ANATOMIC FEATURES OF GROWTH FAILURE IN

CONGENITAL HEART DISEASE

Richard L. Naeye, M.D.
Department of Pathology, Tile Univerrity of Vermont College of Medicine, Burlington, Vermont,
and Congenital Heart Disease Research and Training Center, Chicago, Illinoi.r

NALYSIS of tissue abnormalities in mdi- are listed in Table I. Excluded were those
viduals with congenital cardiac malfor- individuals having disorders in which car-
mations provides a tool for studying the diac malformations and abnormal central
growth retardation often present in such nervous system development are known to
individuals. Many such persons reportedly coexist, i.e., mongolism, other chromosomal
have a retarded intra-uterine growth, and abnormalities, congenital rubella, and su-
some who fail to grow after birth have tis- pravalvular aortic stenosis. Also excluded
sue changes usually associated with severe were individuals having brain abscesses,
2 A slowing of normal eel- infarcts, or evidences of focal cerebral dam-
bular multiplication is apparently responsi- age related to antecedent cardiac surgery.
ble for the retarded postnatal growth in A wide variety of cardiac malformations
some infants having cardiac malformations was represented; some individuals had left-
due to congenital rubella. On the other to-right intra-or extracardiac shunts and
hand, some older children with congenital others had right-to-left shunts (Table I).
cardiac malformations reportedly have a Cyanosis suggesting hypoxemia was evi-
subnormal number of skeletal muscle cells dent in the group with right-to-left shunts;
which Cheek and his associates think may many of this group also had a relative poly-
be related to chronic tissue hypoxia.5 cythemia. Most infants dying in the first 3
Some of the seeming discrepancies in years of life had some degree of chronic
these reports no doubt relate to multiple cardiac failure. In some instances cardiac
factors involved in the growth retardation, surgery also contributed to death. In con-
but consideration of the problem is also trast, less than one quarter of the individ-
made difficult by the character of the pub- uals older than 3 years of age died after
lished studies; such studies have usually in- protracted cardiac failure. A few of these
volved a small number of selected patients, older individuals died during cardiac cath-
often in a narrow age range. The present eterization or angiography, but most died
study attempts a broader perspective. during or immediately following attempted
Organ and body structure were examined corrective cardiac surgery.
in 220 individuals having a wide variety of Autopsy material from 91 control pa-
congenital cardiac anomalies; ages ranged tients was also examined. These individuals
from birth to 44 years. varied in age from birth to 37 years. Fifty-
one were medical examiner cases, dying as
CASE MATERIAL a consequence of major trauma. Twenty
Autopsy material was examined from had some type of acute infectious process.
routine postmortem examinations of 220 in- The remainder died with such disorders as
dividuals with congenital cardiac malfor- cerebral hemorrhage, convulsions of tin-
inations. Ages and cardiac malformations known cause, salicylate poisoning, volvulus,

(Received June 23; revision accepted for publication September 9, 1966.)

This study was supported by grants from the National Heart Institute, Public Health Service, Grants
HE 06469-05 and HE 07605-04 and a grant from the Vermont Heart Association.
ADDRESS: Department of Pathology, The University of Vermont College of Medicine, Burlington.
Vermont 05401.
PEDIATRICS, Vol. 39, No. 3, March 1967

433

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434 CONGENITAL HEART DISEASE

TABLE I
IRINCIPAL DIAGNOSES AND AGE Gnoups ARE LISTED FOR 220 INDIVIDUALS WITH CONGENITAL HEART DissE

. . 0-1 1 vk 1-4 4-12 I 1-8 Oter S

Diagnosis nk Totals
1 flU) 1110 11W yr yr

Ventricular septal defect 7 6 7 6 11 8 45

Transposition great vessels 7 7 1.5 4 4 4 41
Fetralog3 of Fallot 2 3 3 13 13 34
Preductal coarcthtion aorta 8 1 3 1 1 14
Aortic valvular stenosis 3 3 4 1 2 13
Ventricular and atrial septal defect 1 3 2 1 1 2 10
Pulmonic valvular atresia 1 2 3 1 1 8
Tricuspid valvular atresia 2 3 1 2 8
Aortic valvular atresia 6 1 1 8
Anomalous pulmonary venous return 1 1 3 1 6
Atrial septal defect 2 3 5
Common atrioventricular canal 1 1 1 2 5
Aortic valvular stenosis 2 1 1 4
Pulmonic valvular stenosis and atrial septal
defect 1 1 2 4
Pulmonic valvular stenosis and ventricular
septal defect 1 1 1 3
Pulmonic valvular stenosis and tricuspid
valvular stenosis 1 1 1 3
Postductal coarctation of Aorta I 1 2
Single ventricle 1 1 2
Trunchus arteriosus 1 1
Aortic ring 1 1
Pulmonic valvular stenosis 1 1
Mitral valvular atresia 1 1
Cor biloculare I I

