CHRONIC ETHANOL CONSUMPTION MODULATES MYOCARDIAL ISCHAEMIA–REPERFUSION INJURY IN MURINE AIDS

Yinhong Chen1,2, Grace Davis-Gorman2, Ronald R. Watson1,* and Paul F. McDonagh2

1 Division of Health Promotion Science, College of Public Health and
2 Cardiovascular and Thoracic Surgery and The Sarver Heart Center, School of Medicine, University of Arizona, Tucson, AZ 85724, USA

Received 23 November 2001; in revised form 17 July 2002; accepted 30 July 2002


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: The severity of cardiovascular complications in acquired immune deficiency syndrome (AIDS) patients may be associated with acute ischaemia–reperfusion injury. Epidemiological studies suggest that moderate ethanol consumption has myocardial protective effects. However, it is unknown if chronic ethanol consumption benefits acute myocardial ischaemia–reperfusion injury in AIDS. The aim of this study was to determine if chronic ethanol consumption modulates myocardial ischaemia–reperfusion injury in murine AIDS. Methods: Four groups were studied: control, murine AIDS, ethanol, and ethanol plus murine AIDS. All mice were subjected to 30 min of left anterior descending branch (LAD) occlusion and 120 min of reperfusion. Results: We found that the survival from an acute myocardial infarction was reduced in advanced-stage murine AIDS mice. Although early-stage murine AIDS hearts did survive in acute myocardial infarction, the infarct size was significantly larger. Chronic ethanol consumption significantly decreased infarct size compared to the control group. Chronic ethanol consumption also improved the survival of murine AIDS mice from an acute myocardial infarction. However, chronic ethanol consumption did not significantly reduce infarct size in murine AIDS. Conclusions: Our results indicate that multiple deleterious effects may enhance acute ischaemia–reperfusion injury in murine AIDS. The beneficial effects of chronic ethanol consumption in myocardial ischaemia–reperfusion injury may be due to modulation of neutrophil adhesion molecule expression and cytokine secretion.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Acquired immune deficiency syndrome (AIDS) is a health crisis affecting >60 million people worldwide. Since the epidemic began, 21.8 million people have died from AIDS. After the introduction of highly active antiretroviral therapy, the survival rate of HIV-infected patients has been significantly enhanced; however, cardiovascular involvement in AIDS has become more apparent. The prevalence of cardiac involvement in patients with HIV, both asymptomatic and symptomatic, ranges from 28 to 73% (Lewis, 2000Go). The cardiovascular mortality rate associated with HIV infection in the USA is estimated to be 1–6% (Anderson and Virmani, 1990Go). HIV cardiomyopathy was reported to be the fourth leading cause of dilated cardiomyopathy in the USA (Epstein et al., 1996Go). Congestive heart failure has become the leading cause of death in paediatric patients with AIDS, and half of them die within 6–12 months (Johann-Liang et al., 1997Go). The incidence of myocardial infarction in HIV-infected patients increased almost 4-fold from 1983 to 1998 (Rickerts et al., 2000Go). The pathogenesis underlying cardiovascular manifestations in HIV-infected patients is complicated. The increased severity of complications may involve an enhanced reperfusion injury following ischaemia in AIDS.

Recent epidemiological studies suggest that moderate ethanol consumption reduces the risk for developing coronary artery disease, angina pectoris, acute myocardial infarction and sudden death (Iso et al., 1995Go; Poikolainen et al., 1996Go; McKee and Britton, 1998Go; van Tol and Hendriks, 2001Go). Regular moderate drinking may have cardioprotective effects. However, it is unknown if chronic ethanol consumption can attenuate myocardial ischaemia–reperfusion injury in AIDS.

