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[PMID]:28713035
[Au] Autor:Tardieu M; Zérah M; Gougeon ML; Ausseil J; de Bournonville S; Husson B; Zafeiriou D; Parenti G; Bourget P; Poirier B; Furlan V; Artaud C; Baugnon T; Roujeau T; Crystal RG; Meyer C; Deiva K; Heard JM
[Ad] Endereço:Paediatric Neurology Department, Université Paris Sud and Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France. Electronic address: marc.tardieu@aphp.fr.
[Ti] Título:Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.
[So] Source:Lancet Neurol;16(9):712-720, 2017 Sep.
[Is] ISSN:1474-4465
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. METHODS: Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. FINDINGS: Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1-12 months and 3-12 months, respectively, but not at 30 months in three of four patients. INTERPRETATION: Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development. FUNDING: Association Française Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.
[Mh] Termos MeSH primário: Acetilglucosaminidase
Encéfalo/enzimologia
Dependovirus/genética
Terapia Genética/métodos
Vetores Genéticos/farmacologia
Mucopolissacaridose III/terapia
Avaliação de Resultados (Cuidados de Saúde)
[Mh] Termos MeSH secundário: Acetilglucosaminidase/genética
Pré-Escolar
Terapia Genética/efeitos adversos
Vetores Genéticos/administração & dosagem
Seres Humanos
Imunossupressores/uso terapêutico
Lactente
Mucopolissacaridose III/tratamento farmacológico
Síndrome
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); EC 3.2.1.50 (alpha-N-acetyl-D-glucosaminidase); EC 3.2.1.52 (Acetylglucosaminidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


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[PMID]:28601604
[Au] Autor:Beard H; Hassiotis S; Gai WP; Parkinson-Lawrence E; Hopwood JJ; Hemsley KM
[Ad] Endereço:Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA 5001, Australia.
[Ti] Título:Axonal dystrophy in the brain of mice with Sanfilippo syndrome.
[So] Source:Exp Neurol;295:243-255, 2017 Sep.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Axonal dystrophy has been described as an early pathological feature of neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis. Axonal inclusions have also been reported to occur in several neurodegenerative lysosomal storage disorders including Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome). This disorder results from a mutation in the gene encoding the lysosomal sulphatase sulphamidase, and as a consequence heparan sulphate accumulates, accompanied by secondarily-stored gangliosides. The precise basis of symptom generation in MPS IIIA has not been elucidated, however axonal dystrophy may conceivably lead to impaired vesicular trafficking, neuronal dysfunction and/or death. We have utilised a faithful murine model of MPS IIIA to determine the spatio-temporal profile of neuronal inclusion formation and determine the effect of restoring normal lysosomal function. Dopaminergic (tyrosine hydroxylase-positive), cholinergic (choline acetyltransferase-positive) and GABAergic (glutamic acid decarboxylase -positive) neurons were found to exhibit axonal dystrophy in MPS IIIA mouse brain. Axonal lesions present by ~seven weeks of age were Rab5-positive but lysosomal integral membrane protein-2 negative, suggesting early endosomal involvement. By 9-12-weeks of age, immunoreactivity for the autophagosome-related proteins LC3 and p62 and the proteasomal subunit 19S was noted in the spheroidal structures, together with wildtype α-synuclein, phosphorylated Thr-181 Tau and amyloid precursor protein, indicative of impaired axonal trafficking. Sulphamidase replacement reduced but did not abrogate the axonal lesions. Therefore, if axonal dystrophy impairs neuronal activity and ultimately, neuronal function, its incomplete resolution warrants further investigation.
[Mh] Termos MeSH primário: Axônios/patologia
Encéfalo/patologia
Mucopolissacaridose III/patologia
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/metabolismo
Animais
Feminino
Hidrolases/genética
Imuno-Histoquímica
Lisossomos/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Mucopolissacaridose III/diagnóstico por imagem
alfa-Sinucleína/metabolismo
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Snca protein, mouse); 0 (alpha-Synuclein); 0 (tau Proteins); EC 3.- (Hydrolases); EC 3.10.1.1 (N-sulfoglucosamine sulfohydrolase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170612
[St] Status:MEDLINE


