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The terminal complement complex c5b9 a marker of disease activity in patients with systemic lupus erythematosus.

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THE TERMINAL COMPLEMENT COMPLEX, C5b-9, A
MARKER OF DISEASE ACTIVITY IN PATIENTS WITH
SYSTEMIC LUPUS ERYTHEMATOSUS
MARIA S. GAWRYL, DAVID S. CHUDWIN, PAUL F. LANGLOIS, and THOMAS F. LINT
Concentrations of the terminal complement complex (TCC), C5b-9, were examined in 120 serum samples from 28 patients with systemic lupus erythematosus. Eleven patients with various manifestations of the
disease were followed longitudinally for a 2-year period
during active and inactive phases of the disease. In 9 of
the 11 patients, elevations in TCC concentrations correlated with disease exacerbations. In many of these
patients, C3 and C4 levels remained normal during the
study and were less sensitive indicators of disease activity than were TCC concentrations. We believe that
measurements of TCC are useful in monitoring patients
with rheumatic diseases in which complement activation
is a component.
Systemic lupus erythematosus (SLE) is a
chronic autoimmune disease that is characterized by
multiple exacerbations and remissions; its cause is not
known. Although many studies have concentrated on
renal disease in SLE, which results from the deposition of immune complexes in the kidney, other organs
are also involved, including the joints, skin, blood,
brain, lungs, and heart (1).
Serologic abnormalities in patients with SLE
Presented in part at a meeting of the American Federation
for Clinical Research, Midwest Section, Chicago, IL, November
1985.
From the Department of Immunology/Microbiology, RushPresbyterian-St. Luke’s Medical Center, Chicago, Illinois.
Supported by USPHS grant 5-Rot-CA-26143 from the NCI.
Maria S. Gawryl, PhD; David S. Chudwin, MD; Paul F.
Langlois, RN, DNS; Thomas F. Lint, PhD.
Address reprint requests to Thomas F. Lint, PhD, Department of ImmunologyiMicrobiology, Rush-Presbyterian-St. Luke’s
Medical Center, 1653 West Congress Parkway, Chicago, IL 60612.
Submitted for publication December 16, 1986; accepted in
revised form July 23, 1987.
Arthritis and Rheumatism, Vol. 31, No. 2 (February 1988)
include circulating autoantibodies to DNA and other
tissue components and circulating and tissue-associated immune complexes (2). These complexes activate
the classical complement pathway at the site of deposition, which leads to the consumption of complement
components and the generation of complement activation products (3). This activation of complement is
believed to play a prominent role in the pathogenesis
of SLE.
Several studies that have attempted to correlate
levels of individual complement components (Clq, C2,
C3, C4, C9, and CH50) with changes in clinical disease
activity have produced varied results (3-1 1). These
static measures of complement component levels fail
to account for variations in the rate of complement
synthesis or catabolism (10,12,13) and have not always
correlated with the clinical manifestations of SLE,
which may range from minimal tissue injury to severe
end-organ damage. A serologic test that could indicate
which patients have asymptomatic SLE and which
have increased disease activity and might therefore be
at risk for end-organ damage would be extremely
useful.
Assessment of complement activation products
has been a more reliable measure of in vivo complement activation, and thus disease activity, in various
disorders than have measures of individual complement components (1 1,14-25). The primary mechanisms of complement-induced membrane damage include the assembly of the terminal complement
components into the terminal complement complex
(TCC), C5b-9, after initiation of either the classical or
alternative pathway, and the generation of the biologically active products, C3a and C5a, which may initiate cellular events capable of causing tissue damage.
C5b-9 AND SLE ACTIVITY
189
Falk et a1 (14) used a monoclonal antibody
specific for neoantigens that are expressed on C9 after
its incorporation into TCC, to detect the TCC in the
serum of SLE patients. The TCC was undetectable in
healthy subjects, whereas in SLE patients, levels of
TCC varied according to disease state. The investigators measured TCC levels in individual samples, but
they did not perform serial studies of any patient
before, during, and after disease exacerbation or
remission.