Neutrophils are a principal mediator of ischaemia– reperfusion injury (Ritter and McDonagh, 1997Go; Cavanagh et al., 1998Go; Gale et al., 2001Go). Upon neutrophil activation, they express a higher affinity CD11/CD18 to mediate firm adhesion to vascular endothelial cells and eventually transmigrate to heart tissue. Accumulated neutrophils in hearts release proteolytic enzymes and cytotoxic H2O2, resulting in severe ischaemia–reperfusion injury. We found that neutrophils were highly activated in murine AIDS and down-regulated during chronic ethanol consumption (unpublished results). Therefore, we hypothesized in the present work that murine AIDS mice are susceptible to severe neutrophil-mediated reperfusion injury, and that chronic ethanol consumption attenuates the severity of ischaemia–reperfusion injury.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Animals
Female C57BL/6N mice (National Cancer Institute, Bethesda, MD, USA) at 8–12 weeks of age and weighing ~20–22.5 g were randomly assigned to four different groups: control, murine AIDS, ethanol, and murine AIDS plus ethanol. Mice were housed in transparent plastic cages with a stainless wire lid in a room at 20–22°C with constant humidity and a 12-h light:12-h dark cycle. Murine AIDS was induced by LP-BM5 murine leukaemia retrovirus infection. The LP-BM5 viruses were administered intraperitoneally (i.p.), as done previously in our laboratory (Liang et al., 1997Go). In the first week, 10% (v/v) of ethanol in autoclaved tap water was made available to the chronic ethanol-fed groups. The ethanol concentration was increased to 20% (v/v) in the second week and kept at 20% (v/v) for the rest of the treatment periods. The total experimental period was 2 months. The average ethanol intake per mouse was 2.8 ml/day. Mice were active at night; therefore, we took blood samples at night (after lights turned off for 31/2 h) to estimate blood-ethanol concentration (Sigma Diagnostics Alcohol Kit, St Louis, OH, USA). The average blood-ethanol concentration was 66.9 mg/dl (0.0669%). The non-ethanol-fed mice were given the same diet, except that the water bottles contained only pure water. No weight loss was found at the end of the experimental period between the non-ethanol and ethanol-fed mice. No mice died during the 2-month experimental period.

Murine heart model for myocardial ischaemia and reperfusion
We modified a murine model for myocardial ischaemia and reperfusion based on the protocol of Michael et al. (1995)Go. Female C57BL/6 mice were anaesthetized with sodium pentobarbital (55 mg/kg, i.p.). A tracheotomy was performed to facilitate breathing. A section of polyethylene (PE) 90 tubing was inserted into the mouse’s trachea and connected via PE 160 to a respirator (Harvard Rodent Ventilator Model 683, Holliston, MA, USA). The respirator’s tidal volume was set at ~1.0 ml/min with 100% oxygen supplementation, and the rate was set at 120 strokes/min. Normal chest expansion was monitored for adjusting optimal tidal volume. The right carotid artery was then cannulated with PE-10 tubing to monitor arterial blood pressure and heart rate. The arterial cannula was filled with heparinized phosphate-buffered saline (2 U/ml) and connected to a blood pressure transducer and a blood pressure monitor (Gould Windograf, Valley View, OH, USA). After an equilibration period of 10 min, a thoracotomy was performed. With an electrocautery, an incision was made to the left of the sternum. The pericardial sac was then removed. Ligation of the left anterior descending branch (LAD) was performed using a 7–0 silk suture attached to a needle. A small piece of PE-50 was used to secure the ligature without damaging the artery. The animals were subjected to 30 min of LAD occlusion and 120 min of reflow. Blood samples were taken from the carotid catheter for monitoring blood gas. At the end of the 2-h period of reperfusion, the LAD was re-ligated with a 7–0 silk suture. Trypan blue (1.2 ml, 0.4%; Sigma Chemical Co., St Louis, MO, USA) was injected retrogradely into the carotid artery catheter to delineate the in vivo area at risk. At the end of the protocol, the heart was excised and four 1-mm transverse sections were made with one section at the site of the ligature. Each section was scanned with a high-resolution scanner (1200 dpi Hewlett-Packard-model 5370C, Palo Alto, CA, USA). Each slice was then counterstained with 1.0% 2,3,5-triphenyltetrazolium chloride (TTC, Sigma) solution for 5 min at 37°C. The sections were placed in a 10% buffered formalin solution. The next day, each section was scanned again to account for formalin-induced shrinkage and to determine infarct size.