Total 44 26 45 29 41 35 220

and thermal burns. None of the 91 control categories for the cardiac patients and for
patients lived longer than 3 days after trau- the control patients (Fig. 1, Table II).
ma or onset of illness, and most died within The method of line sampling was used to
the first day. quantitate individual components of liver
and adrenal cortex.1#{176} With this method,
METHODS random microscopic fields are projected
Organ weights and body measurements onto measured lines with a camera lucida.
were obtained from autopsy protocols. In Each tissue component to be analyzed (i.e.,
each patient, body weight, body length, cell, nucleus, or cytoplasm) is measured
and weights of organs were calculated in along the line at those points where it inter-
percent of mean values for control patients. sects the line. By this means, the relative
The control data of Stuart and Stevenson6 sizes of cells and the relative mass of such
were used for body weights and body cellular components as the cytoplasm can
lengths, the data of Schulz, et al.7 for organ be determined. In most instances multiple
weights in the first year of life, and the data sections of liver and adrenal were thus ex-
of Coppoletta, et al.8 and Stowens#{176} for amined. These two organs were selected
older patients. A mean percent of control because previous studies have shown that
values was then calculated for each organ reduction of cytoplasmic mass in their
or body measurement in each of several age parenchymal cells is a sensitive index of

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 ARTICLES 435

LENGTH
l00

U,
4,
C
80
0

C
2
0

0-I I WEEK- -4 4-12 -8 OVER

WEEK MONTH MONTHS MONTHS YEARS 8 YEARS

age
FIG. 1. Body length and body and organ weights are charted in percent of control values for individuals
with congenital heart disease. Most values are near control values at birth, become subnormal in the age
period 1 month to 8 years, and then return toward control levels in later years. In the period 1 month to
8 years, adrenals, thvmus, and liver are disproportionately small, a pattern typical of undernutrition.

muSh1 The method of line sam- control values. In contrast, organ and body
pling was also used to determine the rela- measurements became progressively more
tive number of various cell types in an subnormal with increasing age in infants
organ.312 with cardiac malformations (Fig. 1). Mea-
The processing of tissues for histologic surements reached their lowest relative val-
quantitation leads to shrinkage artifacts so ues in infants aged 4 months to 8 years. Al-
that values recorded in the current study
cannot be directly transposed to living tis- TABLE II
sues. Since similar fixation wasused for
GROUP ME.tSL-REMENTS IN 91 CONTROL PATIENTS
study and control tissues, it is hoped that IN PERCENT OF CONTROL \ALUES*

artifacts were relatively constant through

the cases, permitting valid comparisons be- .1 ge Death
-
of
.Ifeasurement
tween groups. The t-test was the statistical 0-1 too 1-12 mo 1-8 no ocer S yr

method most often used to determine the

Body weight 99l% 1O. 6% 1O6.O 98.9%
significance of the data collected. Bodylength 100.3% 100.4% iOO.9% 99.%
Brainweight 101.5% 107.6% i03.5% iGS.i%
RESULTS Liverweight iil.7% 113.6% 1i4.I% i1.O%
Kidneyweight 106.9% 95.9% 97.7% 103.4%
Infants with cardiac malformations were Adrenaiweight 118.9% 19.6% 101.4% 10.i%

92.4% as heavy at birth as expected for ges- Thymusweight 138.3% 148.7% iio.6% 14.9%
Number of cases i7 18 0 36
tational age, a deviation from normal val-
ues of only marginal significance (P < .05). . As published by Stuart and Stevenson, Schub. et a!.,7 Coppo-
leRa and Wolbach, and Stowens. Most values are close to the pub-
Other weights and measurements in the lished data. Exceptions are the adrenal and thymus which are
newborns did not var significantly from heavier in controls used in the current study than in published data.

