© 1999 American Heart Association, Inc.
Original Contributions |
Lipid and Apolipoprotein Predictors of Atherosclerosis in Youth
Apolipoprotein Concentrations Do Not Materially Improve Prediction of Arterial Lesions in PDAY Subjects
From the Southwest Foundation for Biomedical Research (D.L.R., H.C.M) and the University of Texas Health Science Center, San Antonio, TX (C.A.M., H.C.M.); and Louisiana State University Medical Center, New Orleans, LA (G.T.M., W.D.S., P.S.R., J.P.S.).
Correspondence to David L. Rainwater, PhD, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail david{at}darwin.sfbr.org
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Abstract |
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Abstract—We compared serum lipid and apolipoprotein predictors of atherosclerosis in cases from the multicenter study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY). The lipid measures included HDL cholesterol (HDL-C) and non-HDL-C, and the apolipoprotein measures included concentrations of apoA1, apoB, and Lp(a), and sizes of the apo(a) proteins. We tested whether the apolipoprotein measures predicted atherosclerotic lesions as well as the more traditional lipid measures. We estimated extent of lesions as fatty streaks or raised lesions (fibrous plaques, complicated or calcified lesions) in 3 sites: thoracic aorta, abdominal aorta, and right coronary artery. Neither apoA1 nor apoB measures were as strongly or consistently correlated with extent of lesions as the corresponding lipid measure (HDL-C and non-HDL-C, respectively). Beyond the basic model that included sex, age, race, smoking status, hypertension, and the lipid measures, apoA1 and apoB added only an average 1.3% increased explanatory ability to the model, whereas HDL-C plus non-HDL-C added an average 2.5%. The results suggest that the traditional lipid measures are more useful than apolipoprotein measures for detecting young persons at high risk of precocious atherosclerosis. Because of large racial differences, the two Lp(a)-related measures, Lp(a) concentrations and apo(a) size, were evaluated in blacks and whites separately. Under these circumstances, neither of the Lp(a)-related measures was strongly or consistently correlated with extent of lesions.
Key Words: atherosclerosis • PDAY • lipoproteins • apoA1 • apoB • Lp(a) • apo(a)
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Introduction |
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Early studies of the relationship of plasma lipids to atherosclerosis and coronary heart disease (CHD) emphasized the cholesterol content of plasma, although it was known that cholesterol and other lipids were transported as lipid-protein complexes. Ultracentrifugation separated these lipoproteins into classes by their hydrated density1 ; electrophoresis, by electrical charge2 ; and chemical methods, by selective precipitation.3 After the specific protein components were isolated and characterized, methods were developed to measure the proteins (apolipoproteins) directly by immunochemical methods,4 including a rapid and reliable electroimmunoassay method.5 Alaupovic6 first suggested that measuring the apolipoproteins might be more useful in predicting risk of CHD than the lipid components or intact lipoprotein particles.
During the 1970s and 1980s, a number of studies of the ability of plasma or serum apolipoprotein concentrations to predict risk of atherosclerotic disease produced conflicting and inconclusive results (reviewed by Sniderman and Silberberg7 and Vega and Grundy8 ). Some of these studies examined the association of apolipoprotein levels with atherosclerotic lesions measured by angiography or ultrasound in living persons, but none examined the relationship with atherosclerosis measured directly in the arteries of autopsied persons.
A multicenter cooperative study of atherosclerosis in young persons, Pathobiological Determinants of Atherosclerosis in Youth (PDAY),9 has provided an opportunity to compare the usefulness of serum concentrations of apoB and apoA1 with the usefulness of lipoprotein cholesterol concentrations to predict atherosclerotic lesions in 15- to 34-year-old men and women and to determine whether measures of Lp(a) add to prediction of atherosclerotic lesions. The results show that serum lipoprotein cholesterol concentrations are generally better predictors of atherosclerosis than the apolipoprotein concentrations.
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Methods |
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Study Design
Fifteen cooperating centers adopted a standard operating protocol and manual of procedures to collect specimens and information and to submit them to central laboratories for analysis. A statistical coordinating center received all data pertaining to each case from the collection centers and central laboratories.
Subjects
Subjects were persons, 15 through 34 years of age, who died of
external causes (accident, homicide, or suicide) within 72 hours of
injury and who were autopsied within 48 hours of death in one of the
cooperating medical examiners' laboratories. Age and race were
obtained from death certificates. Persons of race other than white or
black were excluded from the study. The Institutional Review Board of
each participating center approved the use of tissue, blood, and data
from the human subjects in this study.
