© 1995 American Heart Association, Inc.
Articles |
Relation of a Postmortem Renal Index of Hypertension to Atherosclerosis in Youth
From the Department of Physiology & Medicine, Southwest Foundation for Biomedical Research, San Antonio, Tex (H.C.M.); the Department of Pathology, Louisiana State University Medical Center, New Orleans, (J.P.S., R.E.T., M.C.O.); and The University of Texas Health Science Center at San Antonio (C.A.M.).
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Abstract In a cooperative multicenter study, Pathobiological Determinants of Atherosclerosis in Youth, of 1164 young men 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories, we measured atherosclerosis of the aorta and the right coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure (MAP) during life, we classified the cases as either normotensive (MAP <110 mm Hg) or hypertensive (MAP
110 mm Hg). By this criterion, the prevalence of hypertension in
blacks was 16%; in whites, 12%. Hypertension was associated directly
with blood level of glycohemoglobin (an indicator of blood glucose
concentration) and with body mass index (BMI) but inversely with
thickness of the panniculus adiposus. Among hypertensive compared with normotensive cases, the extent of raised lesions (mainly fibrous plaques) was greater in the aortas of 30- to 34-year-old men and in the right coronary arteries of 25- to 34-year-old men. The prevalence of raised lesions involving 5% or more of the intimal surface was twofold greater in the aortas and right coronary arteries of hypertensive men throughout the 15-to-34–year age span of the study cases. The association of hypertension with raised lesions was not accounted for by adjusting for glycohemoglobin level, BMI, or thickness of the panniculus adiposus. Hypertension is associated with accelerated atherosclerosis in youth, particularly fibrous plaques.
Key Words: atherosclerosis • hypertension • renal vascular lesions
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Introduction |
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Hypertension, long known to predispose to the clinical manifestations of atherosclerosis,1 emerged from the longitudinal epidemiological studies of the 1950s as one of the three major predictors, along with serum cholesterol concentration and smoking, of risk of coronary heart disease and stroke.2 3 Hypertension is also associated with the extent and severity of atherosclerosis in both middle-aged and older humans4 5 and experimental animals.6 7 8 9
The augmentation of atherosclerosis by hypertension was thought to be primarily a problem of older persons until surveys showed a considerable range of blood pressures in children10 and tracking of blood pressures as the children matured.11 However, observations on the association of blood pressures with atherosclerosis in young persons were limited to a small number of persons.12 13 A multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), of coronary and aortic atherosclerosis in 15- to 34-year-old autopsied young persons showed that serum lipoprotein levels, smoking,14 glycohemoglobin levels, and adiposity15 were associated with atherosclerosis. The availability of kidney samples from these cases provided an opportunity to assess the association of renal vascular changes that are indexes of elevated blood pressure with the extent and severity of atherosclerosis in its early stages.
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Methods |
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Study Design
Fourteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and 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
Study subjects were persons 15 to 34 years of age,
inclusive, who died of external causes (accidents, homicides, or
suicides) within 72 hours after injury and were autopsied within 48
hours after death in one of the cooperating medical examiners'
laboratories. Age and race were obtained from the death certificate.
Persons of race other than black or white and those with congenital
heart disease, Down's syndrome, acquired immunodeficiency syndrome, or
hepatitis were excluded. From a total of 1692 cases collected between
June 1, 1987, and August 31, 1990, 160 cases were excluded because they
did not meet these inclusion criteria or because of incorrect sampling
or incomplete critical information. For this analysis, we did
not include females because there were too few cases. Of the 1181
remaining males, kidney samples were available for 1164 cases, which
form the basis of this report. The Institutional Review Board of each
participating center approved the use of tissue, blood, and data from
the human subjects in this study.
Dissecting and Preserving Arteries
An autopsy technician removed the aorta from a point 2 cm
proximal to the ligamentum arteriosum to a point 2 cm distal from the
iliac bifurcation. Branching arteries were severed close to the aortic
wall, and adventitial fat was removed by sharp dissection. The PDAY
technician opened the aorta along a line on the dorsal surface midway
between the orifices of the intercostal and lumbar arteries, rinsed the
intimal surface with Hanks' balanced salt solution, and flattened it
with the adventitial surface downward. The PDAY technician then
bisected the aorta longitudinally along a line on the ventral surface
and midway between the intercostal and lumbar ostia, prepared the right
half for histochemical and chemical analyses, and placed the
left half on a piece of cardboard with the adventitia downward. This
left half was covered with absorbent cotton and fixed in 10%
neutral-buffered formalin in a flat pan for 48 hours.