Using a double antibody sandwich enzymelinked immunosorbent assay (ELISA) (26), we measured TCC concentrations in 120 serum samples from
28 different SLE patients. Serial serum samples were
obtained from 11 patients over a 2-year period, during
active and inactive phases of the disease. TCC were
detectable in the serum of all 11 SLE patients during
some stage of disease and were increased in concentration during disease exacerbations in 9 of the patients. Measurement of TCC may provide a useful
serologic marker that is needed for the monitoring of
patients with rheumatic diseases involving complement activation (27).
PATIENTS AND METHODS
Patients. We studied 28 patients who fulfilled the
American Rheumatism Association 1982 revised criteria for
the presence of SLE (28). Eleven patients were studied
serially over a 2-year period. Table 1 lists the clinical
features of these patients.
All patients were assessed clinically, and the findings
were recorded independently of the TCC immunoassay
results. Disease activity was scored utilizing a clinical activity scoring method we developed; our system is similar to
those used by other investigators (10,11,14,24). A score of 1
Table 1. Clinical characteristics of 1 I systemic lupus erythematosus (SLE) patients studied serially
point was given for each of the following disease manifestations: arthritis, psychosis, serositis, renal disease, skin involvement, and hematologic abnormalities, as well as for a
required increase in medication and for hospitalization
(Table 2). A score of 0 or 1 was defined as inactive SLE, and
a score of 2 or more was defined as active SLE.
Venous blood samples were obtained from all patients. Serum was separated by centrifugation at 1,200g for
15 minutes at 4°C. Serum was divided into aliquots and
stored at - 70°C until assayed.
Case histories of 4 patients. Patient 1, a 29-year-old
white woman, presented in September 1984, with arthritis,
leukopenia, lymphopenia, antinuclear antibodies (ANA),
and anti-double-stranded DNA (anti-dsDNA) antibodies.
She also had Raynaud’s phenomenon and a positive lupus
band test result; no renal or central nervous system (CNS)
involvement was found. She continued to have active arthritis through the third month after presentation, but by the fifth
month, her condition improved, and the steroid dosage was
reduced. She had flares of arthritis in months 6 and 9, with
improvement after each flare.
Patient 2, a 36-year-old black woman whose SLE
was first diagnosed in June 1983, presented with arthritis,
glomerulonephritis (membranous, with segmental proliferative lesions), ANA, and anti-dsDNA antibodies. She was
treated for a kidney abscess in April 1984 (month l), and her
condition subsequently improved. She had disease flares
during months 5-7 and month 11, as indicated by increased
hypertension, headaches, and dizziness.
Patient 3, a 59-year-old white man, presented in May
1984, with arthritis, psychosis, leukopenia, lymphopenia,
ANA, and anti-Sm antibodies. He also had a positive lupus
band test result and a vasculitic rash, as well as congestive
heart failure due to ischemic cardiomyopathy. No renal
disease was present. He was first studied in October 1984
(month l), during a disease flare that was characterized by
psychosis and active arthritis. With steroid therapy, his
symptoms resolved over the next 2 months. When seen
again during months 7 and 8, he had severe congestive heart
failure, minimal rash, and arthritis. He subsequently died of
cardiac disease.
Patient 4, a 39-year-old black woman, presented in
1980 with arthritis, psychosis, membranous and membrano-
Table 2. Clinical activity scoring scheme*
Patient
~~
SLE criterion*
Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Arthritis
Serositis
Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Antinuclear antibody
1 2 3 4 5 6 7 8 9 1 0 1 1
+
+ +
+
+
+ +
+ +
+
+
+ +
+
+ +
+ +
+ +
+ +
+
+ + +
+
+
+
+ + +
+ + +
+ +
+ +
+
+ +
+
+
+ +
+
+
+
+
+
+
* American Rheumatism Association 1982 revised criteria (28).
+
+
+
+
+
Clinical sign
Arthritis (active, nonerosive arthritis)
Psychosis
Serositis (pleuritis or pericarditis)
Renal disease (active proteinuria or cellular casts)
Skin (malar rash, photosensitivity, or discoid rash)
Hematologic (hemolytic anemia, leukopenia, lymphopenia,
or thrombocytopenia)
Increased medication (steroid or immunosuppressive
agent)
Hospitalization
No. of
points
1
1
1
1
1
I
1
1
* A score of 0 or I was defined as inactive disease; a score of 2 2 was
defined as active disease.