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[PMID]:28334745
[Au] Autor:Roca C; Motas S; Marcó S; Ribera A; Sánchez V; Sánchez X; Bertolin J; León X; Pérez J; Garcia M; Villacampa P; Ruberte J; Pujol A; Haurigot V; Bosch F
[Ad] Endereço:Center of Animal Biotechnology and Gene Therapy.
[Ti] Título:Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID.
[So] Source:Hum Mol Genet;26(8):1535-1551, 2017 Apr 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D. This autosomic recessive, heparan sulphate storage disease is caused by deficiency in N-acetylglucosamine 6-sulfatase (GNS). Mice deficient in GNS showed lysosomal storage pathology and loss of lysosomal homeostasis in the CNS and peripheral tissues, chronic widespread neuroinflammation, reduced locomotor and exploratory activity and shortened lifespan, a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour and extended lifespan of treated mice. Hence, this work represents the first step towards the development of a treatment for MPSIIID.
[Mh] Termos MeSH primário: Terapia Genética
Doenças por Armazenamento dos Lisossomos/terapia
Mucopolissacaridose III/terapia
Sulfatases/genética
[Mh] Termos MeSH secundário: Animais
Dependovirus/genética
Modelos Animais de Doenças
Vetores Genéticos/genética
Vetores Genéticos/uso terapêutico
Seres Humanos
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/patologia
Camundongos
Mucopolissacaridose III/genética
Mucopolissacaridose III/patologia
Fenótipo
Sulfatases/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.6.- (Sulfatases); EC 3.1.6.14 (N-acetylglucosamine-6-sulfatase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx058


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[PMID]:28306536
[Au] Autor:Zeng Q; Fan Y; Wang L; Huang Z; Gu X; Yu Y
[Ad] Endereço:Department of Pediatric Endocrinology/Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, P.R.
[Ti] Título:Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB.
[So] Source:J Pediatr Endocrinol Metab;30(4):463-469, 2017 Apr 01.
[Is] ISSN:2191-0251
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies. CASE PRESENTATION: Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient's blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient's c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up. CONCLUSIONS: Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.
[Mh] Termos MeSH primário: Acetilglucosaminidase/genética
Exoma/genética
Genoma Humano
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Mucopolissacaridose III/genética
Mutação/genética
[Mh] Termos MeSH secundário: Criança
Análise Mutacional de DNA
Seres Humanos
Iduronidase/genética
Masculino
Prognóstico
[Pt] Tipo de publicação:CASE REPORTS
[Nm] Nome de substância:
EC 3.2.1.50 (alpha-N-acetyl-D-glucosaminidase); EC 3.2.1.52 (Acetylglucosaminidase); EC 3.2.1.76 (Iduronidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28181359
[Au] Autor:Kamata M; McKee C; Truxal KV; Flanigan KM; McBride KL; Aylward SC; Tobias JD; Corridore M
[Ad] Endereço:Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
[Ti] Título:General anesthesia with a native airway for patients with mucopolysaccharidosis type III.
[So] Source:Paediatr Anaesth;27(4):370-376, 2017 Apr.
[Is] ISSN:1460-9592
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mucopolysaccharidosis type III is a progressive disease with worsening airway, pulmonary, and cardiac involvement that may complicate anesthetic care. AIM: To prospectively evaluate the incidence of airway issues and complications during magnetic resonance imaging (MRI) and lumbar puncture (LP) during general anesthesia with a native airway for patients with mucopolysaccharidosis type III. METHOD: The study was a part of the natural history study. Anesthesia was induced with sevoflurane, which was discontinued after intravenous access was obtained. General anesthesia with a native airway was provided by dexmedetomidine and propofol. Dexmedetomidine (0.5 µg·kg ) was administered over 5 min followed by a continuous infusion at 0.5 µg·kg ·h . A continuous infusion of propofol was started at 150 µg·kg ·min . A bolus dose of propofol (1 mg·kg ) was administered and the propofol infusion was increased as needed. Airway management and vital signs were recorded for the entire procedure until discharge. RESULTS: Twenty-five patients (6.9 ± 3.1 years) received total of 43 MRI and LP procedures in the cohort. No patient failed sedation. Although mask induction with sevoflurane was not clinically problematic, upper airway obstruction was noted during 14 procedures (33%). This required the application of continuous positive airway pressure, temporary oral airway placement, jaw thrust, or shoulder roll. Airway dynamics improved once the anesthesia was transitioned to intravenous anesthetic agents. Although a small shoulder roll was needed to improve airway patency for 11 cases (26%), a large shoulder roll tended to make the upper airway obstruction worse. Oxygen desaturation (≤90%) was noted during MRI in three cases (7%). CONCLUSION: A combination of dexmedetomidine and propofol provided effective general anesthesia with a native airway during the procedures. Although upper airway obstruction was noted, it resolved with simple airway maneuvers without further airway intervention.
[Mh] Termos MeSH primário: Manuseio das Vias Aéreas/métodos
Anestesia Geral/métodos
Mucopolissacaridose III/complicações
Posicionamento do Paciente/métodos
[Mh] Termos MeSH secundário: Adolescente
Anestésicos Intravenosos
Criança
Pré-Escolar
Dexmedetomidina
Feminino
Seres Humanos
Hipnóticos e Sedativos
Masculino
Éteres Metílicos
Propofol
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Intravenous); 0 (Hypnotics and Sedatives); 0 (Methyl Ethers); 38LVP0K73A (sevoflurane); 67VB76HONO (Dexmedetomidine); YI7VU623SF (Propofol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1111/pan.13108


