Ana Claudia Latronico

Universidade Federal de São Paulo, San Paulo, São Paulo, Brazil

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Publications (179)924.78 Total impact

  • Ana Claudia Latronico · Vinicius Nahime Brito · Jean-Claude Carel
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    ABSTRACT: Central precocious puberty results from the premature activation of the hypothalamic-pituitary-gonadal axis. It mimics physiological pubertal development, although at an inappropriate chronological age (before 8 years in girls and 9 years in boys). It can be attributable to cerebral congenital malformations or acquired insults, but the cause in most cases in girls remains unknown. MKRN3 gene defects have been identified in familial disease, with important basic and clinical results. Indeed, genetic analysis of this gene should be included in the routine clinical investigation of familial and idiopathic cases of central precocious puberty. Gonadotropin-releasing hormone agonists are the gold-standard treatment. The assessment and management of this disease remain challenging for paediatric endocrinologists. In this Series paper, we describe current challenges involving the precise diagnosis and adequate treatment of this disorder.
    No preview · Article · Feb 2016 · The Lancet Diabetes & Endocrinology
  • D.B. Macedo · L.F.G. Silveira · D.S. Bessa · V.N. Brito · A.C. Latronico
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    ABSTRACT: Precocious puberty has been classically defined as the onset of sexual secondary characteristics in girls younger than 8 years and in boys younger than 9 years. The discovery of potential factors which trigger human puberty is one of the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, and (more recently) whole-exome sequencing, have been performed in attempt to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis, resulting in premature sexual development. In the last two decades, it has been well established that autonomous gonadal activation can be caused by somatic (GNAS) or germline (LHCGR)-activating mutations of genes that encode essential elements for signal transduction of G protein-coupled receptors, resulting in peripheral precocious puberty in McCune-Albright syndrome and testotoxicosis, respectively. More recently, dominant activating and inactivating mutations of excitatory (KISS1/KISS1R) and inhibitory (MKRN3) modulators of gonadotropin-releasing hormone secretion, respectively, were associated with central precocious puberty phenotype. Indeed, loss-of-function mutations of MKRN3, a maternal imprinted gene located at chromosome 15q, currently represent a frequent cause of central precocious puberty diagnosed in families from distinct geographic origins. Here, we review the known genetic defects in central and peripheral precocious puberty.
    No preview · Article · Jan 2016
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    ABSTRACT: Background: Inpatient hyperglycemia is associated with adverse outcomes in hospitalized patients, with or without known diabetes. The adherence to American College of Endocrinology and American Diabetes Association guidelines recommendations for inpatient glycemic control is still poor, probably because of their complexity and fear of hypoglycemia. Objective: To create software system that can assist health care providers and hospitalists to manage the insulin therapy orders and turn them into a less complicated issue. Methods: A software system was idealized and developed, according to recommendations of major consensus and medical literature. Results: HTML software was developed to be readily accessed from a workstation, tablet or smartphone. Standard initial daily total dose of insulin was 0.4 units/kg and could be modified by distinct factors, such as chronological age, renal and liver function, and high dose corticosteroids use. Insulin therapy consisted of basal, prandial and correction insulin according to nutritional support, glycemic control and outpatient treatment for diabetes. Human insulin or insulin analogues could be options for insulin therapy. Sensitivity factor was based on 1800 Rule for rapid-acting insulin and the 1500 Rule for short-acting insulin. Insulin-naïve patients with initial BG level less than 250 mg/dL were considered to have an initial step-wise approach with prandial and correction insulin. The calculator system has allowed insulin dose readjustments periodically, according to daily average blood glucose measurements. Conclusion: We developed software that can be a useful tool for all public hospitals, where generally human insulin is the only available. Keywords: Diabetes mellitus, Hyperglycemia, Hospitalization, Insulin
    Full-text · Article · Dec 2015 · Diabetology and Metabolic Syndrome
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    ABSTRACT: Aim: Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. Methods: A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSHβ gene was amplified and sequenced. Results: Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSHβ gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. Conclusion: We herein described an adolescent male with isolated FSH deficiency due to a novel FSHβ gene mutation associated with a prepubertal testes size and normal virilisation.
    No preview · Article · Dec 2015 · Hormone Research in Paediatrics
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    Full-text · Article · Nov 2015 · Diabetology and Metabolic Syndrome
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    Full-text · Dataset · Aug 2015