GAWRYL ET AL
190
proliferative glomerulonephritis, ANA, and anti-Sm antibodies. She also had a positive lupus band test result, alopecia,
and Raynaud’s phenomenon. She was first studied in April
1984 (month l ) , during active nephritis, which required large
doses of prednisone; during month 3, the condition was
complicated by a pelvic abscess. The disease did not respond adequately to steroid therapy, and during month 6,
treatment with cyclophosphamide was started. Over the
next 10 months, she experienced gradual improvement.
Controls. The control group consisted of 50 serum
samples from blood donors. Serial samples of serum obtained
over a 12-day period from 2 patients who underwent openheart surgery were included in the control group. Serum
C-reactive protein (CRP) levels had been measured and
recorded for these sera, which were kindly provided by Karen
K. James, PhD, Central DuPage Hospital, Winfield, IL.
Antisera and reagents. Goat anti-human C9 was purchased from Miles Scientific (Naperville, IL), rabbit antihuman C5 was purchased from Dako (Santa Barbara, CA), and
horseradish peroxidase (HWbonjugated goat anti-rabbit IgG
was purchased from Tag0 (Burlingame, CA). Tween 20 and
ABTS were obtained from Sigma (St. Louis, MO).
Complement assays. Complement components C3
and C4 were determined in the hospital clinical laboratory
using laser nephelometry. The TCC ELISA was performed
as previously described (26). The assay is a double antibody
(anti-human C9 and anti-human C5) sandwich technique that
is sensitive enough to detect 0.3 pg/ml of the TCC in
solution. Titertek 96-wel1, flat-bottom microtitration plates
(Flow Laboratories, McLean, VA) were coated with 10 pg
of goat anti-human C9 IgG (in 0.05M carbonate-bicarbonate
buffer, pH 9.6) for 2 hours at 37°C. Unbound IgG was
removed by washing the plates 3 times with phosphate
buffered saline (PBS) containing 0.05% Tween 20 (PBSTween 20). Bovine serum albumin (1%) was added as a
blocking agent, and incubation was continued for 30 minutes
at 37°C. The plates were washed with PBS-Tween 20, and
test samples, diluted in PBS-Tween 20 containing 10 mM
EDTA to prevent nonspecific complement activation, were
added. Successive 30-minute incubations at 37°C were performed with 4.9 pg/well of rabbit anti-human C5 followed by
goat anti-rabbit IgG HRP conjugate and then ABTS substrate, with washing steps between incubations.
TCC protein concentrations were calculated for each
assay, by reference to a semilogarithmic standard curve
derived from 8 dilutions of purified TCC (26). Serum samples
were tested at 2 dilutions, in duplicate, and if the results
varied by more than lo%, they were rejected.
Statistical analysis. Means and standard deviations
were calculated for all variables. One-way analysis of variance, repeated measures analysis of variance, and least
squares linear regression analysis (29) were performed on
normally distributed data. Discriminant analysis and multivariate regression (30), which, respectively, predict membership in groups and assess effects of independent variables
on a dependent variable, were used to determine which
blood parameters were associated with disease activity in
SLE. All calculations were done on an IBM PC using
advanced statistical packages (30).
RESULTS
Complement activation, as determined by concentrations of TCC, C3, and C4, was compared with
disease activity and dosages of prednisone in 28 SLE
patients (120 sera). In 17 patients who received followup for fewer than 6 months, increased levels of TCC
were seen during active disease. Serial samples (n =
77) obtained over a 2-year period from the other 11
patients, during disease exacerbations and remissions,
showed that in 9 of them, TCC concentrations correlated with an increase in disease activity, whereas C3
and C4 levels did not consistently do so. We present
here a detailed description of 4 patients who were
representative of the 11 studied serially,
During months 1 and 3 of this study, patient 1
41
48
16.0
12.0
TCC
yg/ml
8.0
4.0
0
120
c3
80
mg/dl
40
0
20
_-
c4
mg/dl
lo 0
60
Prednisone 4 0
rng
20
0
Disease
Activity
1
2 3
4
5 6 7
Months
8 91011
Figure 1. Terminal complement complex (TCC), C3, and C4 levels
compared with prednisone dosage and disease activity in patient I .
