INCT-MM_Activity report2009

National Institute of
Science and Technology of
Molecular Medicine
Instituto Nacional de
Ciência e Tecnologia de
INCT-MM
Medicina Molecular
2009 Activity Report
:
INCT
Medicina Molecular
2009 Activity Report
Marco Aurélio Romano-Silva
Director
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Marcus Vinícius Gomez
Vice-director
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Prof. Marco A. Romano-Silva, Director, INCT de Medicina Molecular
$&!$/%
&$!'&! equipment, such as the PET/CT
Discovery D690 from GE Healthcare. At
the time we were writing this report,
civil construction work was under way.
The INCT-MM will be able to provide
its users with first-class tools in
response to our researchers’ needs.
Meanwhile, the research groups have
been
developing
their
specific
protocols, pre-clinical and clinical, to
be ready when the PET/CT systems
become
operational.
Educational
activities are also being developed,
with several training courses and
scientific activities to enlight the public,
specialized and lay, about our Institute.
INCT-MM
This is the first Annual Activity Report
of the Instituto Nacional de Ciência e
Tecnologia – Medicina Molecular (INCTMM). The feeling at this moment is still
of the excitement, having our research
program being recognized as of such
excellence that was selected to be
one of the National Institutes by a
high level international committee. In
2009, our main task was to select the
equipments to setup our main facility,
the Centro de Excelência em Imagem
Molecular (Center for Excellence in
Molecular Imaging). Although we had a
budget constraint, intense negotiations
allowed us to purchase state-of-the-art
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INCT-MM
Prof. Marco Aurélio Romano-Silva
President
PI
Administrative
Committee
Prof. Marcus Vinícius Gomez
Preclinical
Prof. Luiz A. De Marco
Molecular Genetics and Cancer
Pro. Carlos Jorge Simal
Nuclear Medicine
- Define infrastructure policy of use;
-Expenditure policy;
-Protocols approval;
- Autorship and co-autorship policy
- Extramural interface: private and public sectors;
- Ethics;
- Attraction and integration of new groups;
- Reports;
Dr. Carlos Malamut
Cyclotron
Meetings
December 9th 2008
February 6th 2009
May 5th 2009
May 12th 2009
August 17th 2009
INCT-MM
September 17th 2009
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INCT-MM
$%&$'&'$
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!,&! Funded by a joint agreement between
agencies from the Brazilian Federal
and
State
of
Minas
Gerais
Governments, the INCT-MM will operate
multiuser facilities for research in
Molecular Medicine. The headquarter
of the INCT-MM is located at the
School of Medicine (Faculdade de
Medicina) of Universidade Federal de
Minas Gerais, in Belo Horizonte, State
of Minas Gerais, Brazil.
INCT-MM
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INCT-MM
98
+!&$! The PETtrace tracer production system
is a compact, automated cyclotron
designed for the fast, easy and
efficient
production
of
PET
radiotracers. This is a fixed energy
isochronous accelerator, manufactured
by General Electric (GE PETtrace8). The
cyclotron is installed in a bunker with
walls and ceiling of 1.90 meters of
concrete.
The PETtrace is an integrated system
of production of PET tracers that
the
target.
This
facilitates
the
expansion of target systems and
processing for the production of
oxygen-15, carbon-11, nitrogen-13 and
fluorine-18. The CDTN cyclotron has
an external beam placed in separate
concrete bunker.
The Cyclotron Sector includes, besides
the two concrete bunkers, a Control
Room, Technical/Electric and Target
Preparation Areas.
The Laboratory for the production of
the radiopharmaceuticals has three hot
cells with walls of 75 mm of lead, and
with installed equipment for synthesis,
splitting, filling and closing of the vials.
PETtrace.
The
system
can
be
configured with different target systems
and processing for the production of
PET radioisotopes common. The basic
configuration provides six positions of
The
equipment
used
for
FDG
synthesis is a TRACERLAB MX GE
HEALTHCARE. The Lab Production has
two synthesizers TRACERLAB installed
in a Hot Cell Dual COMECER, BBS-2
model. The laboratory has another
dual hot cell model BBS-2 for future
INCT-MM
comprise a negative ion cyclotron
control system with a workstation
operator, target systems and synthesis
systems. It operates with the efficiency
required to match clinical schedules,
the flexibility needed for research
protocols
and
the
performance
necessary to meet regional distribution
demands.
99
use
in
the
radiopharmaceuticals.
synthesis
of
The splitting, filling and closing of the
vials are performed by automated
system, called THEODORICO, made
also by COMECER. THEODORICO is
mounted inside a hot cell wall.
INCT-MM
9:
2
PET/CT, even in areas subject to
motion.
Advanced
processing
techniques allow to reach full clinical
potential with the ability to reconstruct
3D imaging and gated studies at
incredible speeds. 4x faster VUE Point
HD and motion reconstruction times
VUE Point HD ensures intelligent
reconstruction
technology,
a
GE
exclusive, providing outstanding image
quality for most patient types.
By combining the LightSpeed VCT with
the breakthrough motion management
capabilities of the Discovery PET
system, the new Discovery PET/CT
platform provides the next evolution
PET/CT system, bringing clinicallyrelevant innovations designed to open
doors to new and advanced procedure
possibilities in non-invasive diagnostic
imaging.
INCT-MM
The INCT-MM has acquired a state-ofthe-art PET/CT system from GE
Healthcare, at a cost of approximately
USD2 million. The D690 with time-offlight technology delivers truly powerful
options for rserach. From the highest
sensitivity in the industry, the next
generation of MotionFree technology,
advanced information processing and
faster reconstruction with the IBM
BladeCenter™ this system delivers. As
a key component of the image chain,
the Discovery PET/CT 690 includes the
scintillator with a proven track record
and the highest sensitivity in the
industry improving lesion detectably,
potentially
reducing
the
dose
requirement and allowing for faster
scans and increased throughput.
GE
Healthcare has developed a way to
capture detail and precision with
9;
INCT-MM
Layout of the Center of Excellence in Molecular Imaging of the INCT-MM
(Centro de Excelência em Imagem Molecular)
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LabPET 4
PET scanner.
The preclinical PET system will be used in
development of new tracers, and for that
will be installed in a facility adjacent to
the cyclotron, located at the main Campus
of UFMG.
The Institute has a full molecular biology
infrastructure including DNA sequencer,
thermocyclers, two real time PCR systems.
LabPET™: APD based PET Sub-System
INCT-MM
LYSO and LGSO scintillators individually
coupled to Avalanche Photo Diode (APD)
detectors Advanced detector design and
parallel signal processing digital electronics
to achieve high count rate performance.