Measurement of the area at risk and infarct size
A scanned transverse section from 1 mm distal to ligature was analysed using Adobe software (Adobe Photoshop 5.5) and measured for the area at risk and the infarct size (Fig. 1Go). Using a toolbar, a 1 mm2 calibration square was produced and converted to pixels. The entire area of the myocardial section and area at risk (the area not stained by Trypan blue) were outlined and computed into mm2. The fractional area at risk in this section was calculated by dividing the area at risk by the total area. To measure the infarct size, the same section (stained with TTC) was used. The fractional infarct area in the fixed section was calculated by dividing the TTC-stained area by the total area of the fixed section. The fractional infarct area was divided by the fractional area at risk to determine the ratio of the infarct area/area at risk.



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Fig. 1. Representative images of area at risk and infarct size. A Trypan blue-stained transverse section from 1 mm distal to ligature (A–C) was scanned and reopened in Adobe Photoshop. This section was for analysing the area at risk. Using a toolbar, a 1 mm2 area (A) was made and converted into the number of pixels. The total area of the myocardial section (B) and the Trypan blue-unstained area (area at risk) (C) were outlined and computed into mm2. The area at risk in this section was calculated by dividing the area at risk by the total areas. To measure the infarct size, the 2,3,5-triphenyltetrazolium chloride counterstained same section (D, E) was used to determine the total (D) and infarct area (E). The same calculation was made for the infarct areas. The final infarct size/area at risk = [infarct area (E)/total area (D)]/[area at risk (C)/total area (B)].

 
Statistical analysis
Statistical analysis was performed using Prism Statistical Software (version 3.0). Comparisons among groups were made using analysis of variance with Newman–Keuls post hoc testing when significant differences were observed. Survival analysis was performed by SPSS (SPSS Windows 10.0). P < 0.05 was considered statistically significant.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Survival during the ischaemia and reperfusion protocol
Figure 2Go gives the survival results for the 30-min ischaemia and 120-min reperfusion protocol. Two-month murine AIDS mice did not survive in ischaemia–reperfusion surgery. Of a total of 10 mice in the 2-month murine AIDS group, only one mouse survived in the entire period of ischaemia–reperfusion. Nine of 10 mice died during ischaemia–reperfusion. Seventy per cent of those died during ischaemia, especially at 10 min of ischaemia (40% of total). Because survival is required to properly assess infarct area/area at risk ratios, we were not able to measure infarct size in this group. To gain some index of infarction, we used 1-month murine AIDS mice for the ischaemia–reperfusion study. No significant difference in survival was observed in control versus 1-month murine AIDS (A) or 2-month ethanol-fed mice (B). Two of 12 mice died in the control group, respectively, at 20-min ischaemia and 75-min reperfusion. One of 11 mice died at 20-min ischaemia periods in the 1-month murine AIDS (A) and 2-month ethanol-fed (B) groups. Chronic ethanol consumption improved the survival rate in the 2-month murine AIDS mice (P < 0.05) compared to the 2-month murine AIDS mice in the absence of ethanol consumption. In this group, eight of 16 mice (50%) survived the entire 30-min ischaemia and 120-min reperfusion periods. Among the mice that died, half of them died during the ischaemic period and the other half during the reperfusion period.



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Fig. 2. The percentage of survival mice during 30 min ischaemia and 120 min reperfusion. Because the percentage of survival mice from 1-month murine (M) AIDS (A) and 2-month ethanol (EtOH)-fed groups (B) were the same, we created two panels (A, B) to illustrate the data. (A) Survival rates from control, 1- and 2-month murine AIDS mice during ischaemia– reperfusion injury. (B) Survival rates from control, 2-month murine AIDS, murine AIDS plus ethanol-fed, and ethanol-fed groups during ischaemia–reperfusion surgery. During the entire 30-min ischaemia and 120-min reperfusion periods, two of 12 mice died in the control group, one of 11 mice died in the 2-month ethanol-fed and 1-month murine AIDS groups, respectively, nine of 10 mice died in the 2-month murine AIDS group and eight of 16 mice survived in the 2-month murine AIDS with ethanol-fed group. P < 0.001, 2-month murine AIDS vs control. P < 0.05,2-month murine AIDS vs 2-month murine AIDS plus ethanol-fed.