The patient had active arthritis during months 1-3, 6, and 9, with
improvement after each flare; she did not have renal or central
nervous system involvement. C3 and C4 levels were determined by
laser nephelometry. TCC concentrations were measured by an
enzyme-linked immunosorbent assay, as described in Patients and
Methods. Shaded areas show the range of the specific complement
component in normal human serum (full ranges for C3 and C4 not
shown).
C5b-9 AND SLE ACTIVITY
had active arthritis in association with increased TCC
levels and decreased C3 and C4 concentrations (Figure
1). In months 6 and 9, the patient’s arthritis flared.
Coincident with the flares was a rise in TCC concentration, normalization of the C3 levels, and consistent
depression of the C4 levels.
Elevated TCC levels were found in patient 2, in
association with a kidney abscess during month 1
(Figure 2). When this condition subsequently improved, the TCC concentrations decreased. Levels of
TCC were again elevated during months 5-7 and 11,
when the patient had hypertension, headaches, and
dizziness. During the course of this patient’s disease,
C3 levels remained within the normal range. However,
decreases in C4 levels were seen during months 3, 5,
and 7, and the levels correlated with disease flares
during months 5 and 7.
Patient 3 had CNS involvement, but no renal
disease was seen (Figure 3). During a disease flare that
was characterized by psychosis and active arthritis
(month l), TCC levels were highly elevated, while C3
and C4 levels tended to remain normal. Increased
191
concentrations of TCC were also detected when the
patient had congestive heart failure during months 7
and 8 of the study.
Although changes in the levels of C3 and C4
were detected in patient 4, TCC levels remained at the
level of assay detectability (Figure 4). Patient 4 had
membranous and membranoproliferative glomerulonephritis. During disease flares, which were characterized
by active nephritis during month 1 and a pelvic abscess
during month 3, TCC levels were normal, whereas the
C3 and C4 concentrations were decreased.
The validity of the clinical activity scores as-
Months
Figure 2. TCC, C3, and C4 levels compared with prednisone dosage
and disease activity in patient 2, who presented with arthritis and
glomerulonephritis. A kidney abscess during month I was followed
by disease remission; subsequently, disease flares occurred during
months 5-7 and I I. Flares were characterized by increased hypertension, headaches, and dizziness. See Figure 1 for explanations.
Figure 3. TCC, C3, and C4 levels compared with prednisone dosage
and disease activity in patient 3. Central nervous system involvement, but no renal disease, was demonstrated in this patient. During
month 1, the patient presented with psychosis and arthritis, and
during months 7 and 8, he had congestive heart failure. See Figure
I for explanations.
GAWRYL ET AL
192
c3
mg/dl
80 CTX
:
Disease
Activity
:
~
~~
1
2
3
4
5
6
7 8 9 1011 1213141516
Months
Figure 4. TCC, C3, and C4 levels compared with prednisone dosage
and disease activity in patient 4. The patient presented with arthritis,
psychosis, and membranous and membranoproliferative glomerulonephritis. During month I , she had active nephritis, which was
complicated by a pelvic abscess during month 3. Prednisone was
discontinued during month 6, and the patient was started on
Cytoxan (CTX). See Figure I for explanations.
signed to the patients was confirmed by their significant correlation with currently utilized laboratory parameters of disease activity. Correlations of C3, C4,
CH50, and erythrocyte sedimentation rate (ESR) values with the presence or absence of active disease, as
defined above, were significant (P < 0.005).
The mean concentrations of TCC, C3, C4, and
CH50 and the mean ESR in serum samples from the I I
patients followed longitudinally, during either active
disease (clinical activity score 22) or inactive disease
(clinical activity score of 0 or I), are listed in Table 3.
Discriminant analysis identified TCC as the only parameter able to distinguish between active and inactive
SLE, as determined by the lowest Wilks' A (F =
30.74, P < 0.00005). Multivariate regression analysis,
using stepwise selection, identified TCC, ESR, C3,
C4, and CH50 as variables that significantly correlated
with disease activity. These 5 variables correctly classified 85% of the cases. TCC concentrations correlated
with levels of C4 (r = 0.47, P < 0.00005), but not with
levels of C3 (P = 0.56) or CH50 (P = 0.49), or with the
ESR (P = 0.91).
