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1.
Clin Neuroradiol ; 32(1): 69-78, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34586427

RESUMO

BACKGROUND: Adult polycystic kidney disease (ADPKD) still represents a major cause of renal failure and intracranial aneurisms (IA) have a higher prevalence in ADPKD than in the general population. Current guidelines suggest performing brain MRI only in the subjects with a positive familiar history of IAs or subarachnoid hemorrhage (SAH). This is a retrospective case-control analysis to evaluate the usefulness of a MR screening program in ADPKD patients. METHODS: We retrospectively analyzed all ADPKD patients followed in our outpatient clinic between 2016 and 2019 who underwent a brain MRI screening. We evaluated the presence of IAs and others brain abnormalities and compared our results with a non-ADPKD population (n = 300). We performed univariate and multivariate regression analysis to evaluate if general and demographic features, laboratory findings, clinical parameters and genetic test results correlated with IAs or other brain abnormalities presence. RESULTS: Among the patients evaluated 17 out of 156 (13.6%) ADPKD patients had IAs, compared to 16 out of 300 (5.3%) non-ADPKD controls (p < 0.005). Considering ADPKD patients presenting IAs, 12 (70.6%) had no family history for IAs or SAH. Genetic analysis was available for 97 patients: in the sub-population with IAs, 13 (76.5%) presented a PKD1 mutation and none a PKD2 mutation. We found that arachnoid cysts (AC) (p < 0.001) and arterial anatomical variants (p < 0.04) were significantly more frequent in ADPKD patients. CONCLUSION: In our population ADPKD patients showed a higher prevalence of IAs, AC and arterial variants compared to non-ADPKD. Most of the IAs were found in patients presenting a PKD1 mutation. We found a significant number of alterations even in those patients without a family history of IAs or SAH. The practice of submitting only patients with familial IAs or kidney transplantation candidates to MRI scan should be re-evaluated.


Assuntos
Rim Policístico Autossômico Dominante , Adulto , Encéfalo , Humanos , Mutação , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Rim Policístico Autossômico Dominante/genética , Estudos Retrospectivos , Canais de Cátion TRPP/genética
2.
AJNR Am J Neuroradiol ; 41(10): 1916-1922, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32819908

RESUMO

BACKGROUND AND PURPOSE: The association of arterial tortuosity and connective tissue diseases is widely reported in the literature, but only a few studies were based on a quantitative evaluation of this arterial phenotype, and none of the latter examined the intracranial vasculature. The aim of this study was to evaluate the degree of intracranial arterial tortuosity in patients with Marfan syndrome and those with Loeys-Dietz syndrome, and to assess its usefulness in the differential diagnosis. MATERIALS AND METHODS: We performed a retrospective analysis of 68 patients with genetically confirmed Marfan syndrome (n = 36) or Loeys-Dietz syndrome (n = 32), who underwent at least 1 MRA of the brain at our institution. Fifty-two controls were randomly selected among patients who presented with headache and without any known comorbidity. Tortuosity indexes of 4 intracranial arterial segments were measured on a 3D volume-rendered angiogram by using the following formula: [Formula: see text]. RESULTS: Both Marfan syndrome and Loeys-Dietz syndrome showed a significantly higher tortuosity index compared with controls in all examined vessels. The tortuosity index of the vertebrobasilar system showed an excellent interrater reliability (intraclass correlation coefficient, 0.99) and was the strongest independent predictor of Loeys-Dietz syndrome in patients with connective tissue disease (P = .002), with a 97% specificity for this pathology when its value was > 60. CONCLUSIONS: The tortuosity index of intracranial arteries is an easily calculated and highly reproducible measure, which shows a high specificity for Marfan syndrome and Loeys-Dietz syndrome and may be useful in differentiating these 2 entities.


Assuntos
Artérias/patologia , Encéfalo/patologia , Síndrome de Loeys-Dietz/diagnóstico por imagem , Síndrome de Loeys-Dietz/patologia , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/patologia , Adulto , Artérias/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Angiografia Cerebral/métodos , Diagnóstico Diferencial , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
4.
Eur J Paediatr Neurol ; 22(5): 822-830, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29802023