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436 CONGENITAL HEART DISEASE

though thymus, adrenals, and liver were normal values in individuals who die acute-
relatively smaller than were kidney, brain, ly or after a very brief illness, the present
and body length, all values (Fig. 1) were study compared organ and body measure-
significantly less than control values (P < ments of 91 individuals who died acutely
.001). Muscle wasting and scanty subcuta- and had no cardiac anomalies with the pub-
neous adipose tissue were often mentioned lished control measurements used for the
on autopsy protocols of infants aged 4 congenital heart cases (Table II). Most val-
months to 8 years, partially explaining the ues in the 91 acute death cases were close
markedly subnormal body weights re- to published control figures. Exceptions
corded during this period. In older individ- were the adrenal and thymus, which were
uals with cardiac malformations, body and heavier in the acute death controls than in
organ measurements again approached the published controls. These larger adrenal
control values (Fig. 1). and thymic weights in acute death controls
The aforementioned deviations from con- can only increase the significance of the
trob values only have meaning if the control subnormal weights recorded for these or-
values themselves are defined. All pub- gans in infants with congenital heart dis-
lished postmortem control data are some- ease.
what suspect because individuals whose The mean mass of cytoplasm in individ-
body and organ measurements may have ual hepatic cells was plotted in 81 of the 91
been altered by disease have presumably control patients (Fig. 2). Ten of the control
been included. On the assumption that patients were unsuitable because hepatic
body and organ measurements are nearest sections were absent or inadequate in size.

l00 x
S
4, x
V
S
.80
C
x#{174}
. S x S
x S
#{174} S
\60 .
) cohtrol level
. S #{174} S
S S
S S
x X
S
S
X

20 XX
x
X

0 4 8 l22 6 10 14 18
age in months age in years

FIG. 2. The mean mass

of cytoplasm in individual hepatic cells is plotted in 81 control patients who had
no cardiac malformations
(symbol #{149})
and in 115 individuals with cardiac mafformations (symbol x).
Values in the cardiac patients are near control levels at birth but become subnormal in the age group
2 to 24 months. In contrast, most older cardiac patients have an increased mass of cytoplasm in hepatic
cells, especially individuals with cyanotic types of cardiac malformations who are designated by the
symbol 0. In this figure no attempt was made to separately designate infants with cyanotic types of
cardiac malformations who were less than 2 \ears of age. All values are in arbitrary units.

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 ARTICLES 437

20 I I

I I
I
3 I I S
I
a I

> HO I I

II

I
I

10 O II IIIl1 I S
I
II

.
) 111? I
I

I
S 901. I
U
II I

I. I
I11
I I
I
I
C I
I
801 I

-C
.2
S.
I

It I I I

70 I I
C

I #{149} I
-S
60 0 4 I 8 2 6 20 12 20 28 36
age in months age in years

FIG. 3. Brain weights are plotted in percent of mean control values for individuals with congenital heart
disease. As a group, brain weights in stillborn infants with cardiac anomalies do not vary significantly
from control values. In the age period 6 to 24 months, most brain weights are subnormal. Still older
individuals with cardiac anomalies again have brain weights near control values.

Control values rose from a mean of 42 units In infants of 1 to 36 months with cardiac
at birth to a value of 60 units at 18 years of malformations, such values were subnormal,
age (Fig. 2). Hepatic cytopbasmic values while in older infants most values were
were also determined for 115 individuals again at control levels. Nuclear dimensions
with cardiac malformations. In the first few of adrenal cortical cells were close to con-
weeks after birth, values in the cardiac trol values in all age groups.
cases were within normal limits. At subse- Special attention was directed toward the
quent ages these values became progres- brain because of a previous suggestion that
sively smaller (Fig. 2) so that, as a group, undernutrition in congenital heart disease
cardiac infants aged 2 to 16 months had a sometimes leads to a retarded growth of
cytoplasmic value only 59% of the control that organ in the early months after birth.2
mean (P < .001). In the stillborn infants, brain weights as a
In contrast, most older individuals with group did not vary significantly from con-
cardiac malformations had an increased trol values (97.5%, P < .3). At subsequent
rather than a subnormal mass of cytoplasm ages, the relative postmortem weight of this
in individual hepatic cells (Fig. 2). Taking organ progressively decreased in the infants
all cardiac patients 3 years of age and older with malformed hearts (Fig. 3). In the
as a group, the mean hepatic cytoplasmic group aged S to 24 months, only one infant
value was 134% of control values (P < .02). had a brain weight greater than the mean
Dimensions of hepatic cell nuclei were nor- for control infants of the corresponding
mab in congenital heart patients of all ages. age (Fig. 3). As a group, infants aged 8 to
In newborn infants with cardiac mabfor- 24 months had brain weights 87.1% of con-
mations, values for cytoplasm in individual trol values (P < .01). In this age period, the
adrenal cortical cells were at control levels. weight of individual brains bore a direct