In a control group of 50 blood donor sera, TCC
concentrations remained below 0.3 pglml, the limit of
assay detectability, and C3 and C4 levels were within
the normal ranges of 84-132 mgldl and 15-25 mgldl,
respectively. To rule out elevated TCC concentrations
as a nonspecific indicator of acute inflammation, TCC
levels were prospectively measured in 2 patients who
underwent open-heart surgery. Acute inflammation
was documented in these patients by marked elevations in CRP concentrations at 20 hours after surgery,
with a return to normal levels after 4 days; TCC levels
remained undetectable.
DISCUSSION
The role of complement in the pathogenesis of
SLE has been widely studied. Manifestations of the
disease are a consequence of a diverse group of
autoantibodies that combine with antigens to form
both circulating and tissue-deposited immune complexes. These immune complexes activate cornplement, which leads to an inflammatory response and
tissue destruction. Recent studies (12,31) have demonstrated the deposition of individual complement
components and the TCC, C5b-9, in vascular lesions
in patients with SLE, which suggests that there is a
Table 3. Discriminating ability of various blood parameters for active versus inactive systemic lupus erythematosus, in 1 1 patients studied
over a 2-year period
Parameter
(normal)*
TCC ( c0.3 pg/ml)
ESR (<20 mm/hour)
C3 (80-180 mg/dl)
C4 (IS-SO mg/dl)
CHSO (20-40 unitshl)
Active disease
(mean 2 SD)
23.2
35.2
93.6
23.6
26.1
f
t
t
t
t
25.8
29.8
32.1
43.9
8.6
Inactive disease
(mean 2 SD)
Wilks' A t
F value
P
0.98 t 1.0
23.4 t 18.4
98.6 & 29.1
14.6 ? 5 . 3
24.7 t 6.4
0.71
0.96
0.99
0.98
0.99
30.74
2.87
0.39
0.86
0.18
<0.oO005
0.09
0.53
0.35
0.66
~
* TCC
t
~~
~
~~
terminal complement complex (CSb-9); ESR = erythrocyte sedimentation rate (Westergren); CHSO = total hemolytic complement.
The ratio of within-group sum of squares to total sum of squares. A value of I indicates that the group means are similar.
=
C5b-9 AND SLE ACTIVITY
direct role for complement in the mediation of tissue
injury.
Laboratory assays currently used to assess
complement activation do so indirectly, by measuring
concentrations of individual complement components.
The serial measurement of complement, specifically,
CH50 (3,4,19,24), C3, C4, Clq, factor B (4,15,25,32),
and C2 (20), has shown correlations with disease
activity in some patients, but in the majority of patients, these test results were not consistently helpful,
and the values could be misleading (1 1). The conflicting results may be due to the nature of the complement assays used. A major limitation of hemolytic
techniques is that only large magnitudes of complement activation can be detected, and in measuring
CH50, abnormally low levels of some complement
proteins may not be detected. Furthermore, the mechanism responsible for the complement depression is not
defined. Complement activity assays provide only a
static measure of the combined effects of complement
activation, catabolism, and synthesis.
A more sensitive means of determining the
extent of complement activation would be to measure
regulatory complement protein complexes and end
products. Recently, methods have been developed, in
this laboratory (26) and others, to assess the degree of
in vivo complement activation by measuring complement reaction byproducts, including TCC (14,33-39,
C3 cleavage proteins (15-19,21,24), and C5a (22).
These complement activation proteins are stable in the
fluid phase, can be found in the circulation, and are
associated with ongoing inflammatory processes.
Until recently, assays that measure complement activation products have been difficult to perform or have not been readily available. In many
instances, the methods require the use of neoantigen
antibodies, which are difficult to isolate and are not
available commercially. In our investigations, we utilized a TCC-specific ELISA, which uses commercially
available antibodies and is easily established (26).
Using the TCC ELISA, we examined 120 serum
samples from 28 SLE patients for complement activation, and we compared the results with levels of C3
and C4 and with disease activity. While there are no
standard criteria for disease activity in SLE, our
scoring system did correlate with values of C3, C4,
CH50, and ESR ( P < 0.005). Exacerbations of SLE
correlated with increases in TCC levels in 89% of the
patients studied. In contrast, TCC were below the
level of assay detectability in 50 blood bank donor sera
and in serial samples from 2 patients undergoing
193
open-heart surgery in whom inflammation was documented by elevations of CRP levels.