Additional details of criteria for inclusion and exclusion have been
provided elsewhere.10 11 Because we previously have shown
substantial effects of elevated glycohemoglobin10 on
lesions, we also excluded individuals with high levels of
glycohemoglobin (
8%)10 or missing values. Altogether,
715 cases were available for this analysis.
Dissection and Preservation of Arteries
The pathologist removed the aorta from a point 2 cm proximal to
the ligamentum arteriosum to a point 2 cm distal from the iliac
bifurcation. The pathologist opened the aorta along a line on the
dorsal surface that passed midway between the orifices of the
intercostal and lumbar arteries, rinsed the intimal surface with
Hanks' modified balanced salt solution, flattened it with the
adventitial surface down, split it longitudinally along a line that
bisected the celiac, superior mesenteric, and inferior
mesenteric ostia, and fixed the left half in 10% neutral buffered
formalin. The pathologist opened the right coronary artery
along the epicardial surface from its origin to the point at which it
turned downward along the posterior interventricular sulcus
and dissected the artery from the heart. After removing epicardial fat,
the artery was rinsed and fixed as for the aorta. The collection
centers placed each aorta and coronary artery in a plastic bag
with 10% formalin and shipped them monthly to the central laboratory.
The central laboratory stained the arteries with Sudan
IV12 and packaged them in clear plastic bags with 10%
formalin.
Grading Arterial Specimens
Three pathologists independently graded the preserved specimens.
Using procedures developed in the International
Atherosclerosis Project,12 they
visually estimated the extent of intimal surface involved with fatty
streaks and with raised lesions (fibrous plaques, complicated lesions,
and calcified lesions). For each specimen, the average of the 3
gradings was used in the analyses; intraclass correlations
among the pathologists have been reported
elsewhere.9 13
Blood
Blood was collected at autopsy from the aorta, heart, or vena
cava, and serum was isolated by low-speed
centrifugation. Frozen serum was shipped to the central
laboratory for storage at -80°C and later
analysis.
Lipoprotein Cholesterol
The central laboratory measured serum cholesterol
concentrations by the cholesterol oxidase
method,14 precipitated apoB-containing lipoproteins in
serum by heparin-Mn2+, and measured HDL
cholesterol (HDL-C) in the supernatant.15
Non-HDL-C was calculated as the difference between total
cholesterol and HDL-C concentrations. Coefficients of
variation for total cholesterol and HDL-C measurements were
1.3% and 5.2%, respectively.11 Several studies have
demonstrated that postmortem serum cholesterol levels are
representative of premortem levels.16 17 18
However, because emergency medical teams often administer fluids
intravenously to trauma patients, we excluded serum data
from individuals with total serum cholesterol <2.59
mmol/L (100 mg/dL).
Apolipoproteins
The central laboratory measured apoA1 and apoB concentrations by
immunoprecipitin analysis using antibody reagents and
calibrators from INCSTAR, Inc. and an Express Plus clinical chemistry
analyzer (Ciba-Corning Diagnostics). After an
initial incubation of the sample plus antibody diluent and measurement
of a sample blank, monospecific antibodies were added and mixed, and
the increase in light scattering was measured at 340 nm. Samples were
assayed in duplicate and the average values were used. Coefficients of
variation for these measurements were 5.6% for apoA1 at 129 mg/dL and
7.6% for apoB at 115 mg/dL.
The central laboratory measured Lp(a) concentrations by a "sandwich"-style ELISA as described previously.19 20 Capture was with polyclonal antibodies directed against human Lp(a) (Calbiochem), and detection was with monoclonal antibody LHLP-1, which is specific for Lp(a) or apoLp(a), but does not bind apo(a) alone.21 Assays were standardized with reference materials from INCSTAR and showed no cross-reactivity with plasminogen (data not shown). Each sample was run in duplicate on different plates and the values were averaged. Coefficients of variation for control products were 9.7% at 20 mg/dL and 5.8% at 46 mg/dL.
A laboratory at the Southwest Foundation for Biomedical Research
characterized apo(a) size polymorphism by use of
polyacrylamide gradient gel electrophoresis and
immunoblotting as described.22 23 Samples
were run at least in duplicate and size estimates were averaged.
