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1.
Lancet Diabetes Endocrinol ; 7(9): 695-706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377265

RESUMO

BACKGROUND: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. METHODS: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 µg Triac, the daily dose was increased progressively in 350 µg increments, with the goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474. FINDINGS: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 µg/kg of bodyweight (range 6·4-84·3) to attain T3 concentrations within the target range. Serum T3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment. INTERPRETATION: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. FUNDING: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.

2.
Mol Genet Genomic Med ; 7(2): e00527, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30548430

RESUMO

BACKGROUND: The diagnostic workup in patients with a clinical suspicion of lysosomal storage diseases (LSD) is often difficult due to the variability in the clinical phenotype. The gold standard for diagnosis of LSDs consists of enzymatic testing. However, due to the sequential nature of this methodology and inconsistent genotype-phenotype correlations of certain LSDs, finding a diagnosis can be challenging. METHOD: We developed and clinically implemented a gene panel covering 50 genes known to cause LSDs when mutated. Over a period of 18 months, we analyzed 150 patients who were referred for LSD testing and compared these results with the data of patients who were previously enrolled in a scheme of classical biochemical testing. RESULTS: Our panel was able to determine the molecular cause of the disease in 22 cases (15%), representing an increase in diagnostic yield compared to biochemical tests developed for 21 LSDs (4.6%). We were furthermore able to redirect the diagnosis of a mucolipidosis patient who was initially suspected to be affected with galactosialidosis. Several patients were identified as being affected with neuronal ceroid lipofuscinosis, which cannot readily be detected by enzyme testing. Finally, several carriers of pathogenic mutations in LSD genes related to the disease phenotype were identified as well, thus potentially increasing the diagnostic yield of the panel as heterozygous deletions cannot be detected. CONCLUSION: We show that the implementation of a gene panel for LSD diagnostics results in an increased yield in comparison to classical biochemical testing. As the panel is able to cover a wider range of diseases, we propose to implement this methodology as a first-tier test in cases of an aspecific LSD presentation, while enzymatic testing remains the first choice in patients with a more distinctive clinical presentation. Positive panel results should however still be enzymatically confirmed whenever possible.


Assuntos
Testes Genéticos/métodos , Doenças por Armazenamento dos Lisossomos/genética , Análise de Sequência de DNA/métodos , Células Cultivadas , Fibroblastos/metabolismo , Testes Genéticos/normas , Humanos , Imunoensaio/métodos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Análise de Sequência de DNA/normas
3.
Ann Neurol ; 84(5): 788-795, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269351

RESUMO

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

4.
Epileptic Disord ; 19(3): 357-361, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28721938

RESUMO

The WW domain-containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early-infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early-onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly. Metabolic disease was excluded. Whole-exome sequencing showed mutations in the WW domain-containing oxidoreductase gene. Our findings extend the phenotypic traits of this aggressive epileptic encephalopathy, with persistent epileptic spasms and hypsarhythmia as a part of the electroclinical phenotype, demonstrating that microcephaly is not mandatory for diagnosis, even when associated with progressive cerebral atrophy. These mutations might be more frequent than expected among early-onset epileptic encephalopathies. We present practical clues for the diagnosis of WWOX encephalopathy in order to avoid unnecessary investigations and ensure appropriate genetic counselling for the families.


Assuntos
Encéfalo/fisiopatologia , Espasmos Infantis/diagnóstico , Encéfalo/diagnóstico por imagem , Pré-Escolar , Eletroencefalografia , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Espasmos Infantis/fisiopatologia , Oxidorredutase com Domínios WW/genética
5.
Maedica (Buchar) ; 9(4): 344-50, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25705303

RESUMO

UNLABELLED: Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability. OBJECTIVES: The purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort. METHODS: A four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination. RESULTS: 23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment. CONCLUSIONS: The most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics. All children with DS from our cohort have intelectual disability, more severe in those with epilepsy. Slight improvement of intelectual and language capabilities were seen after seizures control.