Digital detector technology delivers high
spatial resolution.
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Leica Confocal Microscopy System
Our Leica TCS SP5 Confocal fully
covers a broad range of requirements
in confoca imaging with excellent
overall
performance.
The
system
provides the full range of scan speeds
at the highest resolution. With its highefficiency SP detection (five channels
simultaneously) and AOBS (Acousto
Optical Bream Splitter), the Leica TCS
SP delivers bright, noise-free images
with minimal photo damage at high
speed.
Carl Zeiss ApoTome system
In traditional microscopy, ApoTome
allows the very fast production of
extremely high-quality optical sections
through fluorescence-labeled biological
specimens – e.g. for the threedimensional visualization of nerve cells.
The technique provides microscope
images with a level of quality rivaling
that of existing methods, but with
lower costs and less equipment.
Therefore, it offers a large number of
users in biomedical research new
possibilities for more exact and more
reliable
results
that
have
been
available
exclusively
to
special
research institutes and large imaging
centers until now.
Nancy Scardua Binda, PhD student
INCT-MM
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Guava Cytometer System
Karen Torres, post-doctoral fellow
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The new Animal Experiment Core has just
been finished, and will be a facility with
capacity
for
maintenance
rooms
experimentation rooms, including primary
cell culturing and a Fluorescence In vivo
imaging system for small animals.
In addition to mice, rats and rabbits, the
core has a zebrafish (Danio rerio) facility,
which is part of the strategy of the INCTMM for developing animal models of
complex diseases, in addition to our
existing C. elegans culture facility at the
Neuroscience lab.
Our
Guava
PCA-96
System
provides
automated, higher throughput screening of
96-well
microplates
or
a
tray
of
microcentrifuge tubes. This flexible sample
format makes the Guava PCA-96 System
ideal for screening in basic research, target
validation, assay development, and clinical
trials. Like its smaller cousin, the Guava
PCA System uses a green laser for
excitation, two fluorescence detectors, and
a forward scatter detector for assessing
relative size. The walkaway automated
sampling of 96-well plates makes it easy
to screen large numbers of samples and
plates in one day.
INCT-MM
Daniela Valadão, post-doc. Zebrafish
aquaria.
Zebrafish (Danio rerio)
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Hospital das Clínicas-UFMG
The HC/UFMG hospital complex is a large
university hospital, consisting of a central
hospital
and
several
annexes.
Hospitalization: offers capacity of 505
beds, providing care to almost all medical
specialties and subspecialties. The hospital
performs around 2100 surgeries monthly
and serves 40 250 patients between
emergency
consultations,
hospitalization
s and outpatient visits. The buildings were
built over the years as the needs of the
time, demand and adequacy (the first
block of the hospital dates from 1950). INCT-MM
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accomplish these objectives we have done:
(1) in vitro experiments with isolated organs,
tissue slices, purified nervous terminations
(sinaptosomes) and cell culture, and (2) in
vivo
tests
with
laboratory
animals.
International contributions as existing with the
Dr. Michael John Brammer, Director of the
Brain Image Analysis Unit, Institute Psychiatry,
University of London, were important in the
field of confocal microscopy and image
analysis. This contribution is being extended
to the functional imaging analysis in animals.
The project was extremely successful, with
several
international
publications,
two
registered patents and one in progress, as
well as several PhD thesis.
Prof. Marcus V. Gomez, Vice-Director, INCT de
Medicina Molecular
Phα1β toxin prevents peripheral and
spinal capsaicin-induced nociception in
rats: role of direct blocking of TRPV1
receptor
Previously, we have shown that the peptide
toxin Phα1β blocked high-threshold voltagesensitive calcium channels (VSCCs), especially
from the N-type, and induced antinociceptive
effect by controlling nociceptive processes in
the spinal cord. In the present study, we
demonstrated that the previous treatment
with Phα1β effectively reduced spontaneous
nociception and mechanical allodynia induced
by peripheral or spinal capsaicin injection in
rats. On the other hand, the selective N-type
calcium channel blocker ω-conotoxin MVIIA
failed to reduce the nociception induced by
capsaicin. Similar to Phα1β, the selective
antagonist of the TRPV1 receptor SB366791
was also able to prevent capsaicin-trigged
spontaneous nociception and mechanical
allodynia. Capsaicin-induced calcium influx in
rat DRG neurons or in HEK cells expressing
TRPV1 was also inhibited by both Phα1β and
SB366791. Moreover, there was no addictive
effect on the inhibitory action of Phα1β and
INCT-MM
Prof. Gomez and his group have been
working
with
peptide
neurotoxins
from
scorpions and spiders for more than 40
years. The initial studies started with the
scorpion neurotoxins (Gomez & Diniz, 1966;
Gomez et al., 1973, 1975).
During last the fifteen years, we have studied
and characterized, in different types of ionic
channels, the pharmacological actions of the
neurotoxins Tx3-3 spider, Tx3-4 and Tx3-6 as
well as their effect in the release of
neurotransmitters (Romano-Silva et al. 1993,
1994) and acetylcholine (Moura et al., 1998).
The group constituted, in 2006, the Institute
of Millennium, aiming to integrate highly
competent researchers to identify new toxins,
to
produce
functional
toxins
for
pharmacological study and, mainly, to carry
out studies to investigate the potential
therapeutical use of toxins to treat cerebral
ischemia, pain and cardiac arrhythmias. Thus,
a group with great experience in molecular
and cellular studies together with several
other
researchers
with
experience
in
functional assays and in vivo studies
analyzed the therapeutical toxin action of the
spider Phoneutria nigriventer. The next step is
to obtain data that prove the effectiveness of
these toxins, and to show that the use of
this new therapeutical armory will not
produce adverse effects in the patients. To
:8
SB366791 on capsaicin-stimulated calcium
transients in DRG neurons, suggesting an
overlap of action. Neither Phα1β nor SB
366791 altered the specific binding of [3H]resiniferatoxin
in
rat
DRG
membranes,
indicating that either substances did not bind
at the vanilloid site in TRPV1. Taken together,
our results demonstrated that the peptide
Phα1β is capable of directly blocking the
TRPV1 receptor, an effect that may be
critical for its antinociceptive action.
INCT-MM
Calcium increase in HEK293VR1 cells is sensitive to Phα1β and SB366791. Transmitted light
merged with fluorescent images (488 nm excitation, 530–570 emission) of VR1 transfected cells
staining with fluo-4. (A) before and (B) after 0.1 nM capsaicin addition. Scale bar 100 μm. VR1
cells were stimulated twice with 0.1 nM capsaicin with a 12-min interval between stimuli, (C)
Control, (D) 10 μM SB366791, and (E) 100nM Phα1β were added at the interval between stimuli. (F)
Amplitude ratio of second and first stimulus *p <0.05 compared to control statistically different .