Repeatability of size estimates was 99.1%. Although most apo(a)
isoform phenotypes appeared normal, some of the samples (5.5%)
were obviously degraded (eg, 3 bands or immunoreactive material with
no distinct bands) and no phenotype could be assigned. The
prevalence of null phenotype samples (ie, no immunoreactive
material in the lane) was 1.0%, lower than the 2.9% previously
reported for Mexican Americans.24 This difference
suggested that the PDAY apo(a) phenotypes were indicative of
antemortem phenotypes (ie, the prevalence of null
phenotype samples was not unusually high owing to degradation).
A single predominant isoform band was identified for each sample. In
the case of double-banded phenotype samples, samples were
immunoblotted with 2D1, a monoclonal antibody believed to
be directed against a nonrepeated epitope of human
apo(a),25 and the predominant isoform band was identified
by curve-fitting procedures.23 24 The smaller isoform was
predominant for about 74% of the samples, compared with 79% observed
in previous studies of Mexican Americans (data not shown). Null
phenotype samples were excluded from analyses involving
apo(a) isoform size.
Statistical Analyses
We analyzed the associations of sex, race, 5-year age
group, apo(a) size, and concentrations of non-HDL-C, HDL-C, apoB,
apoA1, and Lp(a) with extent (percent arterial intimal
surface area involved) of atherosclerotic lesions by multiple linear
regression analysis.26 The linear model included
main effects and selected 2-factor interactions. We applied a logit
transformation to the proportion of surface area involved with lesions
after adding a small constant to avoid the logarithm of
zero.27 We applied a logarithmic transformation to the
serum lipoprotein and apolipoprotein concentrations. Previously, we
have shown strong associations of lesions and hypertension (obtained
from measurements of the small renal arteries)28 29 and
smoking (obtained from the serum thiocyanate concentration measured
postmortem)11 with lesions. We adjusted for the effects of
hypertension and smoking rather than exclude cases because the numbers
of these cases were appreciable (104 hypertensives and 286
smokers).
Because the number of cases available for these analyses was small, we limited our model to second-order terms.26 Previous analyses10 11 28 and preliminary analyses conducted as part of this analysis indicated no interactions of sex or race and the lipid or apolipoprotein concentrations or apolipoprotein size. Therefore, such interactions were not included in the model. The effect of sex was included in the model, allowing men and women to have different extents of lesions, and, similarly, the effect of race was included in the model, allowing blacks and whites to have different extents of lesions. Because Lp(a) levels are different in blacks and whites, we conducted separate analyses for the two races. Interactions of age with the risk factor variables were included in the model. Preliminary analyses did not indicate interactions among the risk factors and these were not included in the model. We did, however, investigate the interaction of non-HDL-C and Lp(a) levels.
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Results |
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Lipid and Apolipoprotein Values
Table 1
gives the mean lipid and
apolipoprotein values according to sex, race, and age group for 715
cases. Non-HDL-C levels increased with age in both sexes
(P=0.0020; no interaction of sex with age), but this
increase was more pronounced in whites (race and age interaction,
P=0.0398). Blacks had higher Lp(a) levels than did whites
(P=0.0001), and white women had higher Lp(a) levels than
white men, but black women did not differ from black men (sex and race
interaction, P=0.0172). Table 2 presents the correlations among the
lipid and apolipoprotein measures. Most of the correlations were
statistically significant, but no variable explained >25% of
variation in another variable. The strongest correlations were
between the 2 measures of ß-lipoproteins (non-HDL-C and apoB) and the
2 measures of HDL (HDL-C and apoA1). Lp(a) concentrations were
associated with the other measures, although not strongly.
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Relationships of Lipid and Apolipoprotein Measures With
Lesions
Lipid and apolipoprotein measures were categorized into thirds.
For non-HDL-C and HDL-C, cut points were based on published
values11 for a larger group from the PDAY study and are
only approximate for this subset. For apoA1 and apoB, cut points were
based on values from the cases used in this analysis. Because
of the large differences among races, Lp(a) cut points were determined
for each race separately.
Table 3 gives mean lesion involvement by
thirds of non-HDL-C and apoB. Non-HDL-C was positively associated with
extent of fatty streaks in all 3 arteries (P=0.0001) and
with extent of raised lesions in the abdominal aorta
(P=0.0465) and the right coronary artery
(P=0.0103). ApoB was significantly, although not as
strongly, associated with fatty streaks in all 3 arteries, but not with
raised lesions.
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Table 4 gives mean lesion involvement by
thirds for HDL-C and apoA1. HDL-C was inversely associated with fatty
streaks in all 3 arteries (thoracic aorta, P=0.0019;
abdominal aorta, P=0.0013; coronary artery,
P=0.0308) and with raised lesions in the thoracic aorta
(P=0.0189) and the right coronary artery
(P=0.0186). ApoA1 was inversely associated with fatty
streaks in the thoracic (P=0.0464) and abdominal
(P=0.0384) aortas and with raised lesions only in the
thoracic aorta (P=0.0011).