6.
Maedica (Buchar) ; 8(4): 321-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24790661

RESUMO

BACKGROUND: Angelman syndrome (AS) is a genetic condition, characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behaviour, movement disorder. It is caused by a variety of genetic mechanisms which all interfere with expression of the UBE3A gene on chromosome 15q11-13. OBJECTIVES: To present our experience regarding diagnosis of children with Angelman syndrome. MATERIAL AND METHODS: 15 children were clinically and genetically diagnosed with AS in the Department of Pediatric Neurology of the "Prof. Dr. Alex. Obregia" Clinical Hospital. In all cases, diagnosis of AS was made by the clinical criteria. The clinical evaluation focused on the patient history, a general examination, dysmorphological evaluation, a neurological examination, psychological evaluation, and paraclinical tests. RESULTS: All patients from this study presented the characteristic facial features and the characteristic behavior phenotype. Psychomotor development was delayed in all children, most of cases (73%) presenting with sever mental retardation. Epileptic seizures were observed in all patients with microdeletion, the partial seizures being the most frequent type. EEG in all children showed the characteristic pattern for AS. CONCLUSIONS: Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features, which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in a child with psychomotor delay should raise the strong suspicion of AS.

7.
Odonto (Säo Bernardo do Campo) ; 19(37): 135-142, jan.-jun.2011. ilus, tab, graf
Artigo em Português | LILACS | ID: lil-789960

RESUMO

Avaliar a resistência da união adesiva, pelo ensaio de microtração, de bases para próteses totais confeccionadas com resina acrílica ativada termicamente (Lucitone 550 - Dentsply) a dentes artificiais de resina acrílica (Biotone - Dentsply), submetidos a diferentes condições pós-prensagem e períodos de armazenagem.Metodologia: foram confeccionados 32 conjuntos dente/base de resina acrílica, separados em quatro grupos (n=8) conforme o tempo pós-prensagem até a acrilização (imediatamente após ou 24 h após a prensagem) e período de armazenagem em água destilada (24 horas ou 30 dias, em água destilada à 37°C). Sendo assim, 4 grupos foram formados: G1 (Imediato; -sem armazenagem); G2 (Mediato - sem armazenagem); G3 (Imediato - com armazenagem); e G4 (Mediato - com armazenagem). Os conjuntos dente/base de resina foram seccionados em dois eixos, x e y, com um disco diamantado sob irrigação constante (área adesiva - 1mm2) obtendo-se aproximadamente 96 corpos de prova (cp) por grupo. Imediatamente após o corte, os cp foram fixados em um dispositivo de microtração acoplado a uma máquina de ensaio universal (EMIC-DL-1000, Brasil) e testado com velocidade de 1mm/min. Os dados foram submetidos ao teste Anova e Tukey (=0,05).Resultado: os valores médios (MPa) obtidos foram: G1: 27,82 ±12,68, G2: 29,92 ±13,73, G3 30,09 ±20,48 e G4: 32,51±13,81.Conclusão: as diferentes condições pós-prensagem e períodos de armazenagem não influenciaram na resistência de união adesiva dente/base de resina...


The objective of this study was to compare the tensile bond strengths by the micro tensile test of conventional heat-cured resin denture (Lucitone 550 – DENTSPLY) with acrylic resin denture teeth (Biotone – DENTSPLY), submit in a different polymerization cycle and storage.Methodology: thirty two specimens were fabricated and divided in four groups (n=8): G1 (immediate; without storage); G2 (mediate; without storage); G3 (immediate; with storage); G4 (mediate; with storage). Theses specimens was storage in distilled water until testing and cut in two axis, X and Y, with a diamond disc, getting 12 specimens with ± 1 mm² of adhesive area. The specimens were fixed in a specific device that was fixed in a universal testing machine (EMIC-DL-1000, Brazil) and tested with a cross-speed 1 mm/min.Results: the microtensile bond strengths values was G1 (27,82 ±12,68), G2 (29,92 ±13,73), G3 (30,09 ±20,48) e G4 (32,51±13,81).Conclusion: within the limitations of this study, there no was difference between these groups...


Assuntos
Humanos , Colagem Dentária/métodos , Resinas Acrílicas/química , Dente Artificial , Teste de Materiais , Polimerização , Reprodutibilidade dos Testes , Propriedades de Superfície , Resistência à Tração , Fatores de Tempo
8.
Oper Dent ; 35(6): 689-96, 2010 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21180009