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[PMID]:28143737
[Au] Autor:Fu H; Meadows AS; Ware T; Mohney RP; McCarty DM
[Ad] Endereço:Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital (NCH-RI), Columbus, OH 43205, USA; Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43202, USA. Electronic address: haiyan.fu@nationwidechildrens.org.
[Ti] Título:Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery.
[So] Source:Mol Ther;25(3):792-802, 2017 Mar 01.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in α-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-month-old MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.
[Mh] Termos MeSH primário: Acetilglucosaminidase/genética
Acetilglucosaminidase/metabolismo
Dependovirus/genética
Terapia Genética
Vetores Genéticos/genética
Metaboloma
Mucopolissacaridose III/genética
Mucopolissacaridose III/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores
Análise por Conglomerados
Modelos Animais de Doenças
Progressão da Doença
Técnicas de Transferência de Genes
Vetores Genéticos/administração & dosagem
Glicosilação
Seres Humanos
Redes e Vias Metabólicas
Metabolômica/métodos
Camundongos
Mucopolissacaridose III/terapia
Neurotransmissores/metabolismo
Fenótipo
Transdução Genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Neurotransmitter Agents); EC 3.2.1.50 (alpha-N-acetyl-D-glucosaminidase); EC 3.2.1.52 (Acetylglucosaminidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE


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[PMID]:28098417
[Au] Autor:Cohen MA; Stuart GM
[Ad] Endereço:Department of Anaesthesia, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
[Ti] Título:Delivery of anesthesia for children with Mucopolysaccharidosis Type III (Sanfilippo syndrome): a review of 86 anesthetics.
[So] Source:Paediatr Anaesth;27(4):363-369, 2017 Apr.
[Is] ISSN:1460-9592
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sanfilippo syndrome (MPS III) is rare, with 97 cases in the United Kingdom between 1988 and 1998. Mucopolysaccharide infiltration of tissues in mucopolysaccharidosis (MPS) causes multi-systemic pathology including difficult airways and cardiac disease. Published anesthesia case reviews of Sanfilippo syndrome have included limited numbers of patients to date. AIM: To identify the perioperative management and complications of anesthesia in children with mucopolysaccharidosis Type III at Great Ormond Street Hospital. METHODS: A retrospective case note review of all children with MPS III in our institution was undertaken. All medical notes and anesthetic charts were analyzed, and conduct of anesthesia, airway management, perioperative complications, and associated comorbidities were identified. RESULTS: There were 43 patients with MPS III, of which 34 required anesthesia, on 86 occasions for 156 procedures between 1993 and 2015. Dental extraction was the likeliest indication for anesthesia (34%) (general surgery [30%]; ear, nose, and throat [26%]; other [10%]). Thirteen of 34 patients had cardiac pathology (valvular [n = 6], functional [n = 6], electrophysiological [n = 1]). Ten of 34 patients had evidence of clotting abnormality (mild prolonged clotting time [n = 5], low von Willebrand factor [n = 2], thrombocytopenia [n = 3]). The majority of intubations were Cormack-Lehane Grade 1 (n = 47) (Grade 2 [n = 14], Grade 3 [n = 1], Grade 4 [n = 1]). In 86 anesthetics, there were 0 cases of difficulty with mask ventilation. There was 1 case of failed intubation. They were subsequently anesthetized by a different operator uneventfully at a later date. Two perioperative complications occurred: a failed intubation and bleeding during adenoidectomy. CONCLUSION: We demonstrate a difficult airway is unlikely when anesthetizing an MPS III patient although a risk does remain. A significant proportion of MPS III have cardiac involvement although no perioperative complications were described. With associated coagulation issues, bleeding tendency, while uncommon, can occur in this group.
[Mh] Termos MeSH primário: Manuseio das Vias Aéreas/métodos
Anestesia/métodos
Mucopolissacaridose III/cirurgia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Masculino
Estudos Retrospectivos
Reino Unido
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1111/pan.13075


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[PMID]:27832416
[Au] Autor:King B; Marshall NR; Hassiotis S; Trim PJ; Tucker J; Hattersley K; Snel MF; Jolly RD; Hopwood JJ; Hemsley KM
[Ad] Endereço:Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
[Ti] Título:Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric-onset neurodegenerative disease, MPS IIIA.
[So] Source:J Inherit Metab Dis;40(3):443-453, 2017 May.
[Is] ISSN:1573-2665
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Intra-cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three- to six-months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra-spinal CSF infusion-treated dogs. The extent of the reduction differed regionally. Pump-delivered rhSGSH was less effective in reducing secondary substrate (G ganglioside) in deeper aspects of cerebral cortex, and although near-amelioration of microglial activation was seen in superficial (but not deep) layers of cerebral cortex in both bolus enzyme-treated groups, pump-infusion of rhSGSH had little impact on microgliosis. While continual low-dose infusion of rhSGSH into MPS IIIA dog CSF reduces disease-based lesions in brain, it was not as efficacious as repeated cisternal or spinal CSF bolus infusion of rhSGSH over the time-frame of these experiments.
[Mh] Termos MeSH primário: Córtex Cerebral/efeitos dos fármacos
Líquido Cefalorraquidiano/metabolismo
Hidrolases/administração & dosagem
Vértebras Lombares/metabolismo
Mucopolissacaridose III/tratamento farmacológico
Doenças Neurodegenerativas/tratamento farmacológico
Proteínas Recombinantes/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Cães
Terapia de Reposição de Enzimas/métodos
Heparitina Sulfato/metabolismo
Seres Humanos
Mucopolissacaridose III/metabolismo
Doenças Neurodegenerativas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 9050-30-0 (Heparitin Sulfate); EC 3.- (Hydrolases); EC 3.10.1.1 (N-sulfoglucosamine sulfohydrolase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161111
[St] Status:MEDLINE
[do] DOI:10.1007/s10545-016-9994-1


  9 / 610 MEDLINE  
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[PMID]:27827379
[Au] Autor:Hu H; Hübner C; Lukacs Z; Musante L; Gill E; Wienker TF; Ropers HH; Knierim E; Schuelke M
[Ad] Endereço:Max Planck Institute for Molecular Genetics, Berlin, Germany.
[Ti] Título:Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).
[So] Source:Eur J Hum Genet;25(2):253-256, 2017 Feb.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.
[Mh] Termos MeSH primário: Acetiltransferases/genética
Síndrome de Kluver-Bucy/genética
Mucopolissacaridose III/genética
[Mh] Termos MeSH secundário: Criança
Exoma
Feminino
Genes Recessivos
Homozigoto
Seres Humanos
Síndrome de Kluver-Bucy/complicações
Síndrome de Kluver-Bucy/diagnóstico
Masculino
Mucopolissacaridose III/complicações
Mucopolissacaridose III/diagnóstico
Fenótipo
Irmãos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.3.1.- (Acetyltransferases); EC 2.3.1.78 (HGSNAT protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161110
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2016.149