 
Haemodynamic parameters
Blood pressures and heart rates were recorded for all groups of mice throughout the myocardial ischaemia–reperfusion protocol and the results are summarized in Fig. 3Go. Heart rate (A), systolic (B) and diastolic (C) blood pressure significantly decreased for the first 10 min after LAD ligation. If mice endured the ischaemic attack, all three haemodynamic parameters partially recovered after 20 min of occlusion and remained constant throughout the remainder of the experiment. Because only one of 10 mice survived the entire period of ischaemia–reperfusion in the 2-month murine AIDS group, we did not include haemodynamic data during reperfusion for this group. We also found that the 2-month murine AIDS mice demonstrated very low blood pressure (<25/15 mmHg) with slow heart rates (<360/min) immediately after LAD ligation, compared to the other groups of mice. No significant group differences in heart rate or systolic and diastolic blood pressure were observed at any point during ischaemia–reperfusion surgery.



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Fig. 3. Heart rate (A), systolic (B) and diastolic blood pressure (C) during ischaemia–reperfusion periods. x-Axis: ischaemia–reperfusion times. O-0: initial occlusion time; O-1: 10 min occlusion; O-2: 20 min of occlusion; and O-3: 30 min of occlusion. R: reperfusion periods; R-0: an initial reperfusion time; R-15: at 15 min of reperfusion. These parameters were recorded every 15 min until the total120-min reperfusion period finished.

 
Myocardial area at risk and infarct size
The infarct size and area at risk were measured at the end of the reperfusion period. The results are summarized in Fig. 4Go and the representative images are given in Fig. 5Go. Despite similar sizes of areas at risk in each group, 1-month murine AIDS hearts had a significantly larger area of infarction (51.6 ± 4.8%) after ischaemia–reperfusion injury. Two-month ethanol-fed mice significantly reduced myocardial infarct size/area at risk (18.5 ± 3.1%) compared to the control mice (38.5 ± 2.8%). However, 2-month ethanol consumption did not significantly reduce myocardial infarct size (46.9 ± 4.6%) in murine AIDS mice.



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Fig. 4. Infarct size and area at risk after 30 min occlusion and 120 min reperfusion. Data are expressed as mean ± SEM in each group. Control (n = 10), 2-month ethanol (n = 10), 1-month murine AIDS (n = 10), 2-month murine AIDS plus ethanol (n = 8). For infarct/area at risk: P < 0.001, 2-month ethanol vs 1-month murine AIDS and 2-month murine AIDS plus ethanol; P < 0.01, 2-month ethanol vs control. For infarct size/total area: P < 0.001, 2-month ethanol vs 1-month murine AIDS; P < 0.01, 2-month ethanol vs 2-month murine AIDS plus ethanol; P < 0.05, 2-month ethanol vs control. For area at risk, no significant difference was observed between the four groups.

 


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Fig. 5. Representative infarct size images after 30 min of ischaemia and 120 min of reperfusion. 2,3,5-Triphenyltetrazolium chloride-stained transverse heart sections (A–D) were after 30 min of left anterior descending branch coronary artery ischaemia and 120 min of reperfusion injury. (A) Control group; (B) 2-month ethanol-fed group; (C) 2-month murine AIDS with ethanol-fed group; (D) 1-month murine AIDS group.