RESUMO

BACKGROUND: Neurofibromatosis type 1 is a genetic disorder associated with cognitive deficits, learning disabilities and behavioral problems. These domains appear to have a still controversial debated association with local areas of T2-hyperintensities on MRI images, called unidentified bright objects (UBOs). METHODS: A cohort of 36 children (aged 7-11 years) included consecutively, underwent neuropsychological and behavioral assessment to determine their cognitive and neuropsychological profile, and the frequency of specific learning disabilities. MRI examination was used to determine the impact of UBOs' presence, number, and location on the cognitive, neuropsychological and behavioral profile, and also the presence of optic glioma. RESULTS: The mean full intelligence quotient was 104.6; only one child had mild intellectual disability. Forty one percent of children had a diagnosis of specific learning disabilities and reading was mainly involved. Twenty per cent had attention problems. All children had normal scores in visuo-motor and visuo-perceptual tests. UBOs were present in 94.0% of the MRI examinations. Two children had optic glioma. Children with UBOs in a specific location and children with UBOs elsewhere were statistically compared, no one of the location seemed to have an impact on general cognition measured with full intelligence quotient. The thalamus was associated with problems in calculation and striatum with behavioral problems. An inverse relationship between the number of UBOs and the full intelligence quotient was present, but without a statistical significance. CONCLUSIONS: In this study, the specific location of UBOs did not seem to influence the general cognitive profile and also the relationship between their number and the full intelligence quotient was not significant; these results are still controversial in literature. Finally, the presence of UBOs in the thalamus and striatum may represent a neuroradiological pattern that influences performances in calculation and behavior respectively in children with Neurofibromatosis type 1.


Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Neurofibromatose 1/patologia , Neurofibromatose 1/psicologia , Adolescente , Criança , Transtornos Cognitivos/epidemiologia , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino
5.
Subcell Biochem ; 45: 55-69, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18193634

RESUMO

Gelsolin is a calcium-activated actin filament severing and capping protein found in many cell types and as a secreted form in the plasma of vertebrates. Mutant mice for gelsolin as well as clinical studies have shown that gelsolin is linked to a number of pathological conditions such as inflammation, cancer and amyloidosis. The tight regulation of gelsolin by calcium is crucial for its physiological role and constitutive activation leads to apoptosis. In the following we will give an overview on how gelsolin is regulated by calcium, and which clinical conditions have been linked to lack or misregulation of gelsolin.


Assuntos
Cálcio/fisiologia , Gelsolina/fisiologia , Actinas/fisiologia , Amiloidose/genética , Animais , Gelsolina/genética , Genes Supressores de Tumor/fisiologia , Humanos , Inflamação/fisiopatologia , Fosfatidilinositóis/fisiologia
6.
J Biol Chem ; 272(48): 30314-21, 1997 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-9374518

RESUMO

The integrin beta4 has a long cytodomain necessary for hemidesmosome formation. A yeast two-hybrid screen using beta4 cytodomain uncovered a protein called p27(BBP) that represents a beta4 interactor. Both in yeast and in vitro, p27(BBP) binds the two NH2-terminal fibronectin type III modules of beta4, a region required for signaling and hemidesmosome formation. Sequence analysis of p27(BBP) revealed that p27(BBP) was not previously known and has no homology with any isolated mammalian protein, but 85% identical to a yeast gene product of unknown function. Expression studies by Northern analysis and in situ hybridization showed that, in vivo, p27(BBP) mRNA is highly expressed in epithelia and proliferating embryonic epithelial cells. An antibody raised against p27(BBP) COOH-terminal domain showed that all beta4-containing epithelial cell lines expressed p27(BBP). The p27(BBP) protein is insoluble and present in the intermediate filament pool. Furthermore, subcellular fractionation indicated the presence of p27(BBP) both in the cytoplasm and in the nucleus. Confocal analysis of cultured cells showed that part of p27(BBP) immunoreactivity was both nuclear and in the membrane closely apposed to beta4. These results suggest that the p27(BBP) is an in vivo interactor of beta4, possibly linking beta4 to the intermediate filament cytoskeleton.


Assuntos
Antígenos CD/metabolismo , Proteínas de Transporte/genética , Células Epiteliais/metabolismo , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Fatores de Iniciação de Peptídeos , Fosfoproteínas , Proteínas de Saccharomyces cerevisiae , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Núcleo Celular/química , Citoplasma/química , Fatores de Iniciação em Eucariotos , Expressão Gênica , Humanos , Hibridização In Situ , Integrina beta4 , Proteínas de Filamentos Intermediários/química , Filamentos Intermediários/química , Camundongos , Dados de Sequência Molecular , Ligação Proteica , RNA Mensageiro/genética , Proteínas Recombinantes , Proteínas Ribossômicas , Saccharomyces cerevisiae , Alinhamento de Sequência , Solubilidade
7.
EMBO J ; 14(18): 4470-81, 1995 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-7556090