The PDAY technician opened the right coronary artery from its origin to the point at which it turned downward along the posterior interventricular sulcus with blunt-point microdissecting scissors, dissected it from the heart, removed the epicardial fat, and fixed it in the same manner as the aorta. The other main branches of the coronary artery system were prepared for other studies.
The collection centers placed each aorta and coronary artery in a plastic bag and shipped accumulated tissues to the central laboratory each month. The central laboratory stained the arteries with Sudan IV16 and packaged each artery with its identification number in a transparent plastic bag with a slight excess of 10% formalin.
Weight
The disrobed body was weighed in the units commonly used by
the local medical examiner or coroner before organs, liquid, or other
material was removed from the body. Weight was recorded to the
nearest one-half kilogram or nearest pound. A record was made
when an amputation or other operative procedure that might alter weight
appreciably was present.
Height
The length of the cadaver, from the vertex of the cranium
to the base of the heel, was measured in units commonly used by the
local medical examiner or coroner. The measuring instrument was laid
parallel to the body, which was in a supine position and with the
inferior extremities extended. Measurements were
recorded to the nearest centimeter or one-half inch.
Panniculus Adiposus
The autopsy technician measured subcutaneous fat, including
the subcutaneous tissue from the inner edge of the rectus sheath, to
the nearest millimeter at a point halfway between the xyphoid process
and the umbilicus. For statistical analysis, cases were
classified into categories of panniculus thickness corresponding to
quartiles of the entire sample.
Body Mass Index
Body mass index (BMI) was computed as weight (kilograms)
divided by height (meters) squared. Cases were classified into
categories of BMI <25, BMI 25 to 30, and BMI >30
kg/m2.17
Heart Weight and Left Ventricular
Thickness
The prosector weighed the heart to the nearest gram after
removing blood clots, measured the thickness of the left ventricle to
the nearest millimeter at its obtuse margin halfway between the mitral
valve and apex, and measured the thickness of the right ventricle at
the conus 1 cm from the pulmonary valve. Cases were classified
into categories of heart weight/height <2.5 and 2.5
g/cm.18
Grading Arteries
Pathologists blinded to demographic, clinical, or
pathological observations and collection site evaluated the right
coronary arteries and left halves of the aortas. They visually
estimated the extent of intimal surface involved with fatty streaks,
fibrous plaques, complicated lesions, and calcified lesions by
procedures developed in the International
Atherosclerosis Project.16 A fatty
streak was defined as a flat or slightly elevated intimal lesion
stained by Sudan IV and without other underlying changes. A fibrous
plaque was a firm, elevated intimal lesion, sometimes partially or
completely covered by sudanophilic deposits. A complicated lesion was a
plaque with hemorrhage, thrombosis, or ulceration. A calcified
lesion was an area in which calcium was detectable, either visually or
by palpation, without overlying hemorrhage, ulceration, or
thrombus. The sum of the percentages of surface involved with fibrous
plaques, complicated lesions, and calcified lesions by gross visual
grading was designated "raised lesions." Most of the raised
lesions were fibrous plaques.19 Consensus grading of
lesions was the average of independent gradings by three pathologists.
Intraobserver variability was assessed by repeated independent gradings
of coded specimens randomly interspersed among new specimens. Agreement
among observers was reported previously.19
Dissecting, Preserving, and Processing Kidney Tissue
Kidneys were stripped of perirenal fat and capsule and
bisected by the PDAY staff. One section that included cortex and
medulla was taken from each kidney, fixed in 10% neutral-buffered
formalin, and shipped to the central laboratory. At the central
laboratory, blocks perpendicular to the capsular surface were embedded
in paraplast, sectioned at 6 µm, and stained with PAS-Alcian blue.
The two sections of tissue represented 2 to 4
cm2 of cross-sectional area of the renal cortex.
Classification of Hypertension Status
Arterial changes associated with hypertension
were measured in histologic sections of kidney by a method developed by
Tracy et al.20 The grader used a microscope equipped with
x10 and x40 objective lenses and an eyepiece ruler marked at units
corresponding to 10 µm under the x10 objective lens. The grader
measured the outer diameter, from one outer media to the other, of the
least axis of the elliptic profile of all arterial profiles
with outer diameters of 80 to 300 µm. The grader then measured the
thickness of the intima, also along the least axis, under the x40
lens. The measurement was made in the better presented of the
two opposite walls; if both were equally well presented, an
average of the two was used. One observer made all measurements. An
average of 36.8 arteries per case were measured (range, 6 to 69).
