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1.
Medicine (Baltimore) ; 98(20): e15532, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096455

RESUMO

INTRODUCTION: Zika virus (ZIKV) has caused one of the most challenging global infectious epidemics in recent years because of its causal association with severe microcephaly and other congenital malformations. The diagnosis of viral infections usually relies on the detection of virus proteins or genetic material in clinical samples as well as on the infected host immune responses. Serial serologic testing is required for the diagnosis of congenital infection when diagnostic molecular biology is not possible. PATIENT CONCERNS: A 2-year-old girl, born to a mother with confirmed ZIKV infection during pregnancy, with a confirmed ZIKV infection in utero, showed at birth a severe microcephaly and clinical characteristics of fetal brain disruption sequence compatible with a congenital ZIKV syndrome (CZS). DIAGNOSIS: ZIKV-RNA and ZIKV-IgM serological response performed at birth and during the follow-up time tested always negative. Serial serologic ZIKV-IgG tests were performed to assess the laboratory ZIKV diagnosis, ZIKV-IgG seroreversion was observed at 21 months of age. ZIKV diagnosis of this baby had to be relied on her clinical and radiological characteristics that were compatible with a CZS. INTERVENTIONS: The patient was followed-up as per protocol at approximately 1, 4, 9, 12, 18-21, and 24 months of age. Neurological, radiological, audiological, and ophthalmological assessment were performed during this period of time. Prompt rehabilitation was initiated to prevent potential adverse long-term neurological outcomes. OUTCOMES: The growth of this girl showed a great restriction at 24 months of age with a weight of 8.5 kg (-2.5 z-score) and a head circumference of 40.5 cm (-4.8 z-score). She also had a great neurodevelopmental delay at the time of this report. CONCLUSION: We presume that as a consequence of prenatal ZIKV infection, the fetal brain and other organs are damaged before birth through direct injury. Following this, active infection ends during intrauterine life, and as a consequence the immune system of the infant is unable to build up a consistent immune response thereafter. Further understanding of the mechanisms taking part in the pathogenesis of ZIKV congenital infection is needed. This finding might change our paradigm regarding serological response in the ZIKV congenital infection.


Assuntos
Complicações Infecciosas na Gravidez/diagnóstico , Infecção por Zika virus/diagnóstico , Encéfalo/anormalidades , Pré-Escolar , Feminino , Humanos , Microcefalia/etiologia , Gravidez , Testes Sorológicos , Espanha , Infecção por Zika virus/complicações
2.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(1. Vyp. 2): 45-49, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31006791

RESUMO

AIM: To determine clinical and psychopathological features of anxiety-depressive disorders in patients with cerebral residual organic insufficiency. MATERIAL AND METHODS: One hundred and fourteen patients with anxiety-depressive disorders and cerebral residual-organic insufficiency were studied. Psychopathological, psychometric, statistical methods were used. RESULTS AND CONCLUSION: Asthenia was identified as a core syndrome in anxiety-depressive disorders developed in patients with cerebral residual-organic insufficiency. Severe anxiety and depression with somatization of symptoms were characteristic of the structure of affective pathology. The somatization of affect, interpersonal sensitivity, marked asthenic and autonomic disorders as well as negative attitudes about their own condition, abilities and activity were main features of affective disorders in patients with cerebral residual-organic insufficiency. Clinical characteristics of cerebral residual-organic insufficiency and the diversity of its manifestations, including the combination with mental disorders, determine the relevance of further research.


Assuntos
Encéfalo , Depressão , Transtornos do Humor , Ansiedade , Transtornos de Ansiedade , Astenia , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Humanos
4.
Mil Med ; 184(Suppl 1): 218-227, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901451

RESUMO

RESEARCH OBJECTIVES: It is widely accepted that mild traumatic brain injury (mTBI) causes injury to the white matter, but the extent of gray matter (GM) damage in mTBI is less clear. METHODS: We tested 26 civilian healthy controls and 14 civilian adult subacute-chronic mTBI patients using quantitative features of MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique. GEPCI data were reconstructed using previously developed algorithms allowing the separation of R2t*, a cellular-specific part of gradient echo MRI relaxation rate constant, from global R2* affected by BOLD effect and background gradients. RESULTS: Single-subject voxel-wise analysis (comparing each mTBI patient to the sample of 26 control subjects) revealed GM abnormalities that were not visible on standard MRI images (T1w and T2w). Analysis of spatial overlap for voxels with low R2t* revealed tissue abnormalities in multiple GM regions, especially in the frontal and temporal regions, that are frequently damaged after mTBI. The left posterior insula was the region with abnormalities found in the highest proportion (50%) of mTBI patients. CONCLUSIONS: Our data suggest that GEPCI quantitative R2t* metric has potential to detect abnormalities in GM cellular integrity in individual TBI patients, including abnormalities that are not detectable by a standard clinical MRI.