:9
Phoneutria
spider
toxins
block
ischemia-induced glutamate release and
neuronal death of cells layers of the
retina.
In this study was investigated the effect
of calcium channel blockers spider toxins
on cell viability and the glutamate content
of ischemic retinal slices. Rat retinal slices
were subjected to ischemia via exposure to
oxygen-deprived
low
glucose
(ODLG)
medium for 45 min.
Slices were either
treated or not treated with the toxins
PhTx3, Tx3-3 and Tx3-4. After ODLG insult,
glutamate content and cell viability were
assessed in the slices by confocal and
optic microscopy. In the retinal ischemic
slices that were treated with PhTx3, Tx3–3
and Tx3–4, confocal imaging showed a
decrease in cell death of 79.5% ± 3.1,
75.5% ± 5.8 and 61% ± 3.8, respectively.
Neuroprotective effects were also observed
15, 30, 60 and 90 min after the onset of
the retinal ischemia injury. As a result of
the ischemia, glutamate increased from 6.2
± 1.0 to 13.2 ± 1.0 nMol/mg protein and
was inhibited by PhTx3, Tx3–3 and Tx3–4
to 8.6 ± 0.7, 8.8 ± 0.9 and 7.4 ± 0.8
nMol/mg protein, respectively. Histological
analysis of the live cells in the outer, inner
and ganglion cell layers of the ischemic
slices showed a considerable reduction in
cell death by the toxins treatment. Spider
toxins reduced glutamate content and cell
death
of
retinal
ischemic
slices.
INCT-MM
Confocal images (10x magnification) of representative retinal slices showing a control retinal slice
submitted to ischemia (A); a retinal slice that was neither submitted to ischemia nor treated with
spider toxins (B); a retinal slice submitted to ischemia in the presence of 1.0 mg/mL PhTx3 (C);
a retinal slice submitted to ischemia in the presence of 8.0 nM Tx3-3 (D); and a retinal slice
submitted to ischemia in the presence of 8.0 nM Tx3-4 (E). Dead cells appear red, and live cells
appear green. The graph (F) shows the percentage of dead cells in retinal slices that were
submitted to ischemia insult. One group was not treated with spider toxins (black bar), and the
others (open bars) were treated with 1.0 mg/mL PhTx3, 8.0 nM Tx3-3 or 8.0 nM Tx3-4. Dead cells
in the treated slices are given as a percentage of their respective ischemic untreated slices (A).
The results are expressed as the mean ± standard error of mean (SEM) of dead cells in ten
fields of at least three different experiments. For other details, see the Materials and Methods
section. *There was a significant difference compared ischemic slices not treated with toxins
treated, p < 0.05. **There was difference compared ischemic slices treated by toxins PhTx3 and
Tx3-4, p < 0.05.
::
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1. Production and characterization of
radiopharmaceuticals
useful
for
research and diagnosis using PET.
First, we developed a target port (FIG. 1)
for solid materials, to engage outside line
of the cyclotron, for research.
In 2009 a project was developed to
evaluate the stability of FDG and the use
of an autoclave in the production process
of FDG. The work was published in the
Annals of the International Nuclear Atlantic
Conference (INAC), held in Rio de Janeiro
in 2009.
Was obtained and characterized, also, the
sodium fluoride (Na18F), a radioisotope
used for studies of tumors and nononcological diseases of the bone. Interest
in Na18F has been resumed, mainly due to
the formation of high-resolution images.
The group UPPR / CDTN produced Na18F
injectable solution with guaranteed quality
from the points of microbiological, physicochemical
and
biological.
Showed
a
biodistribution profile in mice similar to
that available in literature, with clearance
equal to 0.29 mL min -1, volume of
distribution of 14.0 7g.mL-1 and primarily
renal
elimination.
The
maximum
concentration of 5.0 ± 0.5% DI.g-1 was
observed in the bone 30 minutes after
injection. The results strongly indicate that
the Na18F produced in the UPPR CDTN
can be used safely for clinical use in bone
scintigraphy. This paper has been accepted
for publication in the journal "Brazilian
Journal of Pharmaceutical Sciences."
Figure 1 - Port-targets for irradiation of solid
targets
Production of 64 coper
The process for obtaining 64Cu through
the nickel-enriched, was developed with
electrodeposition 64Ni (FIG. 2) on a tablet
of silver. Then insert the electrodeposited
material is placed inside the holder and
irradiated targets under specific conditions.
After the irradiated material is dissolved in
acid and strong 64Cobre is separated
using ion exchange resins.
INCT-MM
For 2010 the goal is the extraction and
characterization of 18F-choline in addition
to implementation of the synthesis module
for radiopharmaceuticals labeled with 11C.
2. Study for the deployment of new
targets
This project's main objective is to obtain
radionuclides using solid targets, needed
for
the
development
of
new
PET
radiopharmaceuticals that do not involve
18F.
Figure 2 - System electrodeposition
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Production
of
nanoparticles.
67Gálio
from
ZnO
Gallium 67 can be obtained from the Znenriched and it is necessary to obtain
pellets of zinc oxide with porosity, density,
mechanical
strength
and
morphology
specific to be irradiated. This work is part
of PhD project in collaboration with the
UFMG. Some work was described in the
article published in "Brazilian Journal of
Physics." And published in the Annals of
the International Conference on Advanced
Materials, 2009, RJ and International
Conference on Nanostructured Materials,
2008, RJ.
Figure 2 - electron microscopy image of ZnO
pellets with satisfactory characteristics can
be used as target
8 Production of Radiopharmaceuticals for
the production of fluorine-18. On this
subject was done a preliminary study,
published in the Annals of the International
Nuclear Atlantic Conference (INAC), held in
Rio de Janeiro in 2009.
The study of the field of neutron and
gamma radiation around the cyclotron will
provide important data to:
(A) optimization of radiological protection
of the individual worker and the public;
(B) optimization / improvement of the
shield so as to increase the life of the
bunker
(eg
placement
of
borated
polyethylene
plates
to
reduce
the
activation of concrete);
(C) use of the radiation field for various
applications: materials science, dosimetry,
etc..