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Table 5 gives mean lesion involvement by
thirds for Lp(a). Because of large differences in Lp(a) concentrations,
blacks and whites were analyzed separately. Except for fatty
streaks in the right coronary artery of whites
(P=0.0006), Lp(a) concentrations were not associated with
either fatty streaks or raised lesions. Lp(a) was positively associated
with raised lesions in the thoracic (Lp(a) and age interaction,
P=0.0075) and abdominal aorta (Lp(a) and age interaction,
P=0.0033) in 25- to 34-year-old blacks and was negatively
associated with raised lesions in the abdominal aorta (Lp(a) and age
interaction, P=0.0487) in 25- to 34-year-old whites. To
investigate whether the association of Lp(a) with lesions depends on
the level of non-HDL-C (that is, an interaction of Lp(a) and
non-HDL-C), we analyzed the data after including non-HDL-C
levels (dichotomized at the median value of 3.35 mmol/L). There
was no significant interaction of Lp(a) and non-HDL-C in their effects
on lesions, and including non-HDL-C levels did not abolish the
significant association of Lp(a) levels with extent of lesions in the
right coronary artery of whites (results not shown). Similarly,
neither apoB concentrations nor the ratio non-HDL-C/HDL-C interacted
with Lp(a) concentrations in their effects on lesions (results not
shown).
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Table 6 shows that apo(a) size was
associated with extent of lesions for several categories (fatty streaks
of the abdominal aorta [P=0.0261] and right
coronary artery [P=0.0058] of blacks and raised
lesions of the abdominal aorta of whites [P=0.0098]). The
association of apo(a) size with raised lesions of the abdominal aorta
in whites remained after adjusting for Lp(a) concentration
(P=0.0184), but the two associations in blacks were not
significant after adjustment for Lp(a) concentrations (results not
shown).
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Fraction of Lesion Involvement Explained by Lipoprotein
Measures
Table 7 shows the fraction of lesion
involvement explained by the basic model (sex, age, race, smoking, and
hypertension), by the basic model plus lipid measurements, by the basic
model plus apolipoprotein measurements, and by the basic model plus
lipids and apolipoproteins. The basic model explained between 6.2% and
12.1% of the variation in fatty streaks and between 7.8% and 23.5%
of the variation in raised lesions. Including the lipid data (model 2),
the apolipoprotein data (model 3), or both (model 4) increased the
fraction of variation explained. However, most of the improvement in
prediction by the combined model was caused by including the lipid
data. Including the apolipoprotein data increased the average
R2 for 6 lesion and artery categories
by 1.3%, whereas including the lipid data increased the average
R2 by 2.5%. Only for raised lesions
of the thoracic aorta did apolipoprotein data significantly improve the
models beyond the basic covariates plus lipids information.
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Table 8 shows results of analyses
that included lipid and Lp(a) data for blacks and whites considered
separately. The basic model (sex, age, smoking, and hypertension)
explained between 2.6% and 16.5% of the variation in fatty streaks
and between 3.2% and 25.6% of the variation in raised lesions.
Including the lipid data yielded an average 4.7% increase in
R2 and a significant increase in 7 of
the race/lesion/artery categories. However, with 3 exceptions (fatty
streaks in the right coronary arteries of blacks and whites and
raised lesions in the abdominal aorta of whites), the Lp(a) data did
not provide a significant improvement over the model with the basic
covariates plus lipids.
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Summary of the Results
Compared with apoB levels, non-HDL-C concentrations were more strongly associated with extent of fatty streaks and raised lesions in the aorta and right coronary artery of young people aged 15 to 34 years. Similarly, HDL-C was more strongly associated with lesions than was apoA1. When both non-HDL-C and HDL-C were included in the predictive model, the 2 apolipoprotein measures generally did not provide a substantial increase in explanatory capability. Compared with Lp(a) concentration, apo(a) size was a slightly better predictor of lesions, but neither concentration of Lp(a) nor apo(a) size was associated with lesions as consistently as were the other lipoprotein measures.