Assuntos
Meios de Contraste/uso terapêutico , Substância Cinzenta/lesões , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos Piloto
5.
Medicina (Kaunas) ; 55(2)2019 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-30781564

RESUMO

Magnetic resonance imaging (MRI) is used as a clarifying technique after a high-resolution ultrasound examination during pregnancy. Combining ultrasound with MRI, additional diagnostic information is obtained or ultrasound diagnosis is frequently corrected. High spatial resolution provides accurate radiological imaging of internal organs and widens possibilities for detecting perinatal development disorders. The safety of MRI and the use of intravenous contrast agent gadolinium are discussed in this article. There is no currently available evidence that MRI is harmful to the fetus, although not enough research has been carried out to prove enduring safety. MRI should be performed when the benefit outweighs the potential side effects. The narrative review includes several clinical cases of fetal MRI performed in Vilnius University Hospital Santaros Clinics.


Assuntos
Abdome/anormalidades , Abdome/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Meios de Contraste/efeitos adversos , Feminino , Gadolínio/efeitos adversos , Hospitais Universitários , Humanos , Lituânia , Imagem por Ressonância Magnética/efeitos adversos , Gravidez , Ultrassonografia Pré-Natal/efeitos adversos
6.
Int J Mol Sci ; 20(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736425

RESUMO

Contemporaneous Zika virus (ZIKV) strains can cause congenital Zika syndrome (CZS). Current ZIKV clinical laboratory testing strategies are limited and include IgM serology (which may wane 12 weeks after initial exposure) and nucleic acid testing (NAT) of maternal serum, urine, and placenta for (+) strand ZIKV RNA (which is often transient). The objectives of this study were to determine if use of additional molecular tools, such as quantitative PCR and microscopy, would add to the diagnostic value of current standard placental ZIKV testing in cases with maternal endemic exposure and indeterminate testing. ZIKV RNA was quantified from dissected sections of placental villi, chorioamnion sections, and full cross-sections of umbilical cord in all cases examined. Quantitation with high-resolution automated electrophoresis determined relative amounts of precisely verified ZIKV (74-nt amplicons). In order to localize and visualize stable and actively replicating placental ZIKV in situ, labeling of flaviviridae glycoprotein, RNA ISH against both (+) and (⁻) ZIKV-specific ssRNA strands, and independent histologic examination for significant pathologic changes were employed. We demonstrate that the use of these molecular tools added to the diagnostic value of placental ZIKV testing among suspected cases of congenital Zika syndrome with poorly ascribed maternal endemic exposure.


Assuntos
Placenta/patologia , Placenta/virologia , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/virologia , Zika virus , Adulto , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imuno-Histoquímica , Transmissão Vertical de Doença Infecciosa , Imagem por Ressonância Magnética , Microcefalia/diagnóstico , Microcefalia/etiologia , Fenótipo , Gravidez , Avaliação de Sintomas , Síndrome , Ultrassonografia Pré-Natal , Adulto Jovem , Infecção por Zika virus/transmissão
7.
Neuroradiol J ; 32(3): 210-214, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30794039

RESUMO

Giant congenital melanocytic nevus (GCMN) is associated with neurocutaneous melanocytosis and various other neurological complications. Its association with migrational anomalies of the brain is extremely rare. Herein, we document the first case of GCMN in a one-day-old baby associated with localized hemimegalencephaly (HME) of the brain with extensive malformation of cortical development including polymicrogyria, pachygyria and sublobar dysplasia, limited to an enlarged quadrant of the brain. HME and GCMN are considered embryological anomalies of cell migration and proliferation. We discuss the unusual magnetic resonance imaging findings along with a brief review of the literature. To the best of our knowledge, our case is the first to report the association of GCMN with localized HME.