RESUMO

PURPOSE: This study evaluated the adhesive quality of simplified self-adhesive and conventional resin cements to Y-TZP in dry and aged conditions. METHODS: Y-TZP ceramic blocks (N = 192) (5 x 5 x 2 mm) were embedded in acrylic resin and randomly divided into two groups, based on surface conditioning: 96% isopropanol or chairside tribochemical silica coating and silanization. Conditioned ceramics were divided into four groups to receive the resin cements (Panavia F 2.0, Variolink II, RelyX U100 and Maxcem). After 24 hours, half of the specimens (n = 12) from each group were submitted to shear bond strength testing (0.5 mm/minute). The remaining specimens were tested after 90 days of water storage at 37 degrees C and thermocycling (12,000x, 5 degrees C-55 degrees C). Failure types were then assessed. The data were analyzed using three-way ANOVA and the Tukey's test (alpha = 0.05). RESULTS: Significant effects of ceramic conditioning, cement type and storage conditions were observed (p < 0.0001). The groups cleaned using alcohol only showed low bond strength values in dry conditions and the bond strength was reduced dramatically after aging. Groups conditioned using silica coating and silanization showed higher bond strengths both in dry and aged conditions. A high number of specimens failed prematurely prior to testing when they were cleaned using 96% isopropanol. CONCLUSION: Overall, silica coating and silanization showed higher, stable bond strengths with and without aging. The durability of resin-ceramic adhesion varied, depending on the adhesive cement type.


Assuntos
Colagem Dentária , Porcelana Dentária/química , Cimentos de Resina/química , Ítrio/química , Zircônio/química , 2-Propanol/química , Corrosão Dentária/métodos , Análise do Estresse Dentário/instrumentação , Humanos , Teste de Materiais , Resistência ao Cisalhamento , Silanos/química , Dióxido de Silício/química , Solventes/química , Estresse Mecânico , Propriedades de Superfície , Temperatura Ambiente , Fatores de Tempo , Água/química
9.
Maedica (Buchar) ; 5(1): 56-61, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21977120

RESUMO

Cohen syndrome is a rare, genetic condition, recessively inherited, associated with specific facial dysmorphism, global developmental delay, hypotonia and ophthalmic abnormalities. A delay in making the diagnosis commonly occurs, because of the lack of a definitive molecular test and also because of the clinical variability of the syndrome. In this paper we describe four cases of Cohen syndrome, together with a comparison with other cases reported in the literature, in order to further delineate this condition.

11.
Ciênc. odontol. bras ; 12(1): 23-30, 2009. tab, ilus, graf
Artigo em Português | LILACS, BBO - Odontologia | ID: lil-524151

RESUMO

Objetivo: Este estudo propôs avaliar a microdureza de diferentes resinas compostas de uso direto (rcd) e indireto (rci). Materiais e Métodos: Com o auxílio de uma matriz metálica (diâmetro: 5,0mm; espessura: 2,0mm) foram confeccionadas 70 amostras, sendo (n=10) três resinas de uso direto: Gr1- Z250(3M ESPE/EUA), Gr2- W3D(Wilcos/Brasil) e Gr3- Esthetic X(Dentisply/EUA); e quatro de uso indireto: Gr4- Resilab Master (Wilcos/Brasil), Gr5- Vita VM LC (Vita Zahnfabrik/Alemanha), Gr6- Vita Zeta (Vita Zahnfabrik/Alemanha) e Gr7- Sinfony (3M ESPE/EUA). As amostras das rcd foram confeccionadas utilizando a técnica incremental, onde cada incremento de resina foi fotopolimerizado durante 40 segundos. Já as amostras da rci foram polimerizadas segundo recomendações dos fabricantes. Todos os espécimes foram armazenados em água destilada a 37ºC durante 24 horas. O teste de microdureza foi realizado em microdurômetro digital (Future-Tech,Modelo FM 700), com carga de 50 kgf por 15 segundos. Os dados obtidos (Kgf/mm2) foram analisados utilizando o teste não paramétrico de Kruskal-Wallis e o de comparação múltipla de Dunn (p<0.05). Resultados: As medidas resumo-numéricas de microdureza obtidas foram (mediana; média ± desvio padrão): Gr1 (100,12; 101,07± 5,99 Kgf/mm2), Gr2 (83,55; 84,20± 5,07 Kgf/mm2), Gr3 (73,98; 73,95± 6,55 Kgf/mm2), Gr4 (52,50; 52,54± 5,9 Kgf/mm2), Gr5 (33,25; 34,36± 2,29 Kgf/mm2), Gr6 (29,60; 29.68± 1.52 Kgf/mm2), Gr7 (25,39; 25.13± 2.08 Kgf/mm2). Verificou-se que os valores de microdureza das rcd analisadas não diferiram estatisticamente entre si (p<0,05). O mesmo não se pode estabelecer para as resinas indiretas, pois a Sinfony diferiu da Resilab (p<0,05). Conclusão: Baseado nos resultados pôde-se concluir que apenas a resina composta direta Z250 apresentou valores de microdureza Vickers superior às demais resinas indiretas.


Assuntos
Resinas Compostas , Testes de Dureza
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