3. Neutron dosimetry in UPPR / CDTN
In the year 2009 were measured and
studies to evaluate the radiation field
around the cyclotron PETtrace GE Section-
INCT-MM
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analysis of the NFATc1 protein showed a
predominant
nuclear
staining
in
the
multinucleated giant cells. CONCLUSION:
The development of giant cells lesions of
the jaws and cherubism are possibly
mediated by overexpression of NFAT in the
nucleus of the multinucleated cells. Amaral
FR, Brito JA, Perdigão PF, Carvalho V,
Souza PE, Gomez MV, De Marco L, Gomez
RS. Journal of Oral Pathology and Medicine
39: 269-274, 2010.
Prof. Luiz A. De Marco, Laboratory of
Molecular Genetics, INCT-MM
Novel mutations of the BSCL2 and
AGPAT2 genes in 10 families with
Berardinelli Seip congenital generalized
lipodystrophy
syndrome.
CONTEXT:
Congenital generalized lipodystrophy, or
Berardinelli-Seip syndrome, is a rare
INCT-MM
NFATc1 and TNFalpha expression in
giant
cell
lesions
of
the
jaws.
BACKGROUND: Activation mutations of
SH3BP2 gene have been demonstrated in
cherubism and central giant cell lesion
(CGCL). In the present study we first
attempted to investigate the SH3BP2 gene
in peripheral giant cell lesion (PGCL). The
effect of SH3BP2 gene mutations on the
transcription of the downstream genes
nuclear factor of activated T cells (NFATc1)
and the cytokine tumor necrosis factoralpha (TNF-alpha) was also investigated
together with the immunolocalization of
NFATc1 protein in a set of cases of PGCL,
CGCL and cherubism with and without
SH3BP2 mutation. METHOD: Fresh samples
of five PGCL, five CGCL and one cherubism
cases were included in this study. One of
the samples of CGCL presented a somatic
heterozygous mutation c.1442A>T in exon
11. The cherubism case showed a
heterozygotic substitution c.320C>T in both
blood and lesion. These mutations were
previously
published.
All
coding
and
flanking regions of the SH3BP2 gene were
sequenced in the cases of PGCL. The realtime polymerase chain reaction (RT-PCR)
was performed to analyze the transcription
of NFATc1 and TNF-alpha genes. The
immunohistochemical
analysis
of
the
NFATc1 protein was also performed.
RESULTS: No SH3BP2 gene mutation was
found in PGCL. The RT-PCR showed
increased expression of NFATc1 and
decreased transcription of TNF-alpha in all
the samples. The immunohistochemical
Novel mutations in the gene associated
with sporadic central giant cell lesions
and cherubism. Central giant cell lesion
(CGCL) is a reactive bone lesion that
occurs
mainly
in
the
mandible,
characterized
by
the
multinucleated
osteoclast-like giant cells in a background
of oval to spindle-shaped mononuclear
cells. The etiology is unknown and occurs
more
commonly
in
young
adults.
Cherubism,
a
rare
disease
found
predominantly in females has histologic
characteristics indistinguishable from those
of CGCL and is caused by mutations
mostly present in exon 9 of the SH3BP2
gene. In this study, we investigated four
cases of CGCL and one case of cherubism.
DNA was extracted from peripheral blood
and tumor tissue and all coding and
flanking regions of the SH3BP2 amplified
by PCR and directly sequenced to identify
underlying mutations. Two novel mutations
were found; a heterozygous missense
mutation c.1442A>T (Q481L) in exon 11 in
one sporadic case of CGCL and a
heterozygous germline and tumor tissue
missense mutation c.320C>T (T107M) in
exon 4 in one patient with cherubism.
These findings open a new window to
investigate
the
possible
relationship
between the pathogenesis of the cherubism
and CGCL. Carvalho VM, Perdigão PF,
Amaral FR, Souza PEA, De Marco L, Gomez
RS. Oral Diseases 15: 106-110, 2009
:=
autosomal recessive disease caused by
mutations in either the BSCL2 or AGPAT2
genes. This syndrome is characterized by
an almost complete loss of adipose tissue
usually diagnosed at birth or early infancy
resulting in apparent muscle hypertrophy.
Common clinical features are acanthosis
nigricans, hepatomegaly with or without
splenomegaly
and
high
stature.
Acromegaloid features, cardiomyopathy and
mental retardation can also be present.
DESIGN: We investigated 11 kindreds from
different geographical areas of Brazil
(northeast and southeast). All coding
regions as well as flanking intronic regions
of both genes were examined. Polymerase
chain reaction (PCR) amplifications were
performed
using
primers
described
previously
and
PCR
products
were
sequenced directly. RESULTS: Four AGPAT2
and two BSCL2 families harboured the
same set of mutations. BSCL2 gene
mutations were found in the homozygous
form in four kindreds (c.412C>T c.464T>C,
c.518-519insA, IVS5-2A>G), and in two
kindreds compound mutations were found
(c.1363C>T, c.424A>G). In the other four
families, one mutation of the AGPAT2 gene
was found (IVS3-1G>C and c.299G>A).
CONCLUSIONS: We have demonstrated four
novel mutations of the BSCL2 and AGPAT2
genes responsible for Berardinelli-Seip
syndrome and Brunzell syndrome (AGPAT2related syndrome). Miranda D, Wajchenberg
BL, Calsolari MR, Aguiar MJ, Silva JMCL,
Ribeiro MG, Fonseca C, Amaral D, Boson
W, Resende BA, De Marco L. Clinical
Endocrinology 71: 512-517, 2009.
INCT-MM
Familial hyperparathyroidism: Surgical
outcome after 30 years of follow-up in
3
families
with
germline
HRPT2
mutations. It is still debatable which is the
best management to familial forms of
hyperparathyroidism. Conservative, minimally
invasive or aggressive surgical approaches
have been proposed from different groups
around the world. Our objective was to
study the gene mutation, expression of
HRPT2 and the clinical outcome after 32
years of follow-up in one Brazilian kindred
with familial isolated hyperparathyroidism
(FIHP). Clinical and biochemical data, direct
sequencing of the HRPT2 gene, analysis of
parafibromin expression using RT-PCR, and
immunohistochemistry
were
done.
A
nonsense mutation was found in exon 1
(c.96G>A)(p.Trp32X) in all affected members
studied. Using RT-PCR, mRNA transcription
was altered with complete absence of both
transcripts
in
tumor
tissue.
Immunohistochemical analysis of tumors
showed
loss
of
parafibromin
immunoreactivity. In this kindred there was
a high prevalence of recurrence (75%), or
persistence
after
less
than
subtotal
parathyroidectomy that led us to consider
a more aggressive surgical approach
should be discussed among the affected
family members, once surgical criteria was
met. We concluded that it is necessary to
individualize the surgical approach for
HRPT2-related hyperparathyroidism until we
can gather a better phenotype-genotype
correlation in larger series, to best define
their treatment. Sarquis M, Dias EP, Eng C,
De Marco L. Surgery 145: 249-250, 2009.
