RESUMEN
INTRODUCTION: Myelomeningocele (MMC) results from incomplete closure of the neural tube, and has a complex multifactorial etiology, including an inflammatory microenvironment. OBJECTIVE: We evaluated the contribution of humoral immune response for development of inflammatory milieu. METHODS: Using public repository Gene Expression Omnibus (GEO), we retrieve dataset transcriptome from the amniotic fluid of ten fetuses with myelomeningocele and ten healthy control fetuses to found differential gene expression associated with disturbances and inflammatory signatures in MMC. The identified DEGs were submitted to enrichment, network, and matrix correlation analyses. RESULTS: Our initial analysis revealed 90 DEGs in MMC, mainly associated with signaling pathways of inflammation, including the immune modules, humoral immune response and IFN-type I signatures. Protein-protein analysis (PPI) revealed an association with three protein networks; positive regulation of B cell proliferation constituted the largest network. Matrix correlation analyses showed that MMC alters the co-expression of genes related to inflammatory processes that promote microenvironment inflammation. CONCLUSION: These results revealed an altered humoral immune response in MMC patients, contributing to an inflammatory profile and providing opportunities for identifying potential biomarkers in myelomeningocele disease.
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Inmunidad Humoral , Meningomielocele , Transcriptoma , Humanos , Meningomielocele/inmunología , Meningomielocele/genética , Inmunidad Humoral/genética , Transcriptoma/inmunología , Femenino , Perfilación de la Expresión Génica , Embarazo , Mapas de Interacción de Proteínas/inmunología , Transducción de Señal/inmunología , Transducción de Señal/genética , Inflamación/inmunología , Inflamación/genética , Biomarcadores/metabolismo , Redes Reguladoras de Genes/inmunologíaRESUMEN
INTRODUCTION: MgSO4 is the drug of choice to prevent seizures in preeclamptic pregnant women, but its mechanism of action at the molecular level remains an enigma. In previous works, we found that treating preeclamptic women with MgSO4 reduces the lipid peroxidation of their red blood cell membranes to normal levels and leads to a significant reduction in the osmotic fragility of the red blood cells that is increased during preeclampsia. In addition, the increase in lipid peroxidation of red cell membranes induced by the Fenton reaction does not occur when MgSO4 is present. METHODS: The antioxidant protection of MgSO4 was evaluated in UV-C-treated red blood cell ghosts and syncytiotrophoblast plasma membranes by measuring their level of lipid peroxidation. The interaction of MgSO4 with free radicals was assessed for its association with the galvinoxyl radical, the quenching of H2O2-induced chemiluminescence and its effect on sensitized peroxidation of linoleic acid. RESULTS: a) MgSO4 protected red blood cell ghosts and the syncytiotrophoblast plasma membranes of normotensive pregnant women against lipid peroxidation induced by UV-C irradiation. b) MgSO4 does not seem to scavenge the galvinoxyl free radical. c) The quenching of the H2O2-enhanced luminol chemiluminescence is increased by the presence of MgSO4. d) The peroxidation of linoleic acid is significantly blocked by MgSO4. DISCUSSION: MgSO4 may provide protection against oxidative damage of plasma membranes through interactions with alkyl radicals.
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Sulfato de Magnesio/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patología , Femenino , Radicales Libres/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Sulfato de Magnesio/farmacología , Preeclampsia/metabolismo , Preeclampsia/patología , Embarazo , Índice de Severidad de la Enfermedad , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismo , Trofoblastos/patologíaRESUMEN
The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.
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Corea/genética , Demencia/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedad de Huntington/genética , Ataxias Espinocerebelosas/genética , Adulto , Brasil , Corea/diagnóstico , Corea/epidemiología , Corea/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Demencia/diagnóstico , Demencia/epidemiología , Demencia/patología , Femenino , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/epidemiología , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/patología , Masculino , Persona de Mediana Edad , Fenotipo , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/patología , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
BACKGROUND: Molecular factors influencing Wilms tumor (WT) development remain largely unknown. TP53 mutations seem to be restricted to the anaplastic WT subtype. However, TP53 polymorphisms do not have a defined role in the disease. PROCEDURE: To assess the impact of TP53 mutations and polymorphisms (PIN2, PIN3, and PEX4) on risk of development, age at diagnosis, and survival in WT, we analyzed 46 blood DNA samples and 31 fresh tumor DNA samples from 52 patients with WT. Sequencing of TP53 exons 2-11 was performed. RESULTS: Tumor DNA analysis revealed TP53 pathogenic missense mutations (p.V197M, p.R213Q, p.R248W, and p.R337C) in four samples (12.9%). Blood DNA samples revealed a novel intronic mutation, IVS2 + 37C > T, in one patient (2.2%). Bilaterality was associated with a twofold decrease in survival (P = 0.00037). Diffuse anaplasia also presented a lower survival probability compared to patients with non-anaplastic tumors, or with focal anaplasia (P = 0.045). Patients with a TP53 somatic mutation showed survival probability of 37.5% versus 85.0% for patients with no somatic mutations, although the difference was not statistically significant (P = 0.0706). PIN3 duplicated allele was associated with a 20-month later mean age at diagnosis (P = 0.0084). TP53 PEX4 C allele showed an increased risk for WT development (P = 0.0379). No relationship was found between survival and gender, age at diagnosis, or the less frequent alleles of PIN2, PIN3, and PEX4. CONCLUSIONS: Our results demonstrate an association between PIN3 and age at diagnosis, as well as an association of PEX4 and risk of development of WT.
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Genes p53 , Neoplasias Renales/genética , Polimorfismo Genético , Tumor de Wilms/genética , Preescolar , Femenino , Genotipo , Humanos , Lactante , Neoplasias Renales/etiología , Neoplasias Renales/mortalidad , Masculino , Mutación , Riesgo , Tumor de Wilms/etiología , Tumor de Wilms/mortalidadRESUMEN
The 5382insC mutation in BRCA1 is a frequently reported mutation, being very prevalent in Central and Eastern Europe. This mutation was recurrently reported in Brazil and one case was reported Portugal, but not in Spain and other South-American countries,. We analyzed the haplotypic profile of seven Brazilian carriers of 5382insC to characterize a possible founder effect. The analyses indicated that mutation carriers shared an identical haplotype. The absence of this mutation in Spain, other South American countries, and sub-Saharan populations, as well as the patients' own ancestry, point to a significant Central or Eastern European contribution to the present genetic background of Brazilian population, different from the population structuring of remaining South American countries.
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Neoplasias de la Mama/genética , Efecto Fundador , Genes BRCA1 , Mutación , Neoplasias Ováricas/genética , Adulto , Secuencia de Bases , Brasil , Cartilla de ADN , Femenino , Haplotipos , Humanos , Persona de Mediana EdadRESUMEN
We developed a procedure for DNA extraction from small volumes of fixed cell suspensions previously prepared for conventional cytogenetic analysis. Good quality DNA was isolated with a fast and simple protocol using DNAzol reagent. This provided suitable DNA for various types of molecular analyses, including polymerase chain reaction, restriction fragment length polymorphism, denaturing high-performance liquid chromatography, and direct sequencing. This technique provides sufficient material for such test, which are important for diagnosis of neoplastic diseases in pediatric patients.
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Citogenética/métodos , ADN/análisis , Cromatografía Líquida de Alta Presión/métodos , Exones , Genoma , Humanos , Cariotipificación , Neoplasias/diagnóstico , Neoplasias/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Secuencia de ADN/métodosRESUMEN
We developed a procedure for DNA extraction from small volumes of fixed cell suspensions previously prepared for conventional cytogenetic analysis. Good quality DNA was isolated with a fast and simple protocol using DNAzol reagent. This provided suitable DNA for various types of molecular analyses, including polymerase chain reaction, restriction fragment length polymorphism, denaturing high-performance liquid chromatography, and direct sequencing. This technique provides sufficient material for such test, which are important for diagnosis of neoplastic diseases in pediatric patients.
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Humanos , Citogenética/métodos , ADN , Genoma , Neoplasias/diagnóstico , Análisis de Secuencia de ADN/métodos , Cromatografía Líquida de Alta Presión/métodos , Exones , Cariotipificación , Neoplasias/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
AIMS: To carry out a retrospective study, screening for mutations of the entire coding region of RB1 and adjacent intronic regions in patients with retinoblastoma. METHODS: Mutation screening in DNA extracts of formalin fixed, paraffin wax embedded tissues of 28 patients using combined "exon by exon" polymerase chain reaction mediated single strand conformational polymorphism analysis, followed by DNA sequencing. RESULTS: Eleven mutations were found in 10 patients. Ten mutations consisted of single base substitutions; 10 were localised in exonic regions (eight nonsense, one missense, and one frameshift) and another one in the intron-exon splicing region. Three novel mutations were identified: a 2 bp insertion in exon 2 (g.5506-5507insAG, R73fsX77), a G to A transition affecting the last invariant nucleotide of intron 13 (g.76429G>A), and a T to C transition in exon 20 (g.156795T>C, L688P). In addition, eight C to T transitions, resulting in stop codons, were found in five different CGA codons (g.64348C>T, g.76430C>T, g.78238C>T, g.78250C>T, and g.150037C>T). Although specific mutation hotspots have not been identified in the literature, eight of the 11 mutations occurred in CGA codons and seven fell within the E1A binding domains (codons 393-572 and 646-772), whereas five were of both types-in CGA codons within E1A binding domains. CONCLUSIONS: CGA codons and E1A binding domains are apparently more frequent mutational targets and should be initially screened in patients with retinoblastoma. Paraffin wax embedded samples proved to be valuable sources of DNA for retrospective studies, providing useful information for genetic counselling.