Our results are consistent with the findings by
Falk et a! (14), who used a monoclonal antibody
specific for a neoantigen expressed on C9 after it
becomes incorporated into the TCC in the sera of SLE
patients. In their study, TCC levels were undetectable
in healthy volunteers, whereas in SLE patients, levels
of TCC correlated with disease activity. Findings from
studies in which other complement activation products
were measured support these results. Measurement of
the C3 cleavage product, C3d, was a better diagnostic
tool for SLE than was C3 or C4 (21,23,25); however, in
some cases, C3d levels were also elevated in patients
who were clinically well (21). Levels of ClrCIs-CI
inhibitor complexes and C2 fragments were elevated
during disease exacerbations (1 1).
Most studies measuring complement activation
products in SLE have emphasized the differences
between patient groups, but serial investigations of
individual patients during disease exacerbations and
remissions have not been widely performed with the
new assays. We studied I 1 SLE patients over a 2-year
period. In all but 2 of these patients, elevations in TCC
levels correlated with the clinical activity of SLE.
Discriminant analysis of the results showed that TCC
was the only variable that was able to distinguish
between active and inactive SLE (see Table 3). Compared with C3 and C4 concentrations, the magnitude
of fluctuations in TCC values was much greater, and
this suggests that TCC levels may be a more sensitive
indicator of potentially damaging complement activation.
In some instances, increases in TCC concentrations were seen prior to a clinical manifestation of the
disease. The amount of tissue damage necessary to
produce a clinical response is unknown. An inflammatory process may be initiated before a clinical response
is manifested; in such a case, elevated levels of TCC
may precede outward signs of disease activity. Similarly, concentrations of TCC may decrease before the
disease activity decreases if inflammatory mediators
are cleared before healing occurs.
TCC concentrations correlated with both renal
and nonrenal flares of disease activity, including CNS
involvement. Of the 11 patients studied in detail, 5
(including those shown in Figures 2 and 4) had renal
involvement. In patient 2, C3 and C4 levels, which
have been reported to be sensitive in diagnosing renal
injury (3,27), were normal, whereas TCC concentrations fluctuated with disease activity. In 2 of the I 1
GAWRYL ET AL
1 94
patients, both of whom presented with membranoproliferative glomerulonephritis, TCC was not detected.
This result is consistent with findings that deposition
of TCC has not been detected in the kidney of patients
with membranoproliferative glomerulonephritis (Kazatchkine MD: unpublished observations). Furthermore, the lack of detection of TCC in these patients
might indicate the involvement of a fundamentally
different process, in which a C5 convertase is not
formed. These results further demonstrate the heterogeneity of this patient group.
S L E with CNS involvement has been more
difficult to diagnose and manage because this form of
the disease is less clearly associated with serologic
abnormalities (2). Although lower C4 concentrations
have been demonstrated in the cerebrospinal fluid of
SLE patients with CNS disease (36), a good serologic
marker is still lacking. We studied in detail 4 SLE
patients with CNS involvement. Patient 3, who was
representative of this group, had normal C3 and C4
levels; however, the TCC concentrations were elevated during disease exacerbations. These findings
suggest that measurement of TCC may be helpful in
identifying SLE patients with CNS involvement. This
approach is supported by the recent studies by Sanders et al (37), who detected TCC in the cerebrospinal
fluid of patients with lupus cerebritis, Guillain-Barre
syndrome, and multiple sclerosis. In preliminary studies from our laboratory, plasma TCC levels correlated
with disease activity in 2 patients with isolated central
nervous system vasculitis (38).
Thus, measurement of the complement activation end product, the TCC, may provide a valuable
tool for the assessment of pathologic activity in patients with SLE and other complement-mediated diseases. SLE is a heterogeneous disease, and because
the course and prognosis of the disease differ markedly
from patient to patient, treatment must be individualized. By using a more specific serologic marker of
disease activity in SLE, such as the TCC, it should be
possible to better match effective treatment with the
patient’s needs.
ACKNOWLEDGMENTS
We thank Mark T. Simon, Joy L. Eatman, and
Kathleen Hardy-Darling for excellent technical assistance,
and Alice F. Robinson for preparing the manuscript.
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