:>
Silva JM, Ribeiro MG, Fonseca C, Amaral D,
Boson WL, Resende BA, De Marco L. Clin
Endocrinol (Oxf). 2009 Oct;71(4):512-7.
Prof. Débora M. Miranda, Laboratory of
Molecular Genetics
INCT-MM
Novel mutations of the BSCL2 and
AGPAT2 genes in 10 families with
Berardinelli-Seip congenital generalized
lipodystrophy
syndrome.
Congenital
generalized lipodystrophy, or BerardinelliSeip syndrome, is a rare autosomal
recessive disease caused by mutations in
either the BSCL2 or AGPAT2 genes. This
syndrome is characterized by an almost
complete loss of adipose tissue usually
diagnosed at birth or early infancy
resulting in apparent muscle hypertrophy.
Common clinical features are acanthosis
nigricans, hepatomegaly with or without
splenomegaly
and
high
stature.
Acromegaloid features, cardiomyopathy and
mental retardation can also be present.
DESIGN: We investigated 11 kindreds from
different geographical areas of Brazil
(northeast and southeast). All coding
regions as well as flanking intronic regions
of both genes were examined. Polymerase
chain reaction (PCR) amplifications were
performed
using
primers
described
previously
and
PCR
products
were
sequenced directly. RESULTS: Four AGPAT2
and two BSCL2 families harboured the
same set of mutations. BSCL2 gene
mutations were found in the homozygous
form in four kindreds (c.412C>T c.464T>C,
c.518-519insA, IVS5-2A>G), and in two
kindreds compound mutations were found
(c.1363C>T, c.424A>G). In the other four
families, one mutation of the AGPAT2 gene
was found (IVS3-1G>C and c.299G>A).
CONCLUSIONS: We have demonstrated four
novel mutations of the BSCL2 and AGPAT2
genes responsible for Berardinelli-Seip
syndrome and Brunzell syndrome (AGPAT2related
syndrome).
Miranda
DM,
Wajchenberg BL, Calsolari MR, Aguiar MJ,
Association of SLITRK1 to Gilles de la
Tourette Syndrome. Previously the Slit
and Trk-like family member 1 (SLITRK1)
gene was identified as a candidate gene
for Gilles de la Tourette Syndrome (GTS)
based on a patient that carried a
chromosomal inversion on 13q, as well as
the identification of two rare DNA variants
in the SLITRK1 gene. Since that report,
studies have tested for the two rare
variants in GTS and either did not find
them, or when found, they did not
segregate with the disorder in families,
casting doubt on the relationship of this
gene to GTS. We tested for these two rare
variants
and
genotyped
three
polymorphisms that tag the currently
identified major haplotypes of this gene in
a sample of 154 nuclear families with GTS.
In addition, the entire coding region was
screened for novel DNA variants. We did
not find the two reported rare variants in
any of the probands or siblings in these
families. We did however find significant
evidence for association of a single
polymorphism and of haplotypes of the
three
tagging
polymorphisms.
These
findings provide the first support for the
original finding indicating SLITRK1 as a
susceptibility gene for GTS and indicate
that further study of this gene in GTS is
warranted. Miranda DM, Wigg K, Kabia EM,
Feng Y, Sandor P, Barr CL. Am J Med
Genet B Neuropsychiatr Genet. 2009 Jun
5;150B(4):483-6.
:?
Prof. Ana Cristina Simões e Silva, Pediatric
Nephrology
Genetic deletion of the angiotensin-(1-7)
receptor Mas leads to glomerular
hyperfiltration and microalbuminuria..
Angiotensin-(1–7), an active fragment of
both angiotensins I and II, generally
opposes the vascular and proliferative
actions
of
angiotensin
II.
Here
we
evaluated effects of the angiotensin-(1–7)
Molecular Pathophysiology of Renal
Tubular Acidosis. Renal tubular acidosis
(RTA)
is
characterized
by
metabolic
acidosis due to renal impaired acid
excretion. Hyperchloremic acidosis with
normal anion gap and normal or minimally
affected glomerular filtration rate defines
this disorder. RTA can also present with
hypokalemia, medullary nephrocalcinosis
and nephrolitiasis, as well as growth
retardation and rickets in children, or short
stature and osteomalacia in adults. In the
past decade, remarkable progress has
been made in our understanding of the
molecular pathogenesis of RTA and the
fundamental molecular physiology of renal
tubular transport processes. This review
summarizes hereditary diseases caused by
mutations in genes encoding transporter or
channel proteins operating along the renal
tubule. Review of the molecular basis of
hereditary tubulopathies reveals various
loss-of-function
or
gain-of-function
mutations in genes encoding cotransporter,
exchanger, or channel proteins, which are
located in the luminal, basolateral, or
endosomal membranes of the tubular cell
or in paracellular tight junctions. These
gene mutations result in a variety of
functional defects in transporter/channel
INCT-MM
Hemostatic changes in patients with
end stage renal disease undergoing
hemodialysis..
Patients
undergoing
hemodialysis may show both thrombotic
complications and bleeding abnormalities.
Hemostatic
changes
in
patients
on
hemodialysis may result from alterations in
vessel wall integrity and platelet function,
and reduced blood flow in the native
arteriovenous fistula. Vascular complications
represent 20–25% of all hospitalizations of
patients on hemodialysis. Literature survey
revealed that changes in the hemostatic
system may play a major role in vascular
complications observed in these patients.
Thus,
it
is
essential
to
investigate
hemostatic alterations in patients on
hemodialysis so that adequate regimes for
anticoagulant
therapy
could
be
implemented. In this review we discuss
hemostatic abnormalities in end stage
renal
disease
patients
undergoing
hemodialysis. Clinica Chimica Acta 2010;
411: 135 - 139
receptor Mas on renal physiology and
morphology using Mas-knockout mice.
Compared to the wild-type animals, Mas
knockout mice had significant reductions in
urine
volume
and
fractional
sodium
excretion without any significant change in
free-water clearance. A significantly higher
inulin
clearance
and
microalbuminuria
concomitant with a reduced renal blood
flow suggest that glomerular hyperfiltration
occurs in the knockout mice. Histological
analysis found reduced glomerular tuft
diameter and increased expression of
collagen IV and fibronectin in the both the
mesangium and interstitium, along with
increased collagen III in the interstitium.