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438 CONGENITAL HEART DISEASE

.
S
3 .
a 120 .

.
.
I00 S . .
. .
B .S
#{149}1 #{149} #{149}
IS 80 . S
.
. S #{149}..#{149}#{149}14
S
60 #{149}#{149} S
. . S. #{149}11#{149} S. . .
U
I . #{149}.
U 40

S
20 S

60 70 80 90 00 110

brain weight in percent of normal values

Ftc. 4. Brain weights in percent of control values are plotted against cvtoplasmic mass of hepatic cells
in infants with congenital heart disease; all infants are aged 1 day to 3 %ears. Infants with relatively
small brains usually have a subnormal mass of cytoplasm in hepatic cells. A significant correlation (r =

.58) exists betveen brain weights and cytoplasm per hepatic cell (t = 5.99, P < .001).

relationship to the cytoplasmic mass in horns with cardiac malformations have

hepatic cells. Infants with relatively small hepatic and adrenal cells with normal di-
brains usually had a subnormal mass of cy- mensions while such cells in undernour-
toplasm in individual hepatic cells (Fig. 4). ished newborns have a markedly subnormal
In contrast, most individuals over 3 years of mass of cytoplasm.h1 Although the cellular
age with cardiac malformations had brain deficit in some newborns with cardiac mal-
weights near control bevels. (Fig. 1, 3). formations may provide a basis for subse-
quent growth retardation, the deficit is usu-
COMMENT ally too slight to explain fully the severe
Three general patterns of tissue abnor- growth disturbance which subsequently de-
mality are observed in individuals who die vebops in many involved individuals.
with congenital heart disease; one is char- In the present study, infants with cardiac
acteristic of the neonatal period, another of malformations dying between 1 month and
infants up to S years of age, and still an- 8 years of age much
were more retarded in
other is found in older individuals. The growth than those dying in the perinatal
present study gives marginal confirmation period. Cellular abnormalities were also
to previous reports that infants with con- different in the two groups. Whereas the
genital cardiac malformations are mildly neonatal group had only a subnormal num-
subnormal in size at birth due to a retarded ber of cells in liver and adrenal cortex, the
intra-uterine growth.lS The liver and adre- older group had a subnormal cytoplasmic
nals, and presumably other organs, often mass in such cells as well. This latter mor-
have a subnormal number of parenchymal phologic abnormality is a prominent fea-
cells. This intra-uterine growth retardation ture in infants without cardiac disturbances
is not due to undernutrition because new- dying with marasmus due to alimentary

