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- and Tumor Necrosis Factor-R1-Deficient Mice during Trypanosoma cruzi Infection
From the Departments of Biochemistry and Immunology,*
School of Medicine of Ribeiräo Preto, University of São
Paulo, Ribeiräo Preto, São Paulo, Brazil; the Federal
University of Minas Gerais,
Belo Horizonte,
Brazil; the Department of Immunology, Fundação Osvaldo
Cruz,
Rio de Janeiro, Brazil; and the
Laboratory of Clinical Investigation,§
National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, Maryland
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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increases the expression of IP-10, it
blocks KC expression. Tumor necrosis factor (TNF)-
,
on the other hand, potentiates KC, IP-10,
macrophage inflammatory protein-1, and JE/monocyte
chemotatic protein-1 expression. Interleukin-10 and transforming growth
factor-ß inhibited almost all chemokines tested. The role of IFN-
and TNF- in chemokine modulation during infection was investigated
in T. cruzi-infected IFN--deficient (GKO) or
TNF-R1/p55-deficient (p55-/-) mice. The expression of
chemokines detected in the inoculation site correlated with the
infiltrating cell type observed. Although GKO mice had a delayed and
intense neutrophilic infiltrate correlating with the expression of KC
and macrophage inflammatory protein-2, none of the above was
observed in p55-/- mice. The detection of infiltrating T
cells, Mig, and IP-10 in the myocardium was observed in
wild-type and p55-/-, but not in GKO mice. Together,
these results suggest that the regulatory roles of IFN- and TNF-
on chemokine expression may play a crucial role in the modulation of
the inflammatory response during T. cruzi infection and
mediate resistance to infection.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The resistance of inbred mice to acute infection with T.
cruzi has been shown to be dependent on interferon (IFN)- that
activates macrophages to produce nitric oxide (NO) and kill the
obligate intracellular amastigote form of the
parasite.1-6
In addition, tumor necrosis factor (TNF)-
provides a second signal stimulating NO production and anti-T.
cruzi activity in IFN--activated macrophages. Because T.
cruzi-infected macrophages produce TNF-, this cytokine seems to
mediate its trypanocidal function via an autocrine
pathway.7
On the other hand, the down-regulatory cytokines interleukin (IL)-10
and transforming growth factor (TGF)-ß are associated with
susceptibility to infection8-9
by inhibiting
IFN--mediated macrophage activation. Thus, neutralization of
endogenous IL-10 leads to an increased T. cruzi-induced
IFN- production and parasite killing.9,10
These results
suggest that IL-10 may be a potent inhibitor of IFN- production
during T. cruzi infection in mice and that the early
resistance to infection is a result of the balance between IFN- and
IL-10 produced.9
The mechanisms by which cytokines control parasite replication and
myocarditis in T. cruzi-infected mice are still a matter of
controversy. One distinct possibility is that cytokines modulate the
expression of chemokines that in turn drive the inflammatory
infiltrates observed during the acute and chronic phases of infection.
In fact, T. cruzi infection induces the production of
inflammatory and regulatory cytokines,7,8,11-13
and the
ß-chemokines macrophage inflammatory protein (MIP)-1, MIP-1ß,
RANTES, and JE in macrophages14
or in
cardiomyocytes.15
The importance of the production of
these chemokines to disease outcome and host immunopathology during
infection is not known.
In the present study, we evaluated the role of IL-10, TGF-ß, IFN-,
and TNF- in regulating chemokine production and expression as well
as leukocyte influx. We found that IFN-, TNF-, IL-10, and TGF-
are indeed able to modulate the expression of various chemokines in
T. cruzi-infected macrophages. Moreover, we found that the
decreased inflammatory infiltrate in the peritoneum and heart of
IFN--deficient (GKO) and in TNF-R1-deficient (p55-/-) mice
correlated with the altered expression of chemokines. These results
suggest an important role for regulatory cytokines, especially IFN-
and TNF-, in the control of chemokine expression and production in
experimental T. cruzi infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five- to 6-week-old female C3H/HeJ, C57BL/6 (WT), or
IFN--deficient (GKO) or TNF- receptor p55 (p55-/-)- or p75
(p75-/-)-deficient mice were bred and maintained under standard
conditions in the animal house of the Department of Immunology,
University of São Paulo, Ribeirão Preto, Brazil. Deficient
mice were obtained from The Jackson Laboratories (Bar Harbor, ME).