These fibrogenic changes and the renal
dysfunction of the knockout mice were
associated
with
an
upregulation
of
angiotensin
II
AT1
receptor
and
transforming growth factor-b mRNA. Our
study suggests that Mas acts as a critical
regulator
of
renal
fibrogenesis
by
controlling effects transduced through
angiotensin II AT1 receptors in the kidney.
Kidney International 2009;75:1184 - 1193
:@
proteins,
including
decreased
activity,
impaired
gating,
defective
trafficking,
impaired endocytosis and degradation, or
defective assembly of channel subunits.
Further molecular studies of inherited
tubular transport disorders may shed more
light on the molecular pathophysiology of
these diseases and may significantly
improve
our
understanding
of
the
mechanisms
underlying
renal
salt
homeostasis, urinary mineral excretion, and
blood pressure regulation in health and
disease. The identification of the molecular
defects in inherited tubulopathies may
provide a basis for future design of
targeted therapeutic interventions and,
possibly, strategies for gene therapy of
these complex disorders. Current Genomics
2009; 10: 51 - 59.
The Vasoactive Peptide Angiotensin-(1
7),
Its
Receptor
Mas
and
the
Angiotensin-converting Enzyme Type 2
are
Expressed
in
the
Human
Endometrium. Angiotensin (Ang)-(1-7) is
INCT-MM
Citocinas e quimiocinas no transplante
renal..
Renal transplantation is currently
the best modality of renal substitutive
therapy. Unfortunately graft survival is
interrupted by episodes of acute rejection
or even interstitial fibrosis/tubular atrophy.
The measurement of urinary chemokines
and cytokines as an alternative tool to
diagnose these complications has been
reported in past years. Those substances
are
clearly
related
to
the
immunoinflammatory mechanisms of renal
transplantation, and can be detected in
renal tissue, plasma, and urine samples of
transplant
recipients.
Anti-inflammatory
drugs, renin-angiotensin system inhibitors,
and
some
antagonists
of
cytokines’
receptors,
although
used
only
experimentally, can interfere with the
expression
of
these
immune
system
mediators and consequently alter renal
transplantation
outcome.
This
article
reviewed studies on the measurement of
cytokines/ chemokines and their receptors
in urine, plasma, and renal tissue of
transplant recipients, aiming at evaluating a
possible association of the levels of those
mediators
with
renal
transplantation
complications and allograft survival. Jornal
Brasileiro de Nefrologia 2009; 31: 286 –
296.
one of the major active components of the
renin-angiotensin system, produced from
cleavage of Ang II by angiotensinconverting-enzyme type 2 (ACE2), which
acts through a specific G protein-coupled
receptor, Mas. We have investigated
whether the human endometrium expresses
these components during menstrual cycle.
By
radioimmunoassay,
Ang-(1-7)
was
detected in endometrial wash fluid at
picomolar
concentrations.
Using
immunofluorescence, both the peptide and
its receptor were identified in cultured
endometrial epithelial and stromal cells. By
immunohistochemistry,
Ang(1-7)
was
localized in the endometrium throughout
menstrual cycle, being more concentrated
in the glandular epithelium of mid- and
late
secretory
phase.
This
pattern
corresponded to the ACE2 mRNA, which
was more abundant in epithelial cells than
in stromal cells (2-fold increase, p < 0.05)
and in the secretory vs. proliferative phase
(6.6-fold increase, p < 0.01). The receptor
Mas was equally distributed between
epithelial and stromal cells and did not
change
during
menstrual
cycle.
The
physiological role of this peptide system in
normal
and
pathological
endometrium
warrants further investigation. Reproductive
Sciences 2009; 16: 247-256.
:A
personality disorder, panic disorder and
alcoholism). The frequency of S allele
carriers was higher only in those patients
who had made a violent suicide attempt in
their lifetime (x(2)=16.969; p=0.0001). In a
logistic regression model including these
factors, S allele carrier (5-HTTLPR) was the
only factor associated with violent suicide
attempt. Sample size and retrospective
assessment of suicide behavior history are
the limitations of this study. Our study
showed that serotonin polymorphism (5HTTLPR) is strongly associated with violent
suicidal behavior in BD patients. If
confirmed, our results could be an
important step to create a genetic tool for
long-term suicide prediction. Neves FS,
Malloy-Diniz LF, Romano-Silva MA, Aguiar
GC, de Matos LO, Correa H. J Affect
Disord. 2010 Jan 20.
Prof. Humberto Correa, Laboratory of
Neuroscience, Clinical Psychiatry
Expression of neuronal calcium sensor-1
(NCS-1) is decreased in leukocytes of
schizophrenia
and
bipolar
disorder
patients. Schizophrenia (SCZ) and bipolar
disorder
(BPD)
are
severe
illnesses
representing an enormous social, familiar
and individual burden that affect 1% of
the
population
world-wide.
Several
evidences indicate abnormalities of the
dopamine system in both SCZ and BPD.
Neuronal calcium sensor-1 (NCS-1) is a
protein that has many functions in
neurotransmission such as inhibition of
dopamine D(2) receptor desensitization,
regulation
of
ionic
channels
and
INCT-MM
Is
the
serotonin
transporter
polymorphism (5-HTTLPR) a potential
marker for suicidal behavior in bipolar
disorder patients? Suicide prediction is a
huge challenge for mental health workers.
Structured
interviews
based
on
epidemiological and clinical factors don't
show effectiveness for suicide prevention.
Biological markers, such as 5-HTTLPR,
could help for identification of potential
suicide
attempters.
METHODS:
We
evaluated 198 bipolar patients and 103
health controls, using a structured interview
according to DSM-IV criteria. Genotyping,
blind
of
clinical
assessment
for
identification of S carriers and structured
interviews were performed in order to
describe
clinical
and
epidemiological
factors which could be associated with
suicide behavior. Statistical analyses were
calculated by the x(2) test and logistic
regression model. We found that 26.77%
and 16.67% had a lifetime history of non
violent suicide attempt and violent suicide
attempt, respectively. The clinical factors
associated with violent and non violent
suicide attempt had several differences.
Violent suicide attempters had an earlier
illness onset and had a higher number of
psychiatric
comorbidities
(borderline
;8
enhancement
of
exocytosis
of
neurotransmitters.
In
addition,
NCS-1
protein expression and mRNA levels were
found increased in pre-frontal cortex (PFC)
of SCZ and BPD patients. NCS-1 expression
in neural and neuroendocrine cells is well
documented and, recently, it was shown
that NCS-1 is also expressed in mast cells
and neutrophils. NCS-1 has important
functions in mast cells since it stimulates
Fc epsilon RI-triggered exocytosis and the
release of arachidonic acid metabolites.