Assuntos
Encéfalo/anormalidades , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/etiologia , Imagem por Ressonância Magnética , Nevo Pigmentado/complicações , Neoplasias Cutâneas/complicações , Anormalidades Múltiplas , Biópsia , Feminino , Humanos , Recém-Nascido
8.
Neuroradiology ; 61(5): 603-611, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796469

RESUMO

PURPOSE: To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values. METHODS: We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses. RESULTS: Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort. CONCLUSION: We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Cardiopatias Congênitas/complicações , Imagem por Ressonância Magnética/métodos , Adulto , Estudos de Casos e Controles , Ecocardiografia , Estudos de Viabilidade , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Interpretação de Imagem Assistida por Computador , Imagem Tridimensional , Tamanho do Órgão , Gravidez , Diagnóstico Pré-Natal , Estudos Prospectivos , Software
9.
Genet Test Mol Biomarkers ; 23(1): 45-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633559

RESUMO

OBJECTIVE: Nonsyndromic orofacial cleft (NSOFC) including cleft lip with or without cleft palate (CL±P) and cleft palate (CP) are multifactorial developmental disorders with both genetic and environmental etiological factors. In this study we investigated the association between CL±P and CP, and two polymorphisms previously determined using genome-wide association studies, as well as the association between consanguinity and CL±P and CP. METHODS: DNA was extracted from saliva specimens from 171 triads consisting of affected individuals and their parents, as well as 189 control triads (matched for age, gender, and location) that were recruited from 11 referral hospitals in Saudi Arabia. Two polymorphisms, rs4752028 and rs7078160, located in the VAX1 gene were genotyped using real-time polymerase chain reaction. A transmission disequilibrium test was carried out using the Family-Based Association Test and PLINK (genetic tool-set) to measure the parent-of-origin effect. RESULTS: Significant differences were found between affected individuals and the control group. In the case of the rs4752028 risk allele in cleft, the phenotypes were: CL±P (fathers: odds ratio [OR] 2.16 [95% CI 1.38-3.4]; mothers: OR 2.39 [95% CI 1.53-3.71]; and infants: OR 2.77 [95% CI 1.77-4.34]) and CP (fathers: OR 2.24 [95% CI 1.15-4.36] and infants: OR 2.43 [95% CI 1.25-4.7]). For CL±P and the rs7078160 risk allele, the phenotypes were: (fathers: OR 1.7 [95% CI 1.05-2.86]; mothers: OR 2.43 [95% CI 1.49-3.97]; and infants: OR 2.34 [95% CI 1.44-3.81]). In terms of consanguinity, we found significant association between consanguinity and the rs4752028 polymorphism minor allele among CL±P compared with controls (p = 0.001). CONCLUSION: This is the first study to find a relationship between these two loci on 10q25 (rs4752028 and rs7078160) and NSOFC in a population with high levels of consanguinity.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Adulto , Alelos , Estudos de Casos e Controles , Consanguinidade , Família , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Arábia Saudita
10.
Cell Prolif ; 52(3): e12573, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30667104

RESUMO

OBJECTIVES: Long non-coding RNAs (LncRNAs) play important roles in epigenetic regulatory function during the development processes. In this study, we found that through alternative splicing, LncRNA C130071C03Riken variants Riken-201 (Riken-201) and Riken-203 (Riken-203) are both expressed highly in brain, and increase gradually during neural differentiation. However, the function of Rik-201 and Rik-203 is unknown. MATERIALS AND METHODS: Embryonic stem cells (ESCs); RNA sequencing; gene expression of mRNAs, LncRNAs and miRNAs; over-expression and RNA interference of genes; flow cytometry; real-time quantity PCR; and Western blot were used in the studies. RNA pull-down assay and PCR were employed to detect any miRNA that attached to Rik-201 and Rik-203. The binding of miRNA with mRNA of Sox6 was presented by the luciferase assay. RESULTS: Repression of Rik-201 and Rik-203 inhibited neural differentiation from mouse embryonic stem cells. Moreover, Rik-201 and Rik-203 functioned as the competing endogenous RNA (ceRNA) to repress the function of miR-96 and miR-467a-3p, respectively, and modulate the expression of Sox6 to further regulate neural differentiation. Knockout of the Rik-203 and Rik-201 induced high ratio of brain developmental retardation. Further we found that C/EBPß might potentially activated the transcription of Rik-201 and Rik-203. CONCLUSIONS: These findings identify the functional role of Rik-201 and Rik-203 in facilitating neural differentiation and further brain development, and elucidate the underlying miRNAs-Sox6-associated molecular mechanisms.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Neurogênese/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXD/genética , Processamento Alternativo , Animais , Sequência de Bases , Encéfalo/anormalidades , Encéfalo/embriologia , Encéfalo/metabolismo , Diferenciação Celular/genética , Epigênese Genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Gravidez , RNA Longo não Codificante/antagonistas & inibidores , RNA Interferente Pequeno/genética
11.
J Comp Pathol ; 166: 29-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30691603