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Mutación , Neoplasias de la Retina/genética , Proteína de Retinoblastoma/genética , Retinoblastoma/genética , Brasil , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Exones/genética , Femenino , Humanos , Masculino , Adhesión en Parafina , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Estudios RetrospectivosRESUMEN
Prenatal exposure to misoprostol has been associated with Moebius and limb defects. Vascular disruption has been proposed as the mechanism for these teratogenic effects. The present study is a multicenter, case-control study that was designed to compare the frequency of prenatal misoprostol use between mothers of Brazilian children diagnosed with vascular disruption defects and matched control mothers of children diagnosed with other types of defects. A total of 93 cases and 279 controls were recruited in eight participating centers. Prenatal exposure was identified in 32 infants diagnosed with vascular disruption defects (34.4%) compared with only 12 (4.3%) in the control group (P<0.0000001). Our data suggest that prenatal exposure to misoprostol is associated to the occurrence of vascular disruption defects in the newborns.
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Anomalías Inducidas por Medicamentos/fisiopatología , Abortivos no Esteroideos/efectos adversos , Feto/irrigación sanguínea , Feto/efectos de los fármacos , Misoprostol/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Abortivos no Esteroideos/administración & dosificación , Administración Oral , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Deformidades Congénitas de las Extremidades/inducido químicamente , Deformidades Congénitas de las Extremidades/fisiopatología , Misoprostol/administración & dosificación , Síndrome de Mobius/inducido químicamente , Síndrome de Mobius/fisiopatología , Oportunidad Relativa , EmbarazoRESUMEN
The human Sonic Hedgehog gene (SHH) is one of the vertebrate homologs related to the Drosophila segment polarity gene hedgehog. The entire coding and promoter region of the SHH gene, including 2 kb 5' of the transcriptional start site has been screened for mutations in families with autosomal dominant sacral agenesis and autosomal dominant triphalangeal thumb, two conditions previously known to be linked to 7q36. We have also studied the SHH gene in five families with mirror polydactyly associated with tibial hemimelia and in 51 unrelated patients with neural tube defects. Except for two sequence variants in exon 3, no mutations were found in these disease categories. OFF
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Anomalías Múltiples/genética , Polidactilia/genética , Regiones Promotoras Genéticas , Proteínas/análisis , Proteínas/genética , Región Sacrococcígea/anomalías , Pulgar/anomalías , Transactivadores , Secuencia de Bases , Cromosomas Humanos Par 7 , Clonación Molecular , Exones , Proteínas Hedgehog , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADNRESUMEN
Duplications in Xp including the DSS (dosage sensitive sex reversal) region cause male to female sex reversal. We investigated two patients from families with Xp duplications. The first case was one of two sisters with karyotype 46,XY,der(22),t(X;22)(p11.3;p11)mat and unambiguous female genitalia. The living sister was developmentally retarded, and showed multiple dysmorphic features and an acrocallosal syndrome. The second case was a boy with a maternally inherited direct duplication of Xp21.3-pter with the breakpoint close to the DSS locus. He had multiple abnormalities and micropenis, but otherwise unambiguous male genitalia. We performed quantitative Southern blot analysis with probes from Xp22.13 to p21.2 to define the duplicated region. Clinical, cytogenetic, and molecular data from both patients were compared with those of previously reported related cases. A comparison of the extragenital symptoms revealed no differences between patients with or without sex reversal. In both cases, the symptoms were non-specific. Among 22 patients with a duplication in Xp, nine had unambiguous female genitalia and a well-documented duplication of the DSS region. Two patients with duplication of DSS showed ambiguous external genitalia. From these data, we conclude that induction of testicular tissue may start in these patients, but that the type of genitalia depends on the degree of subsequent degeneration by a gene in DSS.