Measurements were grouped into those derived from arteries with outer
diameters of 80 through 149 µm (arteries remote from the heart) and
those derived from arteries with outer diameters of 150 through 300
µm (arteries more proximal to the heart). A renal measure of
hypertension (RMH) was calculated by dividing the average thickness of
the intima by the average outer diameter of the artery separately for
the measurements made on the smaller (remote) arteries and the
measurements made on the larger (proximal) arteries.
Each case was classified as normotensive or hypertensive by an
algorithm derived from an equation that predicted mean
arterial pressure (MAP) from RMH and age.21 (A
typographical error in the published equation was corrected by changing
the sign for one coefficient from positive to negative.) The
normotensive category included cases with a predicted MAP <110 mm Hg;
hypertensive, those with predicted MAP 110 mm Hg. These cut points
were selected on the basis of analysis of lengthy lifetime
records of blood pressure measurements in persons whose kidneys
were examined after autopsy.22 The cut points were
similar, but not identical, to MAPs computed from systolic and
diastolic pressures used as cut points in epidemiological
surveys. For example, the frequently used definition of borderline
hypertension as systolic blood pressure between 140 and 160 mm
Hg and diastolic blood pressure between 90 and 95 mm Hg
yields a lower limit of computed MAP (sum of systolic plus
twice diastolic divided by 3) of 107 mm Hg; and the
definition of hypertension as systolic blood pressure greater
than 160 mm Hg and diastolic blood pressure greater than 95
mm Hg yields a limit of computed MAP of 117 mm Hg.23
In repeated classification of subjects as either normotensive or
hypertensive, without knowledge of her previous grade, the single
observer agreed with herself in 88% of a sample of 97 cases (
=0.66,
P<.0001).24 The observer agreed with an
independent observer in 72% of a sample of 65 cases (=0.18,
P=.0103). These findings indicate acceptable
agreement.24
The relation of hypertension classification to atherosclerotic lesions was analyzed by using RMH values derived from proximal and remote arteries separately. The results were similar; therefore, only the results based on measurements of the smaller remote arteries are presented.
Statistical Methods
The associations of hypertension classification, race, and
5-year age group with percent intimal surface area involved with
lesions, heart weight, heart weight/height ratio, and ventricle
thicknesses were analyzed by using ANOVA.25 The
linear model included the main effects of hypertension classification,
race, 5-year age group, and all two-factor interactions. A logit
transformation was applied to the proportion of surface area involved
with lesions.26 A small constant (0.001) was added to
avoid the logarithm of zero. A logarithmic transformation was applied
to the heart weight, heart weight/height ratio, and ventricle
thicknesses. The transformations made the data better satisfy the
assumptions underlying the statistical analysis. The prevalence
of cases classified as hypertensive and the prevalence of cases having
5% or more of the intimal surface involved with lesions were
analyzed by using logistic regression.27 Tests of
hypotheses used the likelihood ratio test. Convergence problems in the
logistic regression maximum likelihood analysis of the
prevalence of cases having 5% or more of the intimal surface involved
with lesions necessitated a model simpler than that used for the ANOVA.
Preliminary investigation indicated a main-effects model was
adequate.
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Results |
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Distribution of Cases by Blood Pressure Classification
Table 1
shows the number and percentage of
cases classified as normotensive and hypertensive by race and age.
There is no significant interaction between race and age. The
percentage of cases classified as hypertensive is higher among blacks
than among whites (blacks, 15.7%; whites, 11.7%;
P=.0250).
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Extent of Lesions by Blood Pressure Classification
Table 2 shows the percent intimal surface area
involved with lesions by age and blood pressure classification.
Hypertension is not associated with fatty streaks in the aorta or the
right coronary artery but is associated with raised lesions in
both segments of the aorta and in the right coronary artery.
Hypertension is associated with more extensive raised lesions in the
thoracic aorta of blacks but not of whites (race by blood pressure
interaction, P=.0006; results not shown). The effect of
hypertension on raised lesions is twofold to threefold after age
30.