RESUMO

Strandings of live new-born West Indian manatees (WIMs; Trichechus manatus) are one of the main challenges for the conservation of this species in Brazil, particularly in the northeastern states. Congenital malformations (CMs) are rare in sirenians. We identified CMs in two of 19 stranded WIMs that were rescued, rehabilitated and subjected to complete pathological examinations in Ceará and Rio Grande do Norte States between 1992 and 2017. In case 1, dilation of the cerebral lateral and fourth ventricles with abundant cerebrospinal fluid (internal hydrocephalus), was diagnosed. Furthermore, this animal developed necrotizing enterocolitis associated with pneumatosis intestinalis and aspiration pneumonia late during rehabilitation. Cardiac malformations in case 2 included: right ventricle hypoplasia with marked stenosis of the tricuspid outflow, high ventricular septal defect, segmental pulmonary artery aneurysm, mitral valve haemocyst and left ventricular hypertrophy. Herein, we provide the first description of a neural tube defect, specifically a developmental internal hydrocephalus, and multiple cardiac congenital anomalies, together with their respective clinicopathological features in manatees. Although the aetiology of the CMs remains unknown in these cases, a genetic basis is plausible given the low genetic variability in this population. These cases add to the body of knowledge on health and disease aspects of manatees and may provide scientific basis for future medical and conservation efforts on neonatal WIMs.


Assuntos
Encéfalo/anormalidades , Cardiopatias Congênitas/veterinária , Trichechus manatus/anormalidades , Animais , Feminino , Masculino
12.
J Neurointerv Surg ; 11(7): 699-705, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30602485

RESUMO

BACKGROUND: The treatment of low grade Spetzler-Martin (SM) brain arteriovenous malformations (AVMs) has been debated in unruptured cases. Nevertheless, in clinical practice there are cases where treatment is preferred; in these cases a very low complication rate is mandatory. In ruptured cases, early and complete obliteration of the nidus is the preferred strategy. OBJECTIVE: To achieve curative embolization, ideally in a single session, by dual microcatheterization techniques with arterial and/or venous access, according to the angioarchitecture. MATERIALS AND METHODS: This is a prospective, single-center study carried out between January 2008 and January 2016. Patients with ruptured and unruptured brain AVMs, with SM grades I and II, treated by endovascular means, were included. Demographics, clinical presentation, angioarchitecture, and procedure-related complications were analyzed. Angiographic and clinical results were reported. RESULTS: Seventy-three patients, aged 40.5±17.8 years, were included. More than 60% of the patients presented with ruptured AVMs. Initial SM grades were I for 22% and II for 78% of the patients. Preprocedural modified Rankin Scale (mRS) score was 0-2 for 53 (72.6%), 3 for 12 (16.4%), 4 for 5 (6.8%) and 5 for 3 (4.1%) patients. Procedure-related morbidity was 2.7% and procedure-related mortality was 0%. Ninety percent (90.5%) of the patients were independent in their everyday lives (mRS score 0-2) at 6 months. In all but one case (95%) the embolization was curative. CONCLUSION: Stand-alone endovascular treatment for SM grade I and II brain AVMs seems safe and effective, allowing for complete obliteration of the nidus, with low complication rates. A study of larger cohorts is needed.


Assuntos
Fístula Arteriovenosa/diagnóstico por imagem , Fístula Arteriovenosa/cirurgia , Procedimentos Endovasculares/métodos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/cirurgia , Adolescente , Adulto , Idoso , Angiografia/métodos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
13.
Prenat Diagn ; 39(1): 38-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548283

RESUMO

OBJECTIVE: To assess the cerebral and vascular development in fetuses with hypoplastic left heart syndrome (HLHS). METHODS: Pregnant women carrying fetuses diagnosed with HLHS who decided to interrupt their pregnancies were included in our study. Aortic size and blood flow were assessed based from fetal echocardiography. Immunohistochemical staining was performed in brain sections obtained from pathology in fetuses with HLHS and control fetuses without heart disease. RESULTS: Twenty-seven midgestation fetal HLHS were included (gestational age, 23.3 ± 3.4 weeks). Head circumference z scores were lower in HLHS fetuses. Middle cerebral artery pulsatility index, a measure of cerebrovascular resistance, was inversely correlated with the ascending aortic z score (P < 0.05). Fetuses with HLHS had lower capillary density in the germinal matrix and their capillaries were larger compared with control fetuses with (P < 0.05). The expression of neuronal differentiation marker, FGFR1, and oligodendrocyte precursor, O4, were lower in HLHS brains compared with controls (P < 0.05). CONCLUSION: Our study identified abnormalities of vascular flow and structural brain abnormalities in fetal HLHS associated with impaired neuronal and oligodendrocyte differentiation, as well as cerebral growth impairment, early in gestation. These findings may be related in part to early vascular abnormalities.


Assuntos
Vasos Sanguíneos/embriologia , Encéfalo/embriologia , Síndrome do Coração Esquerdo Hipoplásico/embriologia , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Encéfalo/anormalidades , Encéfalo/patologia , Capilares/embriologia , Ecocardiografia , Feminino , Doenças Fetais , Coração Fetal , Idade Gestacional , Humanos , Imuno-Histoquímica , Artéria Cerebral Média/embriologia , Gravidez , Fluxo Pulsátil , Ultrassonografia Pré-Natal
14.
Brain ; 142(1): 23-34, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544177

RESUMO

Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.10.1093/brain/awy307_video1awy307media15978667388001.


Assuntos
Malformações Arteriovenosas/genética , Encéfalo/anormalidades , Predisposição Genética para Doença/genética , Malformações do Sistema Nervoso/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Medula Espinal/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Análise de Sequência de DNA/estatística & dados numéricos , Adulto Jovem
15.
São Paulo; s.n; s.n; 2019. 130 p. ilus, graf.
Tese em Português | LILACS | ID: biblio-998563

RESUMO

Uma das principais dificuldades enfrentadas na dependência à cocaína está relacionada aos sintomas de abstinência, como ansiedade, desejo e irritabilidade. Estes efeitos podem durar meses ou anos após a interrupção do consumo prolongado, fazendo com que o indivíduo volte a procurá-la. Os efeitos recompensadores da cocaína levam a alterações neurobiológicas do sistema mesocorticolímbico dopaminérgico, que se origina na área tegmental ventral e se projeta para o núcleo accumbens, e córtex pré-frontal, áreas intimamente ligadas ao desenvolvimento da dependência. Esses neurônios dopaminérgicos recebem estímulos dos neurônios colinérgicos que contribuem para os aspectos cognitivos da dependência. Devido à complexidade neurobilógica envolvida durante a abstinência, pouco se sabe sobre as alterações no sistema colinérgico muscarínico durante este período no encéfalo, objetivo deste estudo. Para tal, camundongos machos adultos Swiss-Webster foram submetidos à cocaína em padrão agudo em binge (3×30 mg/kg/dia) e cronicamente por escalonamento de dose em binge por 14 dias (3×15 mg/kg/dia nos dias 1-4; 3×20 mg/kg/dia nos dias 5-8; 3×25 mg/kg/dia nos dias 9-12; e 3×30 mg/kg/dia nos dias 13 e 14). A atividade locomotora de cada animal foi avaliada em campo aberto (CA), onde permaneceram no aparato por 60 minutos entre cada administração. Após o período de exposição os animais permaneceram 14 dias em abstinência, a fim de avaliar a ansiedade no labirinto em cruz elevado (LCE). Em seguida os animais foram eutaniasiados, sendo o córtex pré-frontal (CPF), o estriado e o hipocampo dissecados e armazenados a -80ºC para a análise dos receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 e M5 (mAChRs) e moléculas colinérgicas (acetilcolinesterase, AChE; colina acetiltransferase, ChAT e transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Os resultados comportamentais mostraram maior atividade locomotora nos animais tratados com cocaína no tratamento agudo ou crônico, quando comparado ao basal. Mais ainda, a sensibilização comportamental foi detectada a partir do segundo dia de administração de cocaína. No teste de LCE, realizado 14 dias após a interrupção da administração de cocaína, não foi observada diferença estatística entre os animais previamente expostos à cocaína e grupo controle. No CPF observou-se diminuição de D2R, M1 mAChRs e aumento M2 e M4 mAChRs no tratamento agudo; no tratamento crônico houve diminuição de M1 e M5 mAChRs e ChAT. No estriado observou-se aumento de D1R, M1 e M2 mAChRs, ChAT no tratamento agudo; e aumento D1R, VAChT, ChAT e diminuição D2R, M1 e M2 mAChRs no tratamento crônico. Já no hipocampo observou-se aumento de D1R, D2R, M2 mAChRs, VAChT e diminuição M1 mAChRs no tratamento agudo; e aumento de D1R, VAChT e diminuição D2R, M1 mAChRs no tratamento crônico. Nossos resultados mostram envolvimento de processo de neuroplasticidade, tanto no sistema dopaminérgico quanto no colinérgico muscarínico, em ambos os protocolos utilizados, mesmo após 14 dias de abstinência