Then, due to the known close relation
between the nervous and immune systems,
we sought to investigate the NCS-1
expression in lymphocytes and monocytes
(CD4+ T lymphocytes, CD56+ NK cells,
CD19+
B
lymphocytes
and
CD14+
monocytes) of SCZ and BPD patients.
Using flow cytometry, our results have
shown
that
NCS-1
expression
was
diminished in CD4+T lymphocytes, CD19+ B
lymphocytes and CD14+ monocytes of BPD
patients and also decreased in CD4+ T
lymphocytes and CD56+ NK cells of SCZ
patients. Results suggest that immune cells
might be a cellular model for studies with
SCZ and BPD patients considering NCS-1
functions. Efforts need to be done to
investigate the motive of the decreased
percentage of immune cells expressing
NCS-1 in patients with SCZ and BPD.
Torres KC, Souza BR, Miranda DM,
Sampaio AM, Nicolato R, Neves FS, Barros
AG, Dutra WO, Gollob KJ, Correa H,
Romano-Silva
MA.
Prog
Neuropsychopharmacol
Biol
Psychiatry.
2009 Mar 17;33(2):229-34
The leukocytes expressing DARPP-32
are
reduced
in
patients
with
schizophrenia and bipolar disorder.
Bipolar disorder (BPD) and schizophrenia
(SCZ) are severe disorders representing an
enormous social, familiar and individual
burden, being SCZ the most disabling
psychiatric
disorder
characterized
by
psychosis and cognitive impairment. It is
well known that SCZ and BPD are
associated with abnormalities in dopamine
signaling pathway. Recent data in the
literature
have
demonstrated
altered
expression levels of some proteins involved
in the modulation of this pathway in both
brain and peripheral tissues. It was shown
that protein and mRNA levels of dopamine
and
cAMP
regulated
phosphoprotein
(DARPP-32)
were
downregulated
in
dorsolateral prefrontal cortex (DLPFC) of
patients with SCZ or BPD when compared
to controls. Due to the difficulty to access
brain tissue and the absence of objective
laboratory
tests
for
bio-markers,
we
measured DARPP-32 expression in blood
INCT-MM
Representative dot-plots from PBMC. The NCS-1 expression by lymphocytes and monocyteswas verified by flowcytometry assays.
PBMC from control individuals or SCZ or BPD patients were stained to surface subpopulation markers and intracellular NCS-1
granularity versus size from PBMC showing the region 1 (R1) for lymphocyte gate and region 2 (R2) for monocyte gate (A). Isotype
control of Abs utilized to extracellular or intracellular stain cells (B). Percentage of CD4+ T cells expressing NCS-1 from control
individual (C), CD19+ B cells expressing NCS-1 (D), CD14+ monocytes expressing NCS-1 (E) and CD56+ NK cells expressing NCS-1
(F). The dot-plots (B–F) demonstrate the frequencies of cells expressing the indicated molecules as detected using antibodies
conjugated with PE or ALEXA 488 as described in Material and methods.
;9
cell sub-populations (CD4+ T lymphocytes,
CD56+ NK cells, CD19+ B lymphocytes and
CD14+ monocytes) taking advantage of the
close relation of nervous and immune
systems. Using flow cytometry as the
analytical method, our results have shown
that
the
DARPP-32
expression
was
diminished in CD4+ T lymphocytes, CD19+
B lymphocytes and CD14+ monocytes of
BPD patients and was also decreased in
CD4+ T lymphocytes and CD56+ NK cells
of SCZ patients. These results showed that
DARPP-32 expression in immune cells
agrees with reports of reduced DARPP-32
protein in the DLPFC of BPD or SCZ
patients. Our data suggest that DARPP-32
expression in PBMC could be used as a
source of bio-markers to help in the
treatment response of neuropsychiatry
disorders as a window to the changes in
the brain of those patients. Torres KC,
Souza BR, Miranda DM, Nicolato R, Neves
FS, Barros AG, Dutra WO, Gollob KJ,
Correa
H,
Romano-Silva
MA.
Prog
Neuropsychopharmacol
Biol
Psychiatry.
2009 Mar 17;33(2):214-9.
'$ cells, the rest of the
regional lymph nodes
may not need to be
removed. Because fewer
lymph
nodes
are
removed, there may be
fewer side effects. When
multiple regional lymph
nodes are removed, the
patient may experience
side effects such as
lymphedema
(swelling
caused by excess fluid
build-up), numbness, a
persistent
burning
sensation, infection, and
difficulty
moving
the
affected body area.
INCT-MM
Standard lymph node removal involves
surgery to remove most of the lymph
nodes in the area of the tumor (regional
lymph nodes). For example, breast cancer
surgery may include removing most of the
axillary lymph nodes, the group of lymph
nodes under the arm. This is called axillary
lymph node dissection (ALND). If Sentinel
Lymph Node biopsy is done and the
sentinel node does not contain cancer
A sentinel lymph node
biopsy is done in two
stages. In the first part
of the procedure, which
takes one to two hours,
the patient goes to the
nuclear medicine department of the
hospital for an injection of a radioactive
tracer known as technetium 99. A doctor
who specializes in nuclear medicine first
numbs the area around the tumor with a
local anesthetic and then injects the
radioactive technetium. He or she usually
injects a blue dye as well. The doctor will
then use a gamma camera to take
pictures of the lymph nodes before
surgery. This type of imaging study is
;:
called
lymphoscintigraphy.
After
the
lymphoscintigraphy, the patient must wait
several hours for the dye and the
radioactive material to travel from the
tissues around the tumor to the sentinel
lymph node. He or she is then taken to
the operating room and put under general
anesthesia. Next, the surgeon injects more
blue dye into the area around the tumor.
The surgeon then uses a hand-held probe
connected to a gamma ray counter to
scan
the
area
for
the
radioactive
technetium. The sentinel lymph node can
be pinpointed by the sound made by the
gamma ray counter. The surgeon makes an
incision
about
0.5
in
long
t
o remove the sentinel node. The blue dye
that has been injected helps to verify that
the surgeon is removing the right node.
The incision is then closed and the tissue
is sent to the hospital laboratory for
examination.