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[PMID]:27220073
[Au] Autor:Fumic B; Koncic MZ; Jug M
[Ad] Endereço:Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
[Ti] Título:Therapeutic Potential of Hydroxypropyl-ß-Cyclodextrin-Based Extract of Medicago sativa in the Treatment of Mucopolysaccharidoses.
[So] Source:Planta Med;83(1-02):40-50, 2017 Jan.
[Is] ISSN:1439-0221
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Mucopolysaccharidoses are inherited metabolic disorders resulting in the dysfunction of enzymes involved in the degradation of glycosaminoglycans, leading to severe clinical symptoms and a significantly shortened life span of patients. Flavonoids are recognized as glycosaminoglycan metabolism modulators, able to correct glycosaminoglycan cell storage. Therefore, the aim of this work was the development of an efficient and eco-friendly extraction process of phytochemicals from by simultaneous use of ultrasound extraction and hydroxypropyl- -cyclodextrin complexation, and investigation of the potential of such an extract as a glycosaminoglycan metabolism modulator. The Box-Behnken design and response surface methodology were used in order to optimize the extraction process, considering hydroxypropyl- -cyclodextrin concentration, ultrasonic power, and extraction time as the key parameters. The dependent variables included total phenolicand total flavonoid content, DPPH radical scavenging activity, and Fe chelating activity, due to the importance of oxidative stress in the pathology of mucopolysaccharidoses. The developed technology using hydroxypropyl- -cyclodextrin led to more selective flavonoid extraction from than obtained either by the use of water or ethanol. The lyophilization of extracts resulted in products with high radical scavenging activity, suitable for further use. The application of 20 mM hydroxypropyl- -cyclodextrin solution, 432 W ultrasonic power, and an extraction time of 45 min resulted in an extract with both the highest total flavonoid content and the lowest radical scavenging activity IC . This extract reduced the levels of glycosaminoglycans in skin fibroblasts of mucopolysaccharidose III patient in a dose-dependent manner. At concentrations of 3 and 6 µg/mL, the observed levels of glycosaminoglycans were reduced by 41.2 and 51.1 %, respectively, clearly demonstrating the validity of the selected approach.
[Mh] Termos MeSH primário: Flavonoides/farmacologia
Glicosaminoglicanos/metabolismo
Medicago sativa/química
Mucopolissacaridose III/tratamento farmacológico
Compostos Fitoquímicos/farmacologia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: 2-Hidroxipropil-beta-Ciclodextrina
Antioxidantes/química
Antioxidantes/isolamento & purificação
Antioxidantes/farmacologia
Relação Dose-Resposta a Droga
Etanol
Fibroblastos/metabolismo
Flavonoides/química
Flavonoides/isolamento & purificação
Depuradores de Radicais Livres/química
Depuradores de Radicais Livres/isolamento & purificação
Depuradores de Radicais Livres/farmacologia
Glicosaminoglicanos/análise
Fenóis/química
Fenóis/isolamento & purificação
Fenóis/farmacologia
Compostos Fitoquímicos/química
Compostos Fitoquímicos/isolamento & purificação
Extratos Vegetais/química
Extratos Vegetais/isolamento & purificação
Pele/metabolismo
Ondas Ultrassônicas
beta-Ciclodextrinas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Flavonoids); 0 (Free Radical Scavengers); 0 (Glycosaminoglycans); 0 (Phenols); 0 (Phytochemicals); 0 (Plant Extracts); 0 (beta-Cyclodextrins); 1I96OHX6EK (2-Hydroxypropyl-beta-cyclodextrin); 3K9958V90M (Ethanol)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160525
[St] Status:MEDLINE
[do] DOI:10.1055/s-0042-107357



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