Una de las dificultades enfrentadas en la dependencia de cocaína son los síntomas de abstinencia, como ansiedad, deseo y irritabilidad. Estos efectos pueden durar meses o años después de la interrupción del consumo prolongado, haciendo que el individuo vuelva a consumirlo. Los efectos recompensadores de la cocaína causa alteraciones neurobiológicas del sistema mesocorticolímbico dopaminérgico, que se origina en el área tegmental ventral y se proyecta hacia el núcleo accumbens y córtex pré-frontal, áreas íntimamente ligadas al desenvolvimiento de la dependencia. Esas neuronas dopaminérgicas reciben estímulos de neuronas colinérgicas la cual contribuyen para los aspectos cognitivos de la dependencia. Debido a la complejidad neurobiológica involucrada durante la abstinencia, poco se sabe sobre las alteraciones del sistema colinérgico muscarínico durante este periodo en el encéfalo, objetivo de este estudio. Por tanto, ratones adultos macho Swiss-Webster fueron sometidos a cocaína en dosis padrón agudo en binge (3×30 mg/kg/día) y crónicamente por escalonamiento de dosis en binge por 14 días (3×15 mg/kg/día en los días 1-4; 3×20 mg/kg/día en los días 5-8; 3×25 mg/kg/día en los días 9-12; y 3×30 mg/kg/día en los días 13 e 14). La actividad locomotora de cada animal fue evaluada en el test de campo abierto (CA), donde permanecieron por 60 minutos entre cada administración. Después del periodo de exposición los animales permanecieron 14 días de abstinencia, a fin de evaluar la ansiedad en el labirinto de cruz elevado (LCE). En seguida los animales fueron eutanasiados, donde el córtex pré-frontal (CPF), estriado y hipocampo fueron disecados y almacenados a -80ºC para analizar los receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 y M5 (mAChRs) y moléculas colinérgicas (acetilcolinesterasa, AChE; colina acetiltransferasa, ChAT y transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Los resultados comportamentales mostraron mayor actividad locomotora en los animales tratados con cocaína en tratamiento agudo y crónico, comparado al control. Por otra parte, la sensibilización comportamental fue detectado a partir de segundo día de administración de cocaína. En la prueba de LCE, realizado después de 14 días de interrupción de la administración de cocaína, no fue observado diferencia estadística entre los animales previamente expuestos a la cocaína y el grupo control. En CPF se observó disminución de D2R, M1 mAChRs y aumento de M2 y M4 mAChRs en tratamiento agudo; en el tratamiento crónico mostro disminución de M1 y M5 mAChRs y ChAT. En el estriado se observó aumento de D1R, M1 y M2 mAChRs, ChAT en el tratamiento agudo; aumento D1R, VAChT, ChAT y disminución de D2R, M1 y M2 mAChRs en el tratamiento crónico. Por último, en el hipocampo se observó aumento de D1R, D2R, M2 mAChRs, VAChT y disminución M1 mAChRs en el tratamiento agudo; aumento de D1R, VAChT y disminución D2R, M1 mAChRs en el tratamiento crónico. Nuestros resultados muestran envolvimiento de procesos de neuroplasticidad, tanto en el sistema dopaminérgico como el sistema colinérgico muscarínico, en ambos protocolos utilizados, después de 14 días de abstinencia