 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
A cardioprotective effect of moderate ethanol consumption has been observed. Some investigators (Redmond et al., 2000Go; Van Tol and Hendricks, 2001) proposed that ethanol induces vascular relaxation, elevates HDL, lowers fibrinogen level, and modulates platelet function. Besides these beneficial factors, we found that neutrophil CD11b expression was down-regulated by chronic ethanol consumption (unpublished data). The down-regulation of CD11b expression may decrease the adherence of neutrophils to endothelial cells and ultimately diminish neutrophil sequestration in the ischaemic heart tissue. Recently, Arbabi et al. (1999)Go demonstrated that ethanol inhibited inflammatory cytokines, including tumour necrosis factor (TNF)-{alpha} and interleukin (IL)-8 production. Ethanol also suppresses cytokine-induced inducible nitric oxide synthase (iNOS) expression (Syapin et al., 2001Go). In addition, moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis (Gu et al., 2001Go). All these findings support our observation that chronic ethanol consumption attenuates myocardial ischaemia– reperfusion injury.

Attenuation of ischaemia–reperfusion injury with regular alcohol consumption could lead to improved myocardial recovery and survival after myocardial infarction. One potential mechanism by which regular drinking may improve survival after myocardial infarction is to reduce ischaemia– reperfusion injury, analogous to experimental ischaemic preconditioning (Klatsky et al., 1990Go; Kawano et al., 1992Go; Hu and Nattel, 1995Go). Ischaemic preconditioning occurs when brief periods of ischaemia and reperfusion protect hearts against injury from subsequent prolonged ischaemia– reperfusion. Recent evidence in experimental animals indicates that ischaemia–reperfusion injury can be reduced by preconditioning the heart with brief episodes of ischaemia and reperfusion prior to prolonged ischaemia (Kawano et al., 1992Go; Headrick, 1996Go). A study demonstrated that hearts from rats fed ethanol for 8 weeks could be preconditioned with a single 5-min episode of ischaemia prior to prolonged ischaemia–reperfusion, whereas hearts from control animals were not protected (McDonough, 1997Go). Studies in guinea-pigs found that regular ethanol consumption mimicked ischaemic preconditioning and reduced ischaemia–reperfusion injury (Miyamae et al., 1997Go). Furthermore, ischaemic preconditioning, a cardioprotective effect of alcohol, is mediated by adenosine and {alpha}1-adrenergic signalling in many species, including guinea-pigs, humans and rats (Miyamae et al., 1998Go).

The incidence and severity of myocardial infarction in AIDS is increasing (Rickerts et al., 2000Go). Severe ischaemic attacks may contribute to sudden death in AIDS patients. Our results strongly support the idea that retrovirus-infected hearts are more vulnerable to a heart attack. When cardiovascular ischaemic events occur in the late stage of AIDS, hearts have reduced protective ability against ischaemia. This may be due to underlying cardiovascular complications by direct and/or indirect retroviral infection. Several causative factors contributing to cardiovascular complications of AIDS may amplify ischaemia–reperfusion injury, such as retroviral infection, multi-opportunistic infection, autoimmune reaction, neutrophil activation and cytokine dysregulation. Overall, ischaemic attack could exaggerate the cardiovascular complications and rigorously affect heart performance.

Retrovirus itself may directly attack the hearts. Researchers have found the presence of HIV-1 in the myocardium of AIDS patients (Calabrese et al., 1987Go; Lipshultz et al., 1990Go). Barbaro et al. (1998)Go found that cardiac myocytes were infected with HIV-1 in 58 patients and nearly two-thirds of those samples had myocarditis. Cardiac complications, such as myocarditis, dilated cardiomyopathy, endocarditis, pericardial effusion, arteriopathy and cardiac malignant neoplasms, have been found in AIDS patients (Currie et al., 1995Go; Odeh et al., 1995Go; Barbaro et al., 1998Go; Shannon et al., 2000Go). These findings suggest that myocarditis is related to a direct action of the retrovirus. Endothelial cells infected by retrovirus may also contribute to cardiovascular dysfunction in AIDS. Altered function of vascular endothelial cells is associated with hyperactivity of the microcirculation and with coronary vasospasm resembling the changes seen in cocaine abuse (Mohan et al., 1995Go). Coronary artery spasm may lead to ischaemic attack and myocardial cellular necrosis, subsequently causing hypertrophy. This evidence suggests that the retrovirus itself causes the cardiovascular complications.