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 ARTICLES 439

undernutrition.2 A similar cellular pattern is most of the newborns with cardiac malfor-
also found in undernourished experimental mations; therefore, it was disturbing to find
animals and in infants undernourished be- that relative brain weights at autopsy pro-
fore birth. 2,11-14 The pattern of gross organ gressively decreased with age (Fig. 1, 3). In
growth retardation found in many cardiac individual infants the degree of retardation
patients dying in childhood is also charac- in brain growth was rather directly related
teristic of human and animal undemutri- to the degree of undernutrition as reflected
tion, i.e., adrenals, liver, and thymus are in hepatic cell cytoplasmic mass (Fig. 4). In
relatively more retarded in growth than are human beings and experimental animals,
kidneys, brain, and bones.21215 severe alimentary undernutrition during the
Available clinical and morphologic data first months of life may lead to perma-
provide clues but no certain answers to the nent impairment of mental and motor
pathogenesis of the apparent undernutri- function. Melchior and Terslev2 found
tion which may develop with congenital that 15% of 196 infants of 1 to 24 months
heart disease. Some involved infants seem with congenital heart abnormalities had
to have a subnormal intake of food which neurologic disorders, i.e., cerebral palsy,
is probably related to chronic cardiac epilepsy, or mental retardation. Mongoboids
failure.2,5 The gap between nutritional were excluded from the data. Undemutri-
need and intake is possibly further in- tion is one factor which might contribute to
creased by the hypermetabolic state en- such mental and motor abnormalities.
countered in such infants, especially in
SUMMARY
those in cardiac failure.67 Another mecha-
nism of tissue undernutrition sometimes ob- A quantitative study was undertaken of
served in cardiac failure is a faulty gas- body size, organ size, and cellular structure
trointestinal absorption of nutrients.8 in 220 individuals dying with congenital
It is not as easy to explain growth retarda- heart disease. Infants dying in the permnatal
tion and tissue abnormalities encountered period had evidences of a mild intra-uter-
in some older individuals with congenital me growth retardation. Infants 1 month to
cardiac malformations. Protracted cardiac 8 years of age had organ and cellular ab-
failure has often been absent in such per- normalities closely resembling those usually
sons. Based on control values, hepatic and found with chronic undernutrition. Older
skeletal muscle cells are often enlarged in individuals dying with congenital cardiac
such individuals while adrenal cortical cells malformations had organ and cellular ab-
are of normal size.5 All three types of cells normalities which may be related to chronic
are often subnormal in number for the pa- hypoxia.
tients age. These cellular abnormalities REFERENCES
may be related to chronic tissue hypoxia;
1. Naeye, R. L. : Unsuspected organ abnormali-
the majority of patients in which such mea- ties associated with congenital heart disease.
surements were made had cyanotic types of Amer. J. Path., 47:905, 1965.
cardiac malformations. In experimental ani- 2. Naeye, R. L.: Organ and cellular development

mals protracted tissue hypoxia retards eel- in congenital heart disease and in alimentary
malnutrition. J. Pediat., 67:447, 1965.
lubar multiplication and leads to an abnor-
3. Naeye, R. L., and Blanc, W.: Pathogenesis of
mal increase of cytoplasmic mass in cells of congenital rubella. J.A.M.A., 194: 1277, 1965.
various organs.12 4. Rawls, W. E., and Melnick, J. L.: Rubella
The present study excluded patients with virus carrier cultures derived from congen-

syndromes in which cardiac malformations itally infected infants. J. Exper. Med., 123:
795, 1966.
and brain disorders are known to coexist
5. Cheek, D. B., Graystone, J., Mehrizi, A.: The
because we wished to assess the influence importance of muscle cell number in chil-
of nongenetic and nonsurgical events on dren with congenital heart disease. Bull.
brain growth. Brains were of normal size in Hopkins Hosp., 118:140, 1966.

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440 CONGENITAL HEART DISEASE

6. Stuart, H. C., and Stevenson, S. S.: Physical heart disease and undernutrition. PEDIATRICS,
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Path., 74:244, 1962. cardiac failure. Brit. Med. J., 1: 1276, 1961.
8. Coppoletta, J. M., and Wolbach, S. B.: Body 19. Davison, A. N., and Dobbing, J.: Myelination
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dren: study of body length and normal Brit. Med. Bull., 22:40, 1966.
weights of more important vital organs be- 20. Dobbing, J.: The influence of early nutrition
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9. Stowens, D.: Pediatric Pathology, ed. 2. Balti- 1964.
more: The Williams and Wilkins Co., p. 3, 21. Chase, H. P., and McKhann, C. M.: The in-

1966. fluence of malnutrition on the synthesis of

10. Uotila, U., and Kannas, 0.: Quantitative histo- myelin. (Abst.) The Society for Pediatric Re-
logical method of determining proportions search, Thirty-sixth Annual Meeting, Atlan-
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ANATOMIC FEATURES OF GROWTH FAILURE IN CONGENITAL HEART
DISEASE
Richard L. Naeye
Pediatrics 1967;39;433
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007.
Copyright 1967 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
Online ISSN: 1098-4275.

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 ANATOMIC FEATURES OF GROWTH FAILURE IN CONGENITAL HEART
DISEASE
Richard L. Naeye
Pediatrics 1967;39;433

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
/content/39/3/433

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright 1967 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 0031-4005. Online ISSN: 1098-4275.

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