Assuntos
Animais , Masculino , Camundongos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Receptores Colinérgicos/análise , Cocaína/efeitos adversos , Colinérgicos/análise , Ansiedade/classificação , Encéfalo/anormalidades , Receptores Dopaminérgicos , Transtornos Relacionados ao Uso de Substâncias/complicações
16.
Eur Radiol ; 29(6): 2740-2750, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30542750

RESUMO

BACKGROUND AND PURPOSE: Fetal postmortem MR Imaging (pmMRI) has been recently used as an adjuvant tool to conventional brain autopsy after termination of pregnancy (TOP). Our purpose was to compare the diagnostic performance of intrauterine MRI (iuMRI) and pmMRI in the detection of brain anomalies in fetuses at early gestational age (GA). MATERIAL AND METHODS: We retrospectively collected 53 fetuses who had undergone iuMRI and pmMRI for suspected brain anomalies. Two pediatric neuroradiologists reviewed iuMRI and pmMRI examinations separately and then together. We used Cohen's K to assess the agreement between pmMRI and iuMRI. Using the combined evaluation iuMRI+pMRI as the reference standard, we calculated the "correctness ratio." We used Somers' D to assess the cograduation between postmortem image quality and time elapsed after fetus expulsion. RESULTS: Our data showed high agreement between iuMRI and pmMRI considering all the categories together, for both observers (K1 0.84; K2 0.86). The correctness ratio of iuMRI and pmMRI was 79% and 45% respectively. The major disagreements between iuMRI and pmMRI were related to postmortem changes as the collapse of liquoral structures and distorting phenomena. We also found a significant cograduation between the time elapsed from expulsion and pmMRI contrast resolution and distortive phenomena (both p < 0.001). CONCLUSIONS: Our study demonstrates an overall high concordance between iuMRI and pmMRI in detecting fetal brain abnormalities at early GA. Nevertheless, for the correct interpretation of pmMRI, the revision of fetal examination seems to be crucial, in particular when time elapsed from expulsion is longer than 24 h. KEY POINTS: • IuMRI and pmMRI showed overall high concordance in detecting fetal brain abnormalities at early GA. • PmMRI corroborated the antemortem diagnosis and it could be a valid alternative to conventional brain autopsy, only when the latter cannot be performed. • Some caution should be taken in interpreting pmMR images when performed after 24 h from fetal death.


Assuntos
Aborto Induzido , Encefalopatias/diagnóstico , Encéfalo/anormalidades , Doenças Fetais/diagnóstico , Feto/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Diagnóstico Pré-Natal/métodos , Encéfalo/diagnóstico por imagem , Encefalopatias/embriologia , Feminino , Morte Fetal , Idade Gestacional , Humanos , Gravidez , Curva ROC , Estudos Retrospectivos
17.
Cogn Behav Neurol ; 31(4): 193-200, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562228

RESUMO

OBJECTIVE: To investigate differences in white matter microstructure between illiterate and low-literate elderly Brazilians. BACKGROUND: High literacy levels are believed to partially counteract the negative effects of neurodegenerative diseases. Investigating the impact of low literacy versus illiteracy on brain structure can contribute knowledge about cognitive reserve in elderly populations with low educational attainment. Fractional anisotropy is a measure derived from diffusion tensor imaging sequences that positively correlate with the integrity of the brain's white matter microstructure. METHODS: Older adults who participated in an epidemiological study to investigate brain aging in Brazil and had magnetic resonance scans with the diffusion tensor imaging acquisition were selected (n=31). Participants were divided into two groups: (a) low-literate (n=21), with 3.4 (1.4) years of education, 79.8 (3.8) years of age, 17 cognitively healthy and four with cognitive impairment-no dementia; and (b) illiterate (n=10) with no formal schooling, 80.7 (4.1) years of age, six cognitively healthy and four with cognitive impairment-no dementia. We contrasted the two groups' white matter microstructure measures using whole-brain and region of interest approaches. RESULTS: The low-literate participants had significantly higher fractional anisotropy values in the right superior longitudinal fasciculus than did the illiterate ones. CONCLUSIONS: Although our results are preliminary because of the sample size, they suggest that low literacy, versus illiteracy, is associated with higher fractional anisotropy values, which are indirect measurements of white matter microstructure. This finding provides insight into a possible mechanism by which literacy, even at low levels, may contribute to cognitive reserve.