A number of opportunistic infections involving the hearts have been reported in AIDS (Kostianovsky et al., 1987Go; Wu et al., 1992Go). Disseminated cytomegalovirus (CMV) infection occurs frequently in HIV-infected patients. CMV antigen and CMV-mediated early gene expression were found in myocytes from HIV-infected patients (Wu et al., 1992Go). Epstein–Barr virus is another opportunistic pathogen involved in the aetiology of cardiac lymphomas (Gill et al., 1987Go). Multiple infections may trigger cellular and humoral-mediated cardiac injury.

An autoimmune reaction in AIDS may also compromise heart function. Acierno et al. (1989) suggested that myocardial damage is related to uncontrolled hyper-gamma-globulinaemia. The murine model of AIDS characteristically develops hyper-gamma-globulinaemia. Many researchers (Hastillo et al., 1991Go; Lieberman et al., 1993Go) proposed an autoimmune mechanism for HIV-related myocardial disease similar to those described with antimyosin antibodies. Viral genes may alter the cell surface of the muscle fibre. Some of these cell surface proteins become immunogenic and elicit a progressive autoimmune reaction. A series of experiments has revealed the presence of circulating cardiac autoantibodies to heavy chain myosin in AIDS patients having cardiovascular complications.

Neutrophil activation and cytokine dysregulation may contribute to the cardiovascular complications in AIDS. We found that neutrophils were significantly activated in murine AIDS (unpublished results). A number of cytokines, including TNF-{alpha}, IL-1, IL-6, and platelet-activating factor (PAF) were increased in AIDS individuals (Akarid et al., 1995Go; Westmoreland et al., 1996Go; Liang et al., 1997Go; Sei et al., 1997Go). These cytokines affect heart performance to various degrees. IL-1 has a suppressive effect on adrenergic agonist-mediated increase in cyclic adenosine monophosphate (cAMP) in cardiomyocytes. IL-2 and IL-6 have reversible myocardial depressant effects in vivo (Finkel, 1992; Barry, 1994Go). Long-term treatment of cardiomyocytes with IL-1 and TNF-{alpha} reduces contractility. The myocardial depressant effects of TNF-{alpha} infusion cause left ventricle dysfunction (Pagani et al., 1992Go). TNF-{alpha} induces cell apoptosis, and PAF acts as a cofactor in accelerating apoptosis (Westmoreland et al., 1996Go). Increased expression of iNOS is found in vitro in cardiac myocytes treated with TNF-{alpha}, IL-1 and interferon-{gamma} (Pinsky et al., 1995Go). Therefore, increased cytokines may contribute to the initiation and perpetuation of activated blood cells, causing heart dysfunction. Upon ischaemia–reperfusion, hypersensitive neutrophils may become more activated. iNOS may be over-expressed and more cytokines released in response to ischaemia–reperfusion injury. Overall, activated neutrophils release reactive oxygen species and the proteolytic enzymes that directly destroy heart tissue. Over-produced cytokines and over-expressed iNOS amplify the local pathological inflammatory reaction and perturb myocardial function. Our data strongly support this notion, because survival in the 2-month AIDS group was poor and a larger infarct size was observed in the 1-month murine AIDS hearts.

In summary, the present study clearly demonstrates that 2-month exposure to murine AIDS increases the vulnerability of the heart to acute ischaemic attack. Even though early stage (1 month) murine AIDS hearts survived the ischaemia– reperfusion protocol, infarction of the myocardium was severe. Chronic ethanol consumption improved survival but did not completely reverse the deleterious effects on hearts due to retroviral infection. These results support the cardioprotective effects of moderate ethanol consumption.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This work was supported by NIH HL 63667 and 59794.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed at: Division of Health Promotion Science, 1501 N. Campbell, College of Public Health, University of Arizona, P. O. Box 245155 Tucson, AZ 85724, USA. Back


    REFERENCES
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 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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