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.
    Full-text · Article · Jun 2015 · Oncotarget
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    ABSTRACT: DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ(2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis. © Georg Thieme Verlag KG Stuttgart · New York.
    Full-text · Article · May 2015 · Hormone and Metabolic Research
  • Vinicius Nahime Brito · Ana Claudia Latronico

    No preview · Article · Apr 2015
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    ABSTRACT: RFamide-related peptide-3 (RFRP-3), the ortholog of avian gonadotropin-inhibitory hormone, and its receptor GPR147 have been recently identified in the human hypothalamus, and their roles on the regulation of reproductive axis has been interrogated. Our aim was to investigate if the presence of variants in the genes encoding human RFRP-3 (NPVF gene) and its receptor, GPR147 (NPFFR1 gene), is associated with the occurrence of GnRH-dependent pubertal disorders. Seventy-eight patients with idiopathic central precocious puberty (CPP) and 51 with normosmic isolated hypogonadotropic hypogonadism (nIHH) were investigated. Fifty healthy subjects comprised the control group. The coding sequences of the NPVF and NPFFR1 genes were amplified and sequenced. The frequencies of polymorphisms were compared among the groups and the odds ratio for the occurrence of CPP or nIHH was determined. All polymorphisms have been already described in the NCBI database. A 3-nucleotide in frame deletion was identified in the NPVF gene (p.I71_K72), with a slightly smaller proportion in the CPP (5%) as compared to the nIHH (15%) group (p=0.06). It results in the deletion of the isoleucine at position 71, adjacent to lysine at an endoproteolytic cleavage site of the precursor peptide. This polymorphism was associated with a reduced risk for the occurrence of CPP (OR 0.33; 95%CI: 0.08-0.88); interestingly, only 2 men with nIHH were homozygotes for this variant. A total of 5 missense polymorphisms were found in the NPFFR1 gene, which encodes GPR147, with similar frequencies among groups and no association with pubertal timing. Our data suggest that RFRP-3/GPR147 may play secondary, modulatory roles on the regulation of pubertal development; a restraining modulatory effect of the NPVF p.I71_K72 variant on the activation of the gonadotropic axis cannot be ruled out and deserves further investigation.This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2014 · Journal of Neuroendocrinology
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    ABSTRACT: ObjectiveLIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumors (ACTs).Patients and methodsLIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analyzed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas.ResultsLIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and non-aggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (p= 0.01), but for overall survival only a trend was detectable (p= 0.117). In the multivariate analysis, only Ki67 index ≥ 10% (HR 4.6, p= 0.000) and weak LIN28 protein expression (HR 2.0, p= 0.03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in non-aggressive ACCs [2076 (from 36 to 9307) vs. 133.4 (from 2.4 to 5193); p= 0.011] and was highly associated with reduced overall (p= 0.01) and disease-free survival (p= 0.01). However, mir-9 prognostic role should be further evaluated in a larger cohort.Conclusion Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2014 · Clinical Endocrinology
  • Delanie Bulcao Macedo · Vinicius Nahime Brito · Ana Claudia Latronico
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    ABSTRACT: A pivotal event in the onset of puberty in humans is the re-emergence of pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of the kisspeptin and its cognate receptor (KISS1- KISS1R), and the inactivation of the MKRN3 in the premature reactivation of the GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located in the long arm of chromosome 15, encodes makorin ring finger protein 3 that is involved with ubiquitination and cell signaling. MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explore the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing. © 2014 S. Karger AG, Basel.
    No preview · Article · Aug 2014 · Neuroendocrinology
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    ABSTRACT: Context: IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and methods: We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results: IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion: We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors.
    Full-text · Article · Jul 2014 · BioMed Research International
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    João Evangelista Bezerra · Ana Claudia Latronico
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    ABSTRACT: MicroRNAs play an essential role in posttranscriptional regulation of gene expression. They are evolutionary conserved, small, noncoding, 19-22-nucleotide RNAs, whose abnormalities, such as up- or downregulated expression, have been associated with several neoplasms, including adrenocortical tumors. Expression levels of distinct microRNAs can distinguish benign from malignant adrenal tumors. This current review provides recent data on the miRNAs profile in benign and malignant adrenocortical tumors diagnosed in adult and pediatric patients.
    Preview · Article · Jun 2014 · BioMed Research International
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    ABSTRACT: Background: The sonic hedgehog (SHH) pathway plays a key role in rodent adrenal cortex development and is involved in tumorigenesis in several human tissues, but data in human adrenal glands are limited. Objectives: To analyze the involvement of the SHH pathway in human adrenal development and tumorigenesis and the effects of SHH inhibition on an adrenocortical tumor (ACT) cell line. Patients & Methods: Expression of SHH pathway components was evaluated by immunohistochemistry (IHC) in 51 normal adrenals (33 fetal) and 34 ACTs (23 pediatric), and by qPCR in 81 ACTs (61 pediatric) and 19 controls (10 pediatric). The effects of SHH pathway inhibition on gene expression and cell viability in the NCI-H295A adrenocortical tumor cell line after cyclopamine treatment were analyzed. Results: SHH pathway proteins were present in fetal and postnatal normal adrenals and showed distinct patterns of spatiotemporal expression throughout development. Adult ACCs presented with higher expression of PTCH1, SMO, GLI3 and SUFU compared with normal adult adrenal cortices. Conversely, pediatric ACTs showed lower mRNA expression of SHH, PTCH1, SMO, GLI1 and GLI3 compared with normal pediatric adrenal cortices. In vitro treatment with cyclopamine resulted in decreased GLI3, SFRP1, CTNNB1 mRNA expression and beta-catenin staining, as well as decreased cell viability. Conclusions: The SHH pathway is active in human fetal and postnatal adrenals, up regulated in adult ACCs and down regulated in pediatric ACTs. SHH pathway antagonism impaired cell viability. The SHH pathway is deregulated in ACTs and might provide a new target therapy to be explored.
    No preview · Article · Apr 2014 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: ContextThe role of planar cell polarity (Wnt/PCP) and calcium-dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown.Objectives To investigate gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome.PatientsExpression of noncanonical Wnt-related genes was evaluated in 91 ACTs (66 children, 25 adults) by qPCR and beta-catenin, P53, and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced.ResultsTP53 p.R337H mutation frequency was higher in children (86% vs 28%) while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric, but not in adult cases. Cytoplasmic/nuclear beta-catenin and P53 accumulation were observed in the majority of pediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults.Conclusions In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2014 · Clinical Endocrinology
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    ABSTRACT: The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.
    Preview · Article · Mar 2014 · Arquivos brasileiros de endocrinologia e metabologia
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    ABSTRACT: Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans. Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability. We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling. Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.-Noel, S. D., Abreu, A. P., Xu, S., Muyide, T., Gianetti, E., Tusset, C., Carroll, J., Latronico, A. C., Seminara, S. B., Carroll, R. S., Kaiser, U. B. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients.
    Preview · Article · Dec 2013 · The FASEB Journal