Assuntos
Encéfalo/anormalidades , Disfunção Cognitiva/etiologia , Alfabetização/psicologia , Substância Branca/anormalidades , Idoso de 80 Anos ou mais , Brasil , Feminino , Humanos , Masculino
18.
P R Health Sci J ; 37(Spec Issue): S66-S72, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30576580

RESUMO

The world has encountered a new and serious epidemic which has disproportionately affected fetuses and infants. What makes the Zika virus (ZIKV) epidemic such a threat in our times, is that a whole generation can be affected by birth defects caused by a seemingly innocuous maternal infection, which in most cases go unnoticed and undiagnosed. Spreading to over 80 countries and affecting millions, it is associated with severe birth defects known as congenital Zika syndrome (CZS), which include fetal brain development abnormalities (microcephaly and brain calcifications), retinal abnormalities, and contractures and hypertonia of the extremities. Testing strategies are challenging because of the lack of symptoms and cross reactivity with other viral infections. Obstetrical complications include fetal loss and the need for an emergency cesarean delivery. The rate of CZS has been described as ranging from 5 to 6% among cohorts in the US, reaching 11% for 1st trimester exposure. Prolonged viremia during pregnancy has been documented in a few cases, reaching 89 days after the onset of symptoms in one case and 109 days after such onset in another. If the ZIKV can infect, multiply in, and persist in diverse placental cells, then movement across the placenta, the fetal brain, and the maternal peripheral blood is possible. There is a sense of urgency, and we need safe and effective vaccines and treatments, particularly for pregnant women. If we do not expand testing and develop methods for early diagnosis and treatment, thousands of infants will be exposed to a neurotropic virus that causes severe birth defects and that could also affect the lives of those who form the next generation.


Assuntos
Anormalidades Congênitas/virologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/epidemiologia , Encéfalo/anormalidades , Encéfalo/virologia , Anormalidades Congênitas/epidemiologia , Epidemias , Feminino , Humanos , Recém-Nascido , Microcefalia/epidemiologia , Microcefalia/virologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico
19.
P R Health Sci J ; 37(Spec Issue): S73-S76, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30576581

RESUMO

OBJECTIVE: Zika virus (ZIKV) infection was identified in Puerto Rico on December 2015, and the outbreak encouraged us to characterize clinical manifestations and laboratory findings of intrauterine exposed infants. METHODS: Retrospective medical record review of infants born to mothers with confirmed ZIKV infection during pregnancy was performed from January 2016-June 2017. We included patients admitted to UPH Neonatal Intensive Care Unit or referred for follow-up at UPH High Risk Clinics. The database was approved by the University of Puerto Rico, Medical Sciences Campus, IRB. RESULTS: 191 infants born to ZIKV positive mothers during pregnancy were identified. Normal head sonogram was found in 93% of the normo cephalic infants. Ocular findings were reported in 50% of the patients with microcephaly and 31% of the normo-cephalics. Fifteen newborns (7.8%) presented with microcephaly, of which 73% showed calcifications in head sonogram, and had severe anomalies on brain MRI. Auditory brainstem response test was performed on all newborns, 80% were within normal limits. CONCLUSION: Among the group of infants born to mothers with Zika positive test 4% had microcephaly. Of concern to us is the fact that 31% of normo cephalic infants had ocular manifestations and 7% of them had findings on head sonogram. While microcephaly is the severest form of Congenital Zika Syndrome, ocular manifestations might characterize the spectrum of disease. These findings reiterate the importance of detailed neonatal evaluations of exposed infants.


Assuntos
Encéfalo/anormalidades , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/epidemiologia , Encéfalo/diagnóstico por imagem , Encéfalo/virologia , Bases de Dados Factuais , Anormalidades do Olho/epidemiologia , Anormalidades do Olho/virologia , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Imagem por Ressonância Magnética , Microcefalia/virologia , Gravidez , Porto Rico , Estudos Retrospectivos , Infecção por Zika virus/congênito
20.
Genet Epidemiol ; 42(7): 664-672, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30277614

RESUMO

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.


Assuntos
Alelos , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Caracteres Sexuais , Estudos de Casos e Controles , Epistasia Genética , Feminino , Frequência do Gene/genética , Loci Gênicos , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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