INCT-MM
;;
'&! $ INCT-MM
;<
$$'&!'$% & !!+
Through the course of Technology in
Radiology and Diagnostic Imaging, UFMG
inaugurates its performance in the business
of technology degrees. Such courses also
form high level professionals, who can
even academic career, studying Masters or
Doctorate. However, this type of degree is
more focused to meet specific demands
from the market. The Technology course in
Radiology and Diagnostic Imaging will be
offered at night, with admission of 80
students per year, 40 per semester. The
student must deal with sophisticated
equipment in the field of diagnostic
imaging, widely used in medicine. The
career demands affinities with the areas of
Health
Informatics
and
The
course
includes,
besides
technical
knowledge
determined
to
humanistic
education.
Students will have the infrastructure of
Medical
College
and
Hospital.
The
technologist in Radiology and Diagnostic
Imaging will be able to work with
equipment in the areas of radiology,
computed tomography, magnetic resonance
imaging,
radiotherapy
and
nuclear
medicine. The spread of courses offered by
UFMG is to form professionals with more
extensive than that offered by other
courses in the area.'ll Be able to work with
the most sophisticated imaging equipment,
and also develop an academic career.
INCT-MM
;=
$'&!'$%% % +
Education and Training
Training
CAMH
Canadá
Training
Center
IOP
Reino Unido
Child
Health
Women's
Health
CDTN
Foreign
collaborators
Medical
Residencies
Internal
Medicin
Graduate
Programs
PUC-MG
Faculdade de
Medicina da UFMG
Surgery
INCT-MM
Molecular
Medicine
Neuroscience
Graduate
Programs
ICBUFMG
Instituto
Milênio de
Neurotoxinas
SCM-MG
UFSM-RS
Graduate
Course
Graduate
course
The INCT-MM has a net of participating graduate programs integrated with medical residencies
in the various participating institutions. See above.
INCT-MM
;>
0
!&)1
The website “Image of the Week” was
created to complement the teaching of
imaging disciplines. It follows the principles
of “Image Challenge” of The New England
Journal of Medicine, available at imagechallenge.nejm.org. In addition, the site will
have links and presentations regarding
principles and use of imaging technology
in molecular medicine. It is coordinated by
Dr. Viviane Parisotto Marino, from the
Nuclear Medicine Service of Hospital das
Clínicas –UFMG, and one of the associated
laboratories of the INCT-MM.
INCT-MM
;?
'&! %
INCT-MM
;@
'&! %766>
1.
13. de Sá MS, Costa JF, Krettli AU, Zalis MG, Maia GL, Sette IM, Câmara Cde A, Filho JM, GiuliettiHarley AM, Ribeiro Dos Santos R, Soares MB. Antimalarial activity of betulinic acid and derivatives
in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice. Parasitol Res.
2009 Jul;105(1):275-9 1.818
14. DIAS, C. S. ; SILVA, José Maria Penido ; DINIZ, José Silvério Santos ; LIMA, Eleonora Moreira ;
MARCIANO, R C ; LANA, L. G. ; TRIVELATO, Ana Luiza L. ; LIMA, M. S. ; Simoes e Silva, Ana
Cristina ; OLIVEIRA, Eduardo Araújo . Risk factors for recurrent urinary tract infections in a cohort
of patients with primary vesicoureteral reflux. The Pediatric Infectious Disease Journal, 2009.
15. Dias-Lopes C.; G. Guimarães ; L. Felicori ; KALAPOTHAKIS, E. ; Paula Fernandes ; NGUYEN, C. ;
MOLINA, Franck ; GRANIER, C. ; Chávez-Olórtegui, Carlos . A protective immune response against
lethal, dermonecrotic and hemorrhagic effects of Loxosceles intermedia venom elicited by a 27residue peptide. Toxicon (Oxford), 2009.
INCT-MM
Almeida, L ; CAROLINO, Rachel Melilo ; Sperandio, D ; Nehemy, M.B. ; DE MARCO, L . A
importância dos fatores genéticos na degeneração macular relacionada à idade (DMRI). Arquivos
Brasileiros de O ftalmologia, 2009.
2. Amaral E, Leite LF, Gomez MV, Prado MA, Guatimosim C. Ouabain evokes exocytosis dependent
on ryanodine and mitochondrial calcium stores that is not followed by compensatory endocytosis
at the neuromuscular junction. Neurochem Int. 2009 55(6):406-13
3. Campos SB, Miranda DM, Souza BR, Pereira PA, Neves FS, Bicalho MA, Melillo PH, Tramontina J,
Kapczinski F, Romano-Silva MA, Correa H. Association of polymorphisms of the tryptophan
hydroxylase 2 gene with risk for bipolar disorder or suicidal behavior. J Psychiatr Res. 2009 Sep
30.
4. Carvalho, VM ; Perdigão, PF ; Amaral, FR ; de Souza, PEA ; DE MARCO, L ; Gomez, RS . Novel
mutations in the gene associated with sporadic central giant cell lesions and cherubism. Oral
Diseases, v. 15, p. 106-110, 2009
5. COSTA, José Eustáquio da ; GOMES, Carolina Cavaliéri ; COTA, L. O. ; PATARO, A. L. ; SILVA,
Jeane de Fátima Correia ; GOMEZ, R. S. ; COSTA, Fernando de Oliveira . Polymorphisms in the
promoter region of the gene for 5-HTT in individuals with aggresive periodontitis. Journal of Oral
Science, v. 50, p. 193-198, 2008.
6. Cunico W, Gomes CR, Facchinetti V, Moreth M, Penido C, Henriques MG, Varotti FP, Krettli LG,
Krettli AU, da Silva FS, Caffarena ER, de Magalhães CS. Synthesis, antimalarial evaluation and
molecular modeling studies of hydroxyethylpiperazines, potential aspartyl protease inhibitors, Part
2. Eur J Med Chem. 2009 v. 44, p. 1363-1368 Apr 8.
7. Cunico, Wilson ; Gomes, Claudia R.B. ; Facchinetti, Victor ; Moreth, Marcele ; Penido, Carmen ;
Henriques, Maria G.M.O. ; Varotti, Fernando P. ; Krettli, Luisa G. ; Krettli, Antoniana U. ; da Silva,
Franklin S. . Synthesis, antimalarial evaluation and molecular modeling studies of
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;A
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<8
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38. MOURA, Mariela Dutra Gontijo ; NOVAES JR, João Batista ; GOMEZ, R. S. ; SOUTO, G. R. ;
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47. PINHEIRO, Sérgio Veloso Brant ; FERREIRA, Anderson José ; KITTEN, Gregory ; SILVEIRA, Katia
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<9
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57. Vaisbich. M.H. ; CARNEIRO, Juliana Garcia ; BOSON, Wolfanga ; RESENDE, Bruna Araujo ; DE
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