Publication Stats

4k Citations
924.78 Total Impact Points

Institutions

  • 2015
    • Universidade Federal de São Paulo
      San Paulo, São Paulo, Brazil
  • 1998-2015
    • Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
      • • Divisão de Neurologia
      • • Serviço de Endocrinologia e Metabologia
      San Paulo, São Paulo, Brazil
  • 1997-2014
    • University of São Paulo
      • • Faculty of Medicine (FM)
      • • Hospital das Clínicas (FMUSP)
      • • Departamento de Fisiologia e Biofísica (ICB)
      San Paulo, São Paulo, Brazil
  • 2000-2011
    • Hospital de Clínicas Niterói
      Vila Real da Praia Grande, Rio de Janeiro, Brazil
  • 2008
    • Brigham and Women's Hospital
      • Division of Endocrinology, Diabetes and Hypertension
      Boston, Massachusetts, United States
  • 2007
    • Clinical Research Management, Inc
      Брауншвейг, Ohio, United States
    • University of Iowa
      • Department of Molecular Physiology and Biophysics
      Iowa City, IA, United States
  • 2002
    • Universidade Federal do Rio Grande do Norte
      Natal, Rio Grande do Norte, Brazil
  • 1999
    • Hospital Samaritano São Paulo
      San Paulo, São Paulo, Brazil
  • 1996
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
  • 1995
    • National Institutes of Health
      베서스다, Maryland, United States