Parasites
The Y strain of T. cruzi was used in all experiments. For in vitro experiments, trypomastigotes were grown and purified from a monkey fibroblast cell line (LLC-MK2). For in vivo experiments, bloodstream trypomastigotes were obtained from infected animals. The levels of parasitemia were evaluated in 5 µl of blood drawn from the tail vein.
Differential Counting of Leukocytes and Detection of Chemokine mRNA Expression in Vivo
Mice were infected intraperitoneally with 1 x 104 bloodstream trypomastigotes. At different times after infection peritoneal cavities were washed with cold phosphate-buffered saline (PBS). Total peritoneal host and parasite cells were counted in a hemocytometer; 1 x 104 peritoneal cells were cytospun to slides and stained with May-Grünwald-Giemsa; leukocyte populations were determined after differential counting using standard morphological criteria.
FACS Analysis
For flow cytometry, 1 x 108 cells were incubated in the presence of 5 µl of the fluorescein isothiocyanate-conjugated antibodies anti-CD3, anti-CD4, anti-CD8, and anti-CD22 (Pharmingen, San Diego, CA) for 30 minutes at 4°C in the dark according to the supplier’s specifications. The cells were then washed and resuspended in PBS-1% formaldehyde. Data acquisition was performed using a FACSorter, (Becton-Dickinson Immunocytometry System Inc., San Jose, CA). The percentage of each subset was used together with the total cell counting described above to calculate total numbers of each lymphocyte subset in the peritoneal exudate.
Macrophage Cultures for RNA Extraction
BALB/c mouse inflammatory macrophages were harvested from peritoneal cavities 3 days after injection of 1 ml of 3% sodium thioglycollate. The cells were washed and suspended to 1 x 106 cells/ml in RPMI 1640 (Sigma), supplemented with 5% fetal bovine serum, 5 x 10-5 mol/L 2-mercaptoethanol, 2 mmol/L L-glutamine, and antibiotics. The adherent cells were obtained after 2 to 4 hours incubation of single-cell suspensions in 24-well tissue-culture plates at 37°C. Nonadherent cells were removed and trypomastigote forms were added at 1:1 parasite:cell ratio to macrophages and incubated for 6 hours at 37°C in a humidified chamber containing 5% CO2. The cells were then washed three times and 0.5 ml of Trizol LS reagent was added to each well, incubated at room temperature for 5 minutes, and stored at -70°C until RNA extraction.
Total RNA Extraction and cDNA Preparation by Reverse Transcription
For reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, cells were collected by centrifugation of the peritoneal lavage fluid and RNA was prepared from the cell pellet. The extraction of total RNA was performed using 1 ml of the Trizol LS reagent according to the manufacturer’s recommendations (Life Technologies, Inc., Gaithersburg, MD). Each RNA sample was resuspended in water at 0.5 µg/µl. cDNA was synthesized from 2 µl of sample using Superscript II reverse transcriptase according to the supplier’s specifications (Life Technologies, Inc.).
Chemokine mRNA Detection
mRNAs for the C-X-C chemokines (Mig, IP-10, KC, MIP-2), the CC
chemokines (MIP-1, RANTES, JE/MCP-1),
hydroxyphosphoribosyltransferase (HPRT), and ß-actin were analyzed by
RT-PCR. PCRs were performed using Taq polymerase (Life
Technologies, Inc.) in a PTC-100 thermal cycler (MJ Research,
Watertown, MA). The primer sequences and PCR product sizes for the
genes above have been previously published14,16
and
validate in the laboratory using plasmid containing the genes for each
chemokine. Reaction conditions were 30 cycles of 1 minute at 94°C, 1
minute at 54°C, and 2 minutes at 72°C, with a final extension step
of 7 minutes at 72°C. For each set of primers a negative sample
(water) was run in parallel. PCR products were separated by acrylamide
gel electrophoresis and stained with silver nitrate.