Limitations of the Study
Hemodilution results from fluids administered in some cases to
trauma patients. After excluding samples with total
cholesterol levels <2.59 mmol/L, we have found that
HDL-C and non-HDL-C levels matched well the values reported in other
studies for similar sex, age, and race categories.11 As
with non-HDL-C and HDL-C, the serum concentrations of apoB and apoA1
are also similar to those reported for young men and
women.30 Furthermore, the average Lp(a) concentration for
blacks in this study (50.7 mg/dL) was similar to 48.1 mg/dL measured
with the same assay in a study of living blacks (n=45; W.D. Scheer,
unpublished observations, 1998). Although the data suggest the values
from these postmortem samples are similar to those taken from living
individuals, any additional variation in the measurements of the
lipoproteins and apolipoproteins because of hemodilution is expected to
reduce or degrade the associations of the lipoproteins and
apolipoproteins with atherosclerosis.
Postmortem degradation of proteins also may affect the results. In earlier work with dogs and nonhuman primates, we found no appreciable differences in apoA1 and apoB concentration values measured in postmortem and antemortem serum samples.18 Kronenberg and colleagues31 have shown that concentrations of Lp(a) particles bearing small apo(a) isoforms, the ones most often reported to be associated with CHD, decrease more rapidly in frozen serum or plasma than larger isoforms. Serum from PDAY cases was stored at -80°C for 1 to 8 years before analysis, so it is possible that Lp(a) concentrations were higher in life than we measured postmortem, thus blunting possible associations with lesions. A related issue is whether apo(a) isoform phenotypes might be altered by postmortem degradation. However, we have found that postmortem apo(a) isoform phenotypes were identical to those in antemortem samples from baboons.32 Our studies of 57 postmortem samples showed that in no case did postmortem degradation create a false apo(a) phenotype.32a Furthermore, after excluding obviously degraded samples from PDAY cases, we found that the frequencies of null and single-banded phenotypes were similar to those in other populations.33
Lipoprotein subpopulation phenotypes are emerging as potentially important predictors of atherosclerosis risk. Subpopulations of HDLs and apoB-containing lipoproteins (eg, Lp(a) and small dense LDLs) have been reported to be associated with risk of CHD and with severity of atherosclerosis.34 35 36 37 38 Except for Lp(a), however, we have not examined in detail associations of lipoprotein subpopulations with extent of lesions owing to the potential for postmortem enzymatic modifications of lipoprotein particle phenotypes.
Relationship of ApoB and ApoA1 Concentrations to
Atherosclerosis
Early reports of the capability of apolipoprotein concentrations
to predict atherosclerosis and CHD suggested that they
might be better predictors than the lipid components of
lipoproteins.39 40 41 42 43 However, later reports showed the
predictive ability of the apolipoproteins to be similar to, but weaker
than, those for the lipid components of lipoproteins, and that
apolipoproteins did not add predictive or discriminatory ability over
that of the lipid components.44 45 46 47 The controversial
nature of the issue was reflected in the titles of reviews and
editorials concerned with the topic.7 8 48 Recent results
from the Québec Cardiovascular Study suggested
that apoB concentrations, in conjunction with insulin levels and LDL
particle size, provide additional information on the risk of
ischemic heart disease compared with conventional lipid
measures.49
Most of these studies of apolipoproteins related serum or plasma levels
to clinical manifestations of CHD. A few used angiographic measures of
coronary artery lesions as end points. No other studies have
examined the association of apolipoprotein concentrations with
atherosclerotic lesions measured directly in autopsied persons.
Although apolipoprotein measures did increase
R2 values for raised lesions of the
thoracic aorta (Table 7
), the present results generally
suggest that the lipid measures are better predictors of
atherosclerosis and are consistent with the
results of most recent studies.
Relationship of Lp(a) With Lesions
With few exceptions,50 51 epidemiological studies
have found a positive association of Lp(a) concentrations and
cardiovascular disease. The basis for this association
is not known, but probably depends in part on the similarity of apo(a),
the diagnostic protein component of Lp(a), to
plasminogen, the zymogen for clot lysis.52 53
The potential for apo(a) to interfere with fibrinolysis
and to bind to fibrin surfaces has been discussed
elsewhere.54 55 Of course, Lp(a) particles also may
contribute to intimal lipid deposition as do LDL particles. Although
not as consistently as the lipid measures, Lp(a) concentrations
were significantly associated with lesions in blacks and whites. We
tested the hypothesis, suggested by other investigators,56
that Lp(a) might be more atherogenic in the presence of high levels of
non-HDL-C, or in the presence of high total
cholesterol/HDL-C ratios.57 However, we found
no evidence for interaction between Lp(a) and non-HDL-C concentrations,
nor between Lp(a) concentrations and total
cholesterol/HDL-C ratios.
Several studies have reported isoform-specific variation in lysine and fibrin binding properties of apo(a).58 59 60 61 Such variation could affect the ability of Lp(a) particles to interact with the vessel wall and has led to the hypothesis of significant variation in the relative atherogenicity of Lp(a) particles bearing different isoforms. Several groups have reported significant associations of apo(a) protein size with measures of cardiovascular disease,62 63 64 65 but for the most part, these associations were not independent of Lp(a) concentrations. That is, because of their well-known inverse relationship, apo(a) size appeared to behave in the models as a surrogate measure of Lp(a). End points for these previous studies included measures of CHD, but not atherosclerosis.
We found that apo(a) size was a significant predictor of fatty streaks in blacks and abdominal aortic raised lesions in whites. The association with fatty streaks became nonsignificant after adjusting for Lp(a) concentration, but the association with raised lesions in the abdominal aorta of whites remained significant (P=0.0184). Thus, the contribution of both Lp(a) concentration and apo(a) size to atherosclerosis in adolescence and young adulthood is, at best, small in comparison with the effects of the 2 major lipoprotein classes and smoking. Taken together with the abundant evidence that Lp(a) concentrations or apo(a) size or both are associated with increased risk of CHD, these results suggest that Lp(a) probably acts by interfering with thrombolysis in the advanced and terminal occlusive stages of atherosclerosis rather than augmenting the early and intermediate stages.
Implications for Primary Prevention
These results suggest that detection of high-risk individuals and
control of risk factors in teenagers and young adults should be focused
on total serum cholesterol and lipoprotein
cholesterol concentrations, and not on apolipoprotein or
Lp(a) concentrations.
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Acknowledgments |
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Grants from the NIH supported this research and they are listed in the Appendix.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The PDAY Research Group
The investigators cooperating in the multicenter study, "The Pathobiological Determinants of Atherosclerosis in Youth," and the grants supporting their activities, are listed below.
Program Director: Jack P. Strong, MD, 1996-date; Robert W. Wissler, PhD, MD, 1985–1996.
Steering Committee: J. Fredrick Cornhill, DPhil; Henry C. McGill, Jr., MD; C. Alex McMahan, PhD; Gray T. Malcom, PhD; Margaret C. Oalmann, DrPH; Jack P. Strong, MD; Robert W. Wissler, PhD, MD.
Participating Centers, Principal and Co-investigators, and Supporting Grants from the National Heart, Lung, and Blood Institute: University of Alabama, Birmingham, AL: Department of Medicine, Steffen Gay, MD (grant HL-33733), and Department of Biochemistry, Edward J. Miller, PhD (HL-33728); Albany Medical College, Albany, NY: Assad Daoud, MD (HL-33765); Baylor College of Medicine, Houston, TX: Louis C. Smith, PhD (HL-33750); University of Chicago, Chicago, IL: Robert W. Wissler, PhD, MD, Dragoslava Vesselinovitch, DVM, MS, Robert J. Stein, MD, and Robert H. Kirschner (HL-33740; HL-45715); The University of Illinois, Chicago, IL.: Abel L. Robertson, Jr., MD, PhD, Edmund R. Donoghue, MD, and Robert J. Buschmann, MD (HL-33758); Louisiana State University Medical Center, New Orleans, LA.: Jack P. Strong, MD, Gray T. Malcom, PhD, William P. Newman III, MD, and Margaret C. Oalmann, DrPH (HL-33746, HL-45720); University of Maryland, Baltimore, MD: Wolfgang Mergner, MD (HL-33752, HL-45693); Medical College of Georgia, Augusta, GA: A. Bleakley Chandler, MD (HL-33772); University of Nebraska Medical Center, Omaha, NE: Bruce M. McManus, MD, PhD (HL-33778); The Ohio State University, Columbus, OH: J. Fredrick Cornhill, DPhil (HL-33760, HL-45694); Southwest Foundation for Biomedical Research, San Antonio, TX: James E. Hixson, PhD (HL-39913) and David L. Rainwater, PhD (HL-50521); The University of Texas Health Science Center at San Antonio, San Antonio, TX: C. Alex McMahan, PhD, and Henry C. McGill, Jr., MD (HL-33749, HL-45719); Vanderbilt University, Nashville, TN: Renu Virmani, MD (HL-33770, HL-45718); and West Virginia University Health Sciences Center, Morgantown, WV: Singanallur N. Jagannathan, PhD (HL-33748).
Received September 15, 1998; accepted October 14, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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