RESUMO

We have examined the mechanism of signal transduction by the hemidesmosomal integrin alpha 6 beta 4, a laminin receptor involved in morphogenesis and tumor progression. Immunoprecipitation and immune complex kinase assays indicated that antibody- or laminin-induced ligation of alpha 6 beta 4 causes tyrosine phosphorylation of the beta 4 subunit in intact cells and that this event is mediated by a protein kinase(s) physically associated with the integrin. Co-immunoprecipitation and GST fusion protein binding experiments showed that the adaptor protein Shc forms a complex with the tyrosine-phosphorylated beta 4 subunit. Shc is then phosphorylated on tyrosine residues and recruits the adaptor Grb2, thereby potentially linking alpha 6 beta 4 to the ras pathway. The beta 4 subunit was found to be phosphorylated at multiple tyrosine residues in vivo, including a tyrosine-based activation motif (TAM) resembling those found in T and B cell receptors. Phenylalanine substitutions at the beta 4 TAM disrupted association of alpha 6 beta 4 with hemidesmosomes, but did not interfere with tyrosine phosphorylation of Shc and recruitment of Grb2. These results indicate that signal transduction by the alpha 6 beta 4 integrin is mediated by an associated tyrosine kinase and that phosphorylation of distinct sites in the beta 4 tail mediates assembly of the hemidesmosomal cytoskeleton and recruitment of Shc/Grb2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD/metabolismo , Antígenos de Superfície/metabolismo , Desmossomos/metabolismo , Integrinas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Antígenos CD/genética , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Adesão Celular/fisiologia , Moléculas de Adesão Celular/metabolismo , Citoesqueleto/metabolismo , Análise Mutacional de DNA , Imunofluorescência , Proteína Adaptadora GRB2 , Humanos , Integrina alfa6beta4 , Integrina beta4 , Modelos Biológicos , Dados de Sequência Molecular , Fosforilação , Proteínas/metabolismo , Ratos , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Transfecção , Domínios de Homologia de src , Calinina
8.
J Cell Biol ; 129(2): 473-87, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7721947

RESUMO

To examine the function of the alpha 6 beta 4 integrin we have determined its ligand-binding ability and overexpressed two potentially dominant negative mutant beta 4 subunits, lacking either the cytoplasmic or extracellular domain, in bladder epithelial 804G cells. The results of cell adhesion and radioligand-binding assays showed that alpha 6 beta 4 is a receptor for several laminin isoforms, including laminin 1, 2, 4, and 5. Overexpression of the tail-less or head-less mutant beta 4 subunit did not suppress alpha 6 beta 4-mediated adhesion to laminins, as both types of transfectants adhered to these ligands in the presence of blocking anti-beta 1 antibodies as well as the controls. However, immunofluorescence experiments indicated that the endogenous alpha 6 beta 4 integrin and other hemidesmosomal markers were not concentrated in hemidesmosomes in cells overexpressing tail-less beta 4, while the distribution of these molecules was not altered in cells overexpressing the head-less subunit. Electron microscopic studies confirmed that cells overexpressing tail-less beta 4 had a drastically reduced number of hemidesmosomes, while cells expressing the head-less subunit had a normal number of these structures. Thus, expression of a tail-less, but not a head-less mutant beta 4 subunit leads to a dominant negative effect on hemidesmosome assembly without suppressing initial adhesion to laminins. We conclude that the alpha 6 beta 4 integrin binds to several laminins and plays an essential role in the assembly and/or stability of hemidesmosomes, that alpha 6 beta 4-mediated adhesion and hemidesmosome assembly have distinct requirements, and that it is possible to use a dominant negative approach to selectively interfere with a specific function of an integrin.


Assuntos
Antígenos de Superfície/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte , Adesão Celular/fisiologia , Colágeno , Proteínas do Citoesqueleto , Desmossomos/metabolismo , Integrinas/metabolismo , Laminina/metabolismo , Proteínas do Tecido Nervoso , Colágenos não Fibrilares , Sequência de Aminoácidos , Animais , Antígenos de Superfície/biossíntese , Antígenos de Superfície/genética , Autoantígenos/análise , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Desmossomos/ultraestrutura , Distonina , Células Epiteliais , Epitélio/química , Humanos , Integrina alfa6beta4 , Integrina beta4 , Integrinas/biossíntese , Integrinas/genética , Cinética , Dados de Sequência Molecular , Penfigoide Bolhoso , Ