channel, and serotonin transporter (J. A. Zablocki, unpublished data on file at CV Therapeutics, Inc.). Thus, at the concentration used in the present study (3 µM), the predominant pharmacological activity of CVT-4325 in the presence of 1.2 mM palmitate was the inhibition of fatty acid oxidation (IC50 = 0.9 µM) and stimulation of glucose oxidation (IC50 = 5.8 µM). Nevertheless, it is conceivable that the lack of myocardial protection associated with CVT-4325 may be due to potentially adverse effects associated with targets independent of fatty acid oxidation inhibition.
It should also be noted that we compared only single concentrations of ranolazine and CVT-4325 rather than using multiple overlapping concentrations, which would have provided a more comprehensive comparison of these agents. However, the primary purpose of this study was to examine the effects of ranolazine at a therapeutically relevant concentration on cardiac metabolism and the response to ischemia and to compare this directly with an inhibitor of fatty acid oxidation. At 300 µM, MacInnes et al. (2003) reported that ranolazine inhibited -oxidation in cardiomyocytes by 30%, demonstrating the potential for ranolazine to inhibit fatty acid oxidation at high concentrations. However, because 10 µM reflects the upper end of the proposed therapeutic concentration range for ranolazine (Belardinelli et al., 2006), it is highly unlikely that its effect on fatty acid oxidation is therapeutically relevant. CVT-4325 is clearly a potent inhibitor of fatty acid oxidation, reducing palmitate oxidation by 80% at a concentration of only 3 µM; consequently, we cannot entirely rule out the possibility that at lower concentrations with more modest inhibition of fatty acid oxidation CVT-4325 may have demonstrated some beneficial effects.
There were some differences in protocols between the isovolumic Langendorff and working heart experiments. For example, in the isovolumic studies, physiologically relevant concentrations of lactate and pyruvate were used in addition to glucose, whereas in the working heart studies glucose was the only carbohydrate source. Furthermore, in the isovolumic studies, hearts were paced at 320 beats/min in both normoxic and ischemia/reperfusion experiments, whereas in the working heart, experiments hearts were paced at 300 beats/min in the normoxic experiments and unpaced in the ischemia/reperfusion experiments. Some of these differences such as the pacing rate would not be expected to affect the metabolic measurements or the response to ischemia; however, substrate availability and pacing during ischemia/reperfusion could potentially affect both. Nevertheless, despite these differences in perfusion conditions, the effects of ranolazine and CVT-4325 were remarkably consistent in these two different experimental models.
In conclusion, we have shown that regardless of the perfusion conditions, ranolazine had no effect on glucose or fatty acid oxidation. Nevertheless, in the isovolumic perfused heart model, it attenuated the development of ischemic contracture and improved recovery of function following ischemia/reperfusion. In contrast, in both the isovolumic and working heart models, CVT-4325 markedly reduced fatty acid oxidation with a concomitant increase in glucose oxidation but did not improve functional recovery. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection associated with ranolazine is mediated by mechanisms other than inhibition of fatty acid oxidation and conversely that significant inhibition of fatty acid oxidation with CVT-4325 is not associated with cardioprotection.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: LV, left ventricular; NMR, nuclear magnetic resonance; DMSO, dimethyl sulfoxide; EDP, end diastolic pressure; LFI, low-flow ischemia; TCA, tricarboxylic acid; LVDP, left ventricular developed pressure; ANOVA, analysis of variance; MVO2, oxygen consumption; RPP, rate-pressure product; RAN, ranolazine; CVT-4325, (R)-1-(2-methylbenzo[d]thiazol-5-yloxy)-3-(4-((5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)propan-2-ol.
Address correspondence to: Dr. John C. Chatham, University of Alabama, McCallum Building, Room 684 1530 3rd Avenue South, Birmingham, AL 35294-0005. E-mail: jchatham{at}uab.edu
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