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1.
J Ethnopharmacol ; 244: 112127, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376515

RESUMO

ETHNOPARMACOLOGICAL RELEVANCE: Artemisia afra is one of the most widely used herbal remedies in South Africa. This highly aromatic shrub is used to treat various disorders including coughs, colds, influenza, and malaria. Due to the long tradition of use and popularity of A. afra, it has been successfully commercialised and can currently be bought from various internet stores and pharmacies. The most notable indication is for the prophylaxis and treatment of Plasmodium falciparum infections. In 2013, the Medicine Control Council (MCC) of South Africa banned the sale of A. afra for the treatment of malaria because it lacks scientific evidence of efficacy. This resulted in a lawsuit being filed in 2017 against the MCC by an herbal company which claimed that artemisinin was responsible for A. afra's antiplasmodial activity. At the time, no scientific literature reported that A. afra contained artemisinin. MATERIALS AND METHODS: This review aims to collate all available scientific literature regarding the phytochemistry and biological activity, focusing on antimalarial activity, of A. afra published from 2009 to 2019 and follows on our earlier review, which covered all literature until 2009. All scientific literature in English published between 2009 and June 2019 were retrieved from scientific databases (Scifinder scholar, Web of Science, Scopus, PubMed, Google scholar) and a number of books regarding medicinal plants in South Africa were also consulted. RESULTS: In the last decade very few compounds have been identified in A. afra, none of which were novel compounds. Based on all the tests that have been conducted using extracts and compounds of A. afra in a disparate variety of in vitro and in vivo bioassays, the results indicate only weak biological activity. The activity of extracts, and in some cases pure compounds, exhibited IC50 or MIC values of 1000-10 000 fold less active than the positive controls. In contrast, and quite surprisingly, two randomised controlled trials were recently conducted (Schistosoma mansoni and Plasmodium falciparum infected patients) and although criticised based on design, execution, statistical analysis and ethical concerns, showed remarkably positive results. CONCLUSIONS: Pre-clinical in vitro and in vivo animal experiments failed to yield any promising drug leads. However, if the recent randomised controlled trials can be independently replicated in well-designed and executed clinical trials it might indicate that A. afra contain powerful 'prodrugs'. Future research on A. afra should therefore focus on reproducing the randomised controlled trials and on artificially metabolising A. afra extracts/compounds in order to identify the presence of any 'prodrugs'.

2.
J Med Genet ; 56(10): 701-710, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451536

RESUMO

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders. METHODS: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. RESULTS: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias. CONCLUSIONS: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

3.
Eur J Med Genet ; 62(8): 103691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176769

RESUMO

Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features. Animal studies indicate BRPF1 as an important mediator in brain development. However, only 5 of 22 previously reported patients show structural brain abnormalities. We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome.

4.
Am J Med Genet A ; 179(7): 1276-1286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31124279

RESUMO

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

6.
Epilepsia ; 60(4): 689-706, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30866059

RESUMO

OBJECTIVE: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. METHODS: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. RESULTS: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. SIGNIFICANCE: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

7.
Biochim Biophys Acta Mol Basis Dis ; 1865(9): 2083-2093, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30557699

RESUMO

Mutations in the X chromosomal tRNA 2'­O­methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.

9.
J Mol Neurosci ; 64(2): 331, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29353437

RESUMO

The original version of this article unfortunately contained mistakes.

10.
Eur J Hum Genet ; 25(1): 43-51, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27804958

RESUMO

Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.


Assuntos
Nanismo/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Fatores de Processamento de RNA/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Nanismo/fisiopatologia , Exoma/genética , Feminino , Mutação da Fase de Leitura , Cardiopatias Congênitas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Processamento de RNA/genética
13.
Am J Med Genet A ; 170(3): 670-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26842493

RESUMO

We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Mutação Puntual , Convulsões/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Facies , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/tratamento farmacológico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Expressão Gênica , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/patologia , Índice de Gravidade de Doença , Síndrome , Adulto Jovem
14.
Eur J Paediatr Neurol ; 20(3): 474-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26818157

RESUMO

BACKGROUND: Biallelic loss-of-function mutations of phospholipase C-ß1 (PLCB1) have been described in three children with an early onset epileptic encephalopathy (EE). In two of them a homozygous deletion of the promotor and first three coding exons was found. The third patient had an almost identical heterozygous deletion in combination with a heterozygous splice site variant. All patients had intractable epilepsy and a severe developmental delay. METHODS AND RESULTS: We present the case of a boy with an infantile EE starting at the age of four months with a fever induced status epilepticus, modified hypsarrhythmia and developmental regression. The epilepsy was reasonably controlled with corticoids and valproate whereupon generalized tonic-clonic seizures appeared only each 3-4 months. However, only a slow developmental progress was seen hereafter, resulting in a severe intellectual disability with absent speech, motor delay and autistic features. We identified a novel homozygous partial deletion of PLCB1, affecting exons 7-9. CONCLUSIONS: This report emphasizes the role of PLCB1 haploinsufficiency in severe EE. We demonstrate a phenotypic variability in patients with a PLCB1-associated EE. In addition, our findings underscore the importance of microarray analysis in all patients with an EE of unknown etiology.


Assuntos
Epilepsia/genética , Mutação/genética , Fosfolipase C beta/genética , Deficiências do Desenvolvimento/genética , Heterozigoto , Homozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Espasmos Infantis/genética
16.
Food Funct ; 6(3): 910-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25629927

RESUMO

Chronic inflammation is a contributing factor in many age-related diseases. In a previous study, we have shown that Sri Lankan cinnamon (C. zeylanicum) was one of the most potent anti-inflammatory foods out of 115 foods tested. However, knowledge about the exact nature of the anti-inflammatory compounds and their distribution in the two major cinnamon species used for human consumption is limited. The aim of this investigation was to determine the anti-inflammatory activity of C. zeylanicum and C. cassia and elucidate their main phytochemical compounds. When extracts were tested in LPS and IFN-γ activated RAW 264.7 macrophages, most of the anti-inflammatory activity, measured by down-regulation of nitric oxide and TNF-α production, was observed in the organic extracts. The most abundant compounds in these extracts were E-cinnamaldehyde and o-methoxycinnamaldehyde. The highest concentration of E-cinnamaldehyde was found in the DCM extract of C. zeylanicum or C. cassia (31 and 34 mg g(-1) of cinnamon, respectively). When these and other constituents were tested for their anti-inflammatory activity in RAW 264.7 and J774A.1 macrophages, the most potent compounds were E-cinnamaldehyde and o-methoxycinnamaldehyde, which exhibited IC50 values for NO with RAW 264.7 cells of 55 ± 9 µM (7.3 ± 1.2 µg mL(-1)) and 35 ± 9 µM (5.7 ± 1.5 µg mL(-1)), respectively; and IC50 values for TNF-α of 63 ± 9 µM (8.3 ± 1.2 µg mL(-1)) and 78 ± 16 µM (12.6 ± 2.6 µg mL(-1)), respectively. If therapeutic concentrations can be achieved in target tissues, cinnamon and its components may be useful in the treatment of age-related inflammatory conditions.


Assuntos
Acroleína/análogos & derivados , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cinnamomum aromaticum/química , Cinnamomum zeylanicum/química , Suplementos Nutricionais , Macrófagos/metabolismo , Acroleína/análise , Acroleína/química , Acroleína/isolamento & purificação , Acroleína/metabolismo , Animais , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Linhagem Celular , Cinnamomum aromaticum/crescimento & desenvolvimento , Suplementos Nutricionais/análise , Etnofarmacologia , Ativação de Macrófagos , Macrófagos/imunologia , Medicina Tradicional , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Casca de Planta/química , Casca de Planta/crescimento & desenvolvimento , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Sri Lanka , Estereoisomerismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
17.
Planta Med ; 80(14): 1227-33, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25098933

RESUMO

We applied an acute stress model to zebra fish in order to measure the changes in the metabolome due to biological stress. This was done by submitting the fish to fifteen minutes of acute confinement (netting) stress, and then five minutes for the open field and light/dark field tests. A polar extract of the zebra fish was then subjected to (1)H nuclear magnetic spectroscopy. Multivariate data analysis of the spectra showed a clear separation associated to a wide range of metabolites between zebra fish that were submitted to open field and light/dark field tests. Alanine, taurine, adenosine, creatine, lactate, and histidine were high in zebra fish to which the light/dark field test was applied, regardless of stress, while acetate and isoleucine/lipids appeared to be higher in zebra fish exposed to the open field test. These results show that any change in the environment, even for a small period of time, has a noticeable physiological impact. This research provides an insight of how different mechanisms are activated under different environments to maintain the homeostasis of the body. It should also contribute to establish zebra fish as a model for metabolomics studies.


Assuntos
Metaboloma , Estresse Fisiológico , Estresse Psicológico , Peixe-Zebra , Animais , Feminino , Espectroscopia de Ressonância Magnética/métodos , Masculino , Metabolômica , Análise Multivariada , Restrição Física
18.
J Neurodev Disord ; 6(1): 25, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25136376

RESUMO

Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.

19.
Eur J Med Genet ; 57(4): 151-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24534801

RESUMO

After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.


Assuntos
Hibridização Genômica Comparativa/métodos , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Diagnóstico Pré-Natal/métodos , Bélgica , Consenso , Feminino , Humanos , Guias de Prática Clínica como Assunto , Gravidez
20.
Chem Biodivers ; 10(10): 1774-90, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24130022

RESUMO

Species of the carnivorous genus Drosera L. have long been a source of valuable natural products. The various phytochemicals characteristic of these species, particularly 1,4-naphthoquinones and flavonoids, have contributed to the diverse utilization of sundews in traditional medicine systems worldwide. A growing number of studies have sought to investigate the comparative phytochemistry of Drosera species for improved sources of pharmaceutically important compounds. The outcomes of these studies are here collated, with emergent trends discussed in detail. Important factors which affect production of secondary metabolites in plants are critically examined, such as environmental influences and in vitro culture, and recommendations subsequently presented based on this. Explicitly, the current review aims to i) present an updated, comprehensive listing of the phytochemical constituents of the genus (including quantitative data where available), ii) summarize important factors which may influence the production of phytopharmaceuticals in plants, and iii) recommend guidelines for future research based on the above, including improved standardization and quality control. We have also included a section discussing future perspectives of research on Drosera spp. based on three different research lines i) the potential to produce much needed lead compounds for treatment of tuberculosis, ii) the potential role of anthocyanins in nitrogen transport, and iii) research into 'Natural Deep Eutectic' solvents produced by Drosera spp. in the droplets or 'dew' employed to capture insect prey.


Assuntos
Antocianinas/química , Drosera/química , Etnofarmacologia , Flavonoides/química , Naftoquinonas/química , Extratos Vegetais/química , Antocianinas/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Drosera/metabolismo , Sinergismo Farmacológico , Flavonoides/isolamento & purificação , Humanos , Inflamação/tratamento farmacológico , Naftoquinonas/isolamento & purificação , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico
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