Immunofluorescence
Cryostat sections of heart tissue harvested during the acute phase of the infection were air-dried for 1 hour and fixed in acetone before immunostaining with rabbit anti-mouse IP-10, anti-mouse Mig, or rabbit Ig (control). Sections were then incubated with a biotin goat anti-rabbit IgG (Santa Cruz Biotechnology, Santa Cruz, CA) followed by a 30-minute incubation with streptavidin-APC (Pharmingen, San Diego, CA). For three-color analysis, infiltrating leukocytes were immunostained using the primary antibodies rat anti-mouse CD4-fluorescein isothiocyanate and anti-mouse CD8-PE (Pharmingen) or the respective isotype controls. Nonspecific binding was blocked with PBS-bovine serum albumin 1%. The slides were analyzed using a fluorescent microscope (Leica, Wetzlar, Germany) and the images processed using SlideBook software (Intelligent Imaging Innovations, Inc., Denver, CO).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-, IL-10, and TGF-ß Regulate the Expression of
Chemokine mRNAs by T. cruzi-Infected Macrophages
Noninfected control macrophages only express little message for
the chemokine RANTES (Figure 1A)
.
Addition of TNF- or IFN- increased message for RANTES and IP-10
and TNF- also induced MIP-1 message (Figure 1A)
. IL-10 induced
significant message for KC but none for the other chemokines, whereas
TGF-ß only blocked RANTES expression (Figure 1A)
. The infection of
macrophages with T. cruzi induced significant message for
MIP-1, MIP-1ß, KC, and IP-10, and enhanced the message for RANTES
(Figure 1B)
. To test the effects of modulatory cytokines on the
regulation of chemokines in vitro, macrophages were infected
with T. cruzi together with modulatory cytokines. The
addition of TNF- enhanced the expression of MIP-1, KC, and IP-10
and had no apparent effect on RANTES or MIP-1ß expression (Figure 1B)
. The addition of IFN- to infected macrophages down-modulated KC
and MIP-1 and enhanced RANTES and IP-10 expression (Figure 1B)
.
Similarly to its effects on control macrophages, IL-10 increased KC
expression in infected cells (Figure 1B)
. Interestingly, TGF-ß
decreased the expression of all chemokines tested in these experiments
(Figure 1B)
.
|
- and TNF-Rl-Deficient Mice
To evaluate the contribution of IFN- and TNF-R p55 and p75 in
the response against T. cruzi infections, GKO, p55-/- and
p75-/- mice were infected intraperitoneally with trypomastigote forms
of the Y strain and parasitemia and mortality evaluated throughout the
acute phase. As shown in Figure 2A
, GKO
presented an uncontrolled parasitemia that kept growing until mortality
began. Similarly, p55-/- mice had a significantly higher parasitemia
than either to wild-type (WT) or p75-/- mice. The survival rates were
found to be consistent with the levels of parasitemia observed (Figure 2B)
, ie, both GKO and p55-/- mice had an early mortality, which was
not observed in WT and p75-/- mice. The above data suggest the
critical role of IFN- and p55 in controlling parasite replication
in vivo. Once these genes seemed to play an important role
for resistance against T. cruzi, we questioned whether
IFN- and TNF-RI could also play a role in the modulation of the
inflammatory cell infiltrates in vivo. To achieve this goal
the composition of inflammatory infiltrates in the site of inoculation
was evaluated in WT, GKO, and p55-/- mice infected with
trypomastigote forms of T. cruzi.
|
, top,
middle, and bottom). Two peaks of macrophage infiltration were noted on
days 1 and 8. The neutrophil, macrophage, and lymphocyte infiltrate
observed in infected GKO mice was late, peaking 9 days after infection,
and it was more intense than that observed in WT animals (Figure 3
,
top, middle, and bottom). No neutrophil or macrophage infiltration was
noted in p55-/- mice throughout the observation period. On the other
hand, in p55-/- mice lymphocytes were raised as early as 2 days after
infection and were persistently elevated throughout the observation
period (Figure 3
, bottom). The parasite counting at the inoculation
site (peritoneal cavity, Table 1
)
showed a consistent correlation with the parasitemia levels
(Figure 2A)
and both GKO and p55-/- mice exhibited a significantly
higher parasite replication than WT mice.