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Anomalías Múltiples/genética , Trastornos del Desarrollo Sexual , Aberraciones Cromosómicas Sexuales/genética , Cromosoma X , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 22 , Femenino , Genitales Femeninos/anatomía & histología , Genitales Femeninos/patología , Genitales Masculinos/anatomía & histología , Genitales Masculinos/patología , Humanos , Lactante , Cariotipificación , Masculino , Núcleo Familiar , Linaje , Translocación GenéticaRESUMEN
We describe a family with Stanescu osteosclerosis. The propositus and his mother were short and had cortical sclerosis of the long bones, deficient facial sinus development, cranial bone malformations, and normal intelligence. To the best of our knowledge, only two such families have been described previously. The autosomal dominant pattern of inheritance of this skeletal dysplasia is reinforced, as there are many other reportedly affected relatives, including the maternal grandfather, uncles, and aunts of the propositus. The findings of wormian bones and calcification of the falx, not previously described, may be added to the phenotype.
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Osteosclerosis/genética , Adulto , Niño , Femenino , Humanos , Lactante , Masculino , Osteosclerosis/diagnóstico por imagen , Osteosclerosis/patología , Linaje , Fenotipo , RadiografíaRESUMEN
A clinical follow up of 165 Down Syndrome (DS) patients in an outpatient clinic programme at the Centro de Genética Médica (IFF - FIOCRUZ) was undertaken retrospectively. Clinical and laboratorial investigations were performed, such as cytogenetics and hematological analysis, thyroid hormones survey, abdominal ultrasound and cervical column X Rays. The clinical diagnosis of Down Syndrome was mostly performed during the first year of life, and 70% of all patients were under 4 years of age, being predominantly males. Trisomy 21 derived from non disjunction was found in 85% of the patients. The most common congenital malformation was cardiopathy (37.5%) and among all the clinical complications, repeated pneumonia could be evidenced in 30% of the patients, mainly during the first year of life. Leukopenia was observed in 14% of the patients and abdominal ultrasound scans allowed the early detection of biliary stones in 4.3% of the patients examined, a significative finding in the paediatric population. A prospective clinical programme aiming to anticipate the detection of clinical complications on at risk DS populations will fulfill its objectives and may act as a reducing factor in the infantile mortality rate.
RESUMEN
We report on a young girl with psychomotor delay, cataracts, abnormally shaped teeth, malformed ears, and radiological findings of spondylo-epiphyseal dysplasia. The clinical picture resembles the CODAS syndrome described by Shebib et al. [Am J Med Genet 40: 88-93, 1991].
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Anomalías Múltiples/diagnóstico por imagen , Osteocondrodisplasias/diagnóstico por imagen , Anomalías Múltiples/genética , Preescolar , Femenino , Humanos , Osteocondrodisplasias/genética , RadiografíaRESUMEN
We report on a family in which the autosomal dominant Werner syndrome (WS) (MIM# 188770) affects ten members in three generations. Besides the absent tibiae the propositus had duplication of the fibulae. Possible pathogenetic mechanism is discussed.
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Anomalías Múltiples/genética , Huesos/anomalías , Polidactilia/genética , Adolescente , Adulto , Peroné/anomalías , Genes Dominantes , Humanos , Lactante , Masculino , Linaje , Síndrome , Pulgar/anomalías , Tibia/anomalíasRESUMEN
Misoprostol, a synthetic analog of prostaglandin, has been widely used in Brazil as an abortifacient. Abortion is illegal in Brazil. An uncertain number of these abortion attempts are unsuccessful and the pregnancy continues. We report on 7 patients whose mothers attempted to abort using this drug in the first trimester of gestation without success. The 7 patients presented with limb defects and in 4 of them a diagnosis of Möbius sequence was made.
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Anomalías Inducidas por Medicamentos , Anomalías Múltiples/inducido químicamente , Enfermedades de los Nervios Craneales/congénito , Ectromelia/inducido químicamente , Parálisis Facial/congénito , Misoprostol/efectos adversos , Aborto Criminal , Brasil , Enfermedades de los Nervios Craneales/inducido químicamente , Parálisis Facial/inducido químicamente , Femenino , Deformidades Congénitas del Pie/inducido químicamente , Deformidades Congénitas de la Mano/inducido químicamente , Humanos , Recién Nacido , Masculino , Embarazo , SíndromeRESUMEN
We report on a boy with severe radial hypoplasia, absent thumbs and patellae, short stature, persistent diarrhea, slender nose and normal intelligence as another example of the RAPADILINO syndrome.