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Prevalence of Lesions by Blood Pressure
Classification
Table 3 gives the estimated prevalence of
cases having lesions covering 5% or more of the intimal surface by age
and blood pressure classification. Prevalence of fatty streaks covering
5% or more of the aortic intimal surface area is near 100% (results
not shown). Prevalence of raised lesions covering 5% or more of the
intimal surface is greater in hypertensive persons than normotensive
persons for the abdominal aorta and right coronary artery
throughout all age groups from 15 to 34 years.
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Heart Size and Blood Pressure Classification
Table 4 gives the mean heart weight, heart
weight/height ratio, right ventricle thickness, and left ventricle
thickness by age and blood pressure classification. There is little or
no association between these variables and the blood pressure
classification.
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Heart Size and Atherosclerosis
Table 5 gives the percent intimal surface area
involved with lesions by race and heart weight/height ratio. Heart
weight/height ratio 2.5 is associated with more extensive fatty
streaks and raised lesions in the right coronary artery. Whites
having a heart weight/height ratio 2.5 have greater involvement with
raised lesions in the right coronary artery than blacks.
Although heart weight/height ratio is not associated with the blood
pressure classification (Table 4
), individuals having a large heart
weight/height ratio have more extensive coronary lesions.
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Relation of Blood Pressure Classification to Glycohemoglobin
and Adiposity
Table 6 shows the prevalence of hypertension
by glycohemoglobin level, BMI, and thickness of the panniculus. Cases
with elevated glycohemoglobin have a higher prevalence of hypertension
than those with normal glycohemoglobin levels. Cases with BMI >30
kg/m2 also have a higher prevalence of hypertension.
However, as the thickness of the panniculus increases, the prevalence
of hypertension decreases.
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Relation of Lesions to Blood Pressure, Adiposity, and
Glycohemoglobin
When the relation of blood pressure classification to extent
of atherosclerotic lesions (as shown in Tables 1 through 3) is adjusted
for BMI and glycohemoglobin, the results are similar to those obtained
without adjustment (results not shown). The adjustment for
glycohemoglobin, which had a substantial effect on raised lesions in
the 30- through 34-year age group,15 increases the
estimated effect of hypertension on extent of raised lesions in the
right coronary artery from about threefold to fourfold. The
relation of blood pressure classification to lesions in cases with
normal glycohemoglobin levels (that is, <8%) is similar to that in
Table 2 (results not shown).
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Discussion |
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Summary of Results
Hypertension, as measured by the intimal thickness of small renal arteries, is associated with about a twofold greater prevalence of raised lesions in the aortas and right coronary arteries of young white and black men between 15 and 34 years of age (Table 3
). Hypertension is associated with a greater
extent of raised lesions in aortas of 30- through
34-year-old men, and in right coronary arteries of 25-
through 34-year-old men (Table 2). There is no consistent
association of hypertension with extent of fatty streaks or with
cardiac mass. Although hypertension is associated with elevated blood
glycohemoglobin and adiposity, the effect of hypertension on
atherosclerosis is not accounted for by those
variables.
Validity of Blood Pressure Measured by Renal Intimal
Thickness
From 166 subjects whose blood pressure was measured during
life and whose renal vessels were measured in kidney samples obtained
at autopsy, Tracy et al20 developed an equation that
estimated mean arterial blood pressure. This equation took
into account the age of the subject. The predictive equation was tested
in 154 subjects whose blood pressures were measured in a longitudinal
epidemiological study (Honolulu Heart Program) and who were later
autopsied.28 The multiple correlation coefficient was .44
(P=.0001). This association is consistent with
evidence indicating that increased intrarenal vascular resistance is
closely associated with hypertension and that abnormal renal
vasoconstriction exists in the prehypertensive
state.29
Comparison With Previous Results
Many studies have reported an association of hypertension
with more extensive and more severe atherosclerosis in
middle-aged and older persons.5 In a small number of
subjects between 7 and 24 years of age from the Bogalusa Heart Study
whose blood pressures had been measured during life, Newman et
al12 reported a borderline-significant association of
systolic and diastolic pressure with
coronary artery fibrous plaques; and later, in a larger number
of cases from the same study, Berenson et al13 reported an
association of systolic blood pressure with coronary
artery fatty streaks in white males. The results reported here extend
those limited observations and indicate that elevated blood pressure
begins to accelerate the conversion of fatty streaks to raised lesions
as early as the latter part of the second decade of life, even before
it leads to cardiac hypertrophy.
Prevalence of Hypertension
The prevalence of hypertension among these young men, which is
based on an MAP 110 mm Hg, is lower than the prevalence among 18- to
34-year-old men in the NHANES II survey for 1976 to 1980. That
survey, using thresholds of 140 mm Hg systolic and 90 mm Hg
diastolic (equivalent to an MAP of 
107 mm Hg), found
that 16% of 18- to 24-year-old and 21% of 25- to 34-year-old
white men were hypertensive and that 11% of 18- to 24-year-old
(small number of cases) and 23% of 25- to 34-year-old black men
were hypertensive.30 The prevalence rates had declined
since the NHANES I survey of 1971 to 1975.31 Thus, the
prevalence of hypertension predicted by renal artery intimal thickness
is similar to the prevalence based on measuring blood pressures in
samples of the living population.
Association of Blood Pressure With Heart Size
Most32 33 34 but not all35 36
echocardiographic studies in children and adolescents
have shown correlations of heart size with blood pressure. Most
echocardiographic surveys of adults have obtained
similar results.37 38
However, in the largest single population-based study of 946
healthy subjects 18 through 38 years of age, there was no association
of borderline hypertension with left ventricular mass,
although there were numerous associations with cardiac functional
variables.36 Consequently, the lack of a positive
association of heart weight, heart weight/height ratio, or
ventricular wall thickness with predicted blood pressure
classification (Table 4) should not be surprising. This observation
suggests that renal artery intimal thickness, which is strongly
associated with atherosclerotic raised lesions, may be a marker for an
early stage of elevated arterial blood pressure or a
precursor of elevated arterial blood pressure, as suggested
by Tracy et al.21 It is also possible that both renal
arterial intimal hyperplasia and whatever processes convert
fatty streaks to fibrous plaques may result from the same humoral agent
involved in the early natural history of hypertension.
Conclusion
Intimal thickness of small renal arteries, an anatomic marker
for hypertension, is strongly associated with raised lesions (mainly
fibrous plaques) of the aortas and right coronary arteries of
young adults. The effect of hypertension on
atherosclerosis begins in the second decade of life and
precedes an effect on cardiac mass. The results suggest that the early
stages of hypertension accelerate atherogenesis primarily by
accelerating the conversion of fatty streaks to fibrous plaques.
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Acknowledgments |
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Grants from the National Institutes of Health (National Heart, Lung, and Blood Institute) supporting this research are listed after the name of the recipient in the "Appendix."
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Footnotes |
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Reprint requests to Jack P. Strong, MD, Department of Pathology, LSU Medical Center, 1901 Perdido St, New Orleans, LA 70112.
1 A list of participants is given in the Appendix. 
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Program Director
Robert W. Wissler, PhD, MD, University of Chicago; Associate Director: Abel L. Robertson, Jr, MD, PhD, The University of Illinois.
Steering Committee
J. Fredrick Cornhill, DPhil, The Ohio State University; Henry C.
McGill, Jr, MD, Southwest Foundation for Biomedical Research; C. Alex
McMahan, PhD, The University of Texas Health Science Center at San
Antonio; Abel L. Robertson, Jr, MD, PhD, The University of Illinois;
Jack P. Strong, MD, Margaret C. Oalmann, Dr PH, Gray T. Malcolm, PhD,
Louisiana State University Medical Center; Robert W. Wissler, PhD, MD,
University of Chicago.
Standard Operating Protocol and Manual of Procedures
Committee Chair
Margaret C. Oalmann, Dr PH, Louisiana State University Medical
Center.
Participating Centers
University of Alabama, Birmingham. Department of Medicine:
principal investigator, Steffen Gay, MD; coinvestigators, Renate E.
Gay, MD, Guoquiang Huang, MD (HL-33733). Department of Biochemistry:
principal investigator, Edward J. Miller, PhD; coinvestigators, Donald
K. Furuto, PhD, Margaret S. Vail, Annie J. Narkates (HL-33728).
Albany Medical College, NY. Principal investigator, Assad Daoud, MD; coinvestigators, Adriene S. Frank, PhD, Mary A. Hyer, E. Carol McGovern (HL-33765).
Baylor College of Medicine, Houston, Tex. Principal investigator, Louis C. Smith, PhD; coinvestigator, Faith M. Strickland, PhD (HL-33750).
University of Chicago, Ill. Principal investigator, Robert W. Wissler, PhD, MD; coinvestigators, Dragoslava Vessellinovitch, DVM, MS, Akio Komatsu, MD, PhD, Yoshiaki Kusumi, MD, Gregory M. Culen, DPM, Alyna Chien, BA, Alexis Demopoulos, BA, Gertrud Friedman, BA, R. Timothy Bridenstein, MS, Robert J. Stein, MD, Robert H. Kirschner, MD, Manuela Bekermeier, ASCP, Blanche Berger, ASCP, Laura Hiltscher, ASCP (HL-33740, HL-45715).
The University of Illinois, Chicago. Principal investigator, Abel L. Robertson, Jr, MD, PhD; coinvestigators, Robert J. Stein, MD, Edmund R. Donoghue, MD, Robert J. Buschmann, PhD, Yoshihisa Katsura, MD, Tae Lyong An, MD, Eupil Choi, MD, Nancy Jones, MD, Mitra S. Kalelkar, MD, Yuksel Konakci, MD, Barry Lifschultz, MD, V. Ramana Gumidyala, MD, Rose M. Harper, BS, Francis Norris, HTL (ASCP) (HL-33758).
Louisiana State University Medical Center, New Orleans. Principal investigator, Jack P. Strong, MD; coinvestigators, Gray T. Malcom, PhD, William P. Newman, III, MD, Margaret C. Oalmann, Dr PH, Paul S. Roheim, MD, Ashim K. Bhattacharyya, PhD, Miguel A. Guzman, PhD, Ali A. Hatem, MD, Conrad A. Hornick, PhD, Carlos D. Restrepo, MD, Richard E. Tracy, MD, PhD, Cecilia C. Breaux, MS, Stephanie E. Hubbard, Cynthia S. Zsembik, DeAnne G. Gibbs, Dana A. Troxclair (HL-33746, HL-45720).
University of Maryland, Baltimore. Principal investigator, Wolfgang Mergner, MD, PhD; coinvestigators, James H. Resau, PhD, Robert D. Vigorito, MS, PA, Q-C Yu, MD, J. Smialek, MD (HL-33752, HL-45693).
Medical College of Georgia, Augusta. Coprincipal investigators, A. Bleakley Chandler, MD, Raghunatha N. Rao, MD; coinvestigators, D. Greer Falls, MD, Ross G. Gerrity, PhD, Benjamin O. Spurlock, BA; associate investigators, Kalish B. Sharma, MD, Joel S. Sexton, MD; research assistants, K.K. Smith, HT (ASCP), G.W. Forbes (HL-33772).
University of Nebraska Medical Center, Omaha. Principal investigator, Bruce M. McManus, MD, PhD; coinvestigators, Jerry W. Jones, MD, Todd J. Kendall, MS, Jerrold A. Remmenga, BS, William C. Rogler, BS (HL-33778).
The Ohio State University, Columbus. Principal investigator, J. Fredrick Cornhill, DPhil; coinvestigators, William R. Adrion, MD, Patrick M. Fardel, MD, Brian Gara, MS, Edward Herderick, John Meimer, MS, Larry R. Tate, MD (HL-33760, HL-45694).
Southwest Foundation for Biomedical Research, San Antonio, Tex. Principal investigator, James E. Hixson, PhD (HL-39913).
The University of Texas Health Science Center at San Antonio. Principal investigator, C. Alex McMahan, PhD; coinvestigators, George M. Barnwell, PhD (deceased), Henry C. McGill, Jr, MD, Yolan Marinez, MA, Thomas J. Prihoda, PhD, Herman S. Wigodsky, MD, PhD (HL-33749, HL-45719).
Vanderbilt University, Nashville, Tenn. Principal investigator, Renu Virmani, MD; coinvestigators, James B. Atkinson, MD, PhD, Charles W. Hartland, MD, Linda Gleaves, RA, Crystal Gleaves, HT, Manik Paul, RA (HL-33770, HL-45718).
West Virginia University Health Sciences Center, Morgantown. Principal investigator, Singanallur N. Jagannathan, PhD; coinvestigators, Bruce Caterson, PhD, James Frost, MD, K. Murali K. Rao, MD, Syamala Jagannathan, Peggy Johnson, Nathaniel F. Rodman, MD (HL-33748).
Received August 9, 1995; accepted September 27, 1995.
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