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|
- and TNF-R1-Deficient Mice
The changes in lymphocyte subtypes at the site of inoculation
during the course of T. cruzi infection in WT animals were
mild with a tendency toward a decrease of CD22+
and increase of CD3+, CD4+,
and CD8+ lymphocyte numbers in days 5 to 8 after
infection. Overall, the lymphocyte subtypes in infected GKO mice were
similar to those found in WT animals with a small but significant
increase in CD22+ cells at day 8 after infection.
The major variations of lymphocyte subtype infiltration were observed
in p55-/- mice. In these animals, there was an increase in the
numbers of lymphocyte subtypes from day 1 to 8 of the infection, with
CD3+, CD4+, and
CD8+ lymphocytes peaking at day 8 and
CD22+ lymphocytes peaking earlier after infection
(Figure 4)
.
|
and TNF-R1-Deficient Mice
The kinetics of in vivo mRNA expression of chemokines
was evaluated in peritoneal exudate cells and is shown in Figure 5
. In WT mice, there was significant
expression of KC mRNA that was limited to the early days after
infection and was not accompanied by the expression of MIP-2. In GKO
mice, both KC and MIP-2 mRNAs were expressed persistently in higher
levels. No expression of KC or MIP-2 was observed in p55-/- mice.
Significant levels of IP-10, Mig, and RANTES were detected in WT
animals from day 3 after infection. In GKO animals no message for these
chemokines was detected, whereas in p55-/- mice the chemokine message
was detected in higher levels after 5 days of infection. Interestingly,
only low levels of MIP1- were detected in WT or p55-/- mice
whereas mRNA for this chemokine was persistently elevated in infected
GKO mice.
|
The modulation of subpopulations of infiltrating lymphocytes and
the expression of chemokines in the myocardium of GKO and p55-/- mice
were evaluated by immunofluorescence. WT animals showed increased
numbers of CD4- and CD8-positive cells in the myocardium on the ninth
day after infection (Figure 6, a and b)
.
In contrast, GKO mice did not show significant increases in the numbers
of CD4- or CD8-positive cells (data not shown). On the other hand and
in contrast to the increased number of lymphocytes at the site of
inoculation, p55-/- mice showed a trend toward decreasing numbers of
CD4- or CD8-positive cells when compared to WT animals, at least until
the ninth day of the infection (Figure 6, c and d)
. Interestingly, GKO
mice showed an increased number of F4/80+ cells
on the ninth day after infection, which was not observed in WT mice
(data not shown). To establish a correlation between the modulation of
lymphocyte migration and chemokine expression, serial sections of heart
tissue from infected mice were immunostained for the chemokines IP-10
and Mig, well-known lymphocyte chemoattractants. Heart sections of WT
animals (Figure 6, a and b)
were found to be strongly positive for
IP-10 and Mig on the ninth day after infection, in agreement with the
presence of CD4- and CD8-positive cells in the tissue. On the other
hand, we did not detect production of Mig and IP-10 in GKO mice (data
not shown), p55-/- mice showed a restricted pattern of Mig staining
associated with modest perivascular infiltrates (Figure 6, c and d)
. To
confirm these data we evaluated chemokine mRNA expression in the
myocardium of these animals before and in the ninth day after
infection. We found a strong infection-induced expression of the C-X-C
chemokines Mig and IP-10 in the heart of infected WT mice (Figure 7)
. Confirming the immunohistochemical
observations, GKO mice did not show detectable levels of mRNA for Mig
and IP-10, whereas infected p55-/- mice did. Despite the complete
absence of Mig and IP-10 expression and CD4 and CD8 cells in GKO mice,
a significantly increased number of nests were found in the myocardium
(25.0 ± 3.3 parasite nests per section in GKO mice
versus 3.5 ± 1.1 and 7.2 ± 1.9 in WT and
p55-/- mice, respectively).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, for the modulation of chemokine expression in vivo
and suggesting important roles for chemokines during T.
cruzi infection.
Our results show that trypomastigote-induced expression of KC could be
inhibited by the addition of IFN- (Figure 1)
in a similar manner to
the inhibitory effects of this cytokine on LPS-treated
macrophages.19
The inhibitory effects of IFN- on KC
expression could also be observed indirectly during infection in GKO
mice. These animals had a progressive increase in KC expression
which, together with an increased expression of MIP-2, was likely
responsible for the dramatic accumulation of polymorphonuclear
neutrophils in the peritoneal cavity (Figure 3)
. These results suggest
that IFN- is a potent inhibitor of KC-mediated neutrophil migration
in vivo.
On the other hand, the enhancing effects of TNF- on
trypomastigote-mediated KC expression (Figure 1)
were consistent with
the observations made during infection of p55-/- mice. These animals
lack TNF--driven KC production and did not show expression of KC at
any point during infection. Moreover, no neutrophilic infiltrate was
found at the inoculation site or in the myocardium. It is possible
that, in the absence of TNF- signaling via the p55 receptor, reduced
induction of KC occurred and this led to a failure to recruit
neutrophils. Together, these data suggest that KC is a main factor that
mediates neutrophil migration in vivo during T.
cruzi infection and that, at least in this infection, TNF-R1 is
essential for the production of KC. In contrast, animals deficient in
the p75 TNF- receptor did not differ from WT mice in respect to
leukocyte recruitment or infection levels, suggesting that signaling
via the latter receptor does not play a role in acute T.
cruzi infection.
Lymphocyte recruitment in vivo was found to be significantly
enhanced in p55-/- animals. Interestingly, these animals had lower
expression of almost all chemokines so far tested (Figure 5)
, with the
exception of Mig. The accumulation of lymphocytes in the peritoneal
cavity of p55-/- animals was predominantly composed of
CD3+, CD8+, and
CD22+ cells on day 1 and
CD3+, CD4+, and
CD8+ cells on day 7 after infection (Figure 4)
.
These results suggest that TNF- down-regulates the recruitment of
lymphocytes to the site of infection via activation of the TNF-R1
receptor. A possible beneficial consequence of a limited recruitment of
lymphocytes might be to decrease the number of autoreactive cells
within the infiltrates. This is in agreement with the increased number
of inflammatory cells found in the late phase of T. cruzi
infection in the heart of p55-/- mice.20
On the other
hand, a possible negative consequence would be the decrease of the
number of parasite-specific cells, which might contribute to the less
efficient response to infection. Our findings also suggest that, in the
absence of an adequate TNF-R1 signaling, Mig seems to be the main
mediator of lymphocyte migration in vivo during T.
cruzi infection. However, although GKO mice did not express mRNA
for the chemokines Mig, IP-10, and RANTES, these animals showed intense
lymphocyte accumulation intraperitoneally, suggesting that other
chemokines, such as MIP-1 and JE/MCP-1 might be involved in
lymphocyte recruitment to the latter site (Figures 3 and 4)
.
The direct correlation found between the presence of CD4- and
CD8-positive cells (Figure 6)
in the myocardium and the production of
the chemokines Mig and IP-10 in this tissue suggests that these
chemokines may be involved in the attraction of lymphocyte populations
to the hearts of infected mice. Moreover, the limited lymphocytic
infiltrates in GKO and p55-/- mice, concomitantly with the complete
absence of Mig and IP-10 expression and production in the heart of GKO
and low levels in p55-/- mice, strengthen the correlation. This could
also be observed during chronic chagasic myocarditis, in which the
expression of Mig and IP-10 remained high concomitantly to an intense
expression of IFN- mRNA.21
Considering that Mig and
IP-10 are able to induce the preferential migration of
IFN--producing cells by signaling via CXCR3,22,23
the
above results raise the possibility that the cytokines IFN- and
TNF- may contribute to the genesis of myocarditis through induction
of Mig and IP-10, which in turn, lead to the accumulation of
IFN--producing T cells as a part of a positive feedback loop. To
provide further support for this observation, recently published data
showed that IP-10 is essential for the accumulation of effector T cells
that are required for resistance to infection with Toxoplasma
gondii.24
In GKO mice, not only did we observe a greater number of parasite nests
but also a large increase in the size of each nest (data not shown).
This is in marked agreement with our recent observation showing that
cardiomyocytes controlled the replication of parasites in the presence
of IFN- or TNF- in a NO-dependent manner.15
Of
interest, we also showed that T. cruzi-infected
cardiomyocytes could produce a significant amount of lymphocyte-active
chemokines. These results raise the interesting possibility that the
production of chemokines by cardiomyocytes could, in turn, increase the
infiltration of inflammatory cells in the heart and, then, control the
infection via the production of IFN--driven NO production. On the
other hand, this cardiomyocyte/lymphocyte cross talk could also be a
relevant interaction explaining the major pathological alterations
observed in chronic chagasic heart disease.
The role of chemokines and their receptors in modulating innate as well as acquired immunity may not remain only in driving cell trafficking to target organs and tissues. Recent observations also point to direct effects of chemokines in the activation of key cell populations for innate and acquired immunity.25 The results presented herein contribute to our understanding of the genesis and modulation of inflammatory reactions in T. cruzi-infected mice both at the inoculation site and in the myocardium. Inasmuch as inflammation seems to play a major role in the pathophysiology of Chagas heart disease, our results suggest that antagonizing the action of chemokines, especially IP-10 and Mig, might be of benefit in the treatment of chagasic myocarditis.
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Acknowledgements |
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Footnotes |
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Supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico.
Accepted for publication December 21, 2000.
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References |
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-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-ß. Eur J Immunol 1992, 22:2501-2506[Medline]
is required for resistance to acute Trypanosoma cruzi infection in mice. J Immunol 1991, 146:3626-3632[Abstract]
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 S. Nakae, Y. Komiyama, S. Narumi, K. Sudo, R. Horai, Y.-i. Tagawa, K. Sekikawa, K. Matsushima, M. Asano, and Y. Iwakura IL-1-induced tumor necrosis factor-{alpha} elicits inflammatory cell infiltration in the skin by inducing IFN-{gamma}-inducible protein 10 in the elicitation phase of the contact hypersensitivity response Int. Immunol., February 1, 2003; 15(2): 251 - 260. [Abstract] [Full Text] [PDF]
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 L. R. P. Ferreira, E. F. Abrantes, C. V. Rodrigues, B. Caetano, G. C. Cerqueira, A. C. Salim, L. F. L. Reis, and R. T. Gazzinelli Identification and characterization of a novel mouse gene encoding a Ras-associated guanine nucleotide exchange factor: expression in macrophages and myocarditis elicited by Trypanosoma cruzi parasites J. Leukoc. Biol., December 1, 2002; 72(6): 1215 - 1227. [Abstract] [Full Text] [PDF]
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M. C. Waghabi, C. M. L. M. Coutinho, M. N. C. Soeiro, M. C. S. Pereira, J.-J. Feige, M. Keramidas, A. Cosson, P. Minoprio, F. Van Leuven, and T. C. Araujo-Jorge Increased Trypanosoma cruzi Invasion and Heart Fibrosis Associated with High Transforming Growth Factor {beta} Levels in Mice Deficient in {alpha}2-Macroglobulin Infect. Immun., September 1, 2002; 70(9): 5115 - 5123. [Abstract] [Full Text] [PDF]
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P. S. Coelho, A. Klein, A. Talvani, S. F. Coutinho, O. Takeuchi, S. Akira, J. S. Silva, H. Canizzaro, R. T. Gazzinelli, and M. M. Teixeira Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-{gamma}-primed-macrophages J. Leukoc. Biol., May 1, 2002; 71(5): 837 - 844. [Abstract] [Full Text] [PDF]
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S. Lacroix-Lamande, R. Mancassola, M. Naciri, and F. Laurent Role of Gamma Interferon in Chemokine Expression in the Ileum of Mice and in a Murine Intestinal Epithelial Cell Line after Cryptosporidium parvum Infection Infect. Immun., April 1, 2002; 70(4): 2090 - 2099. [Abstract] [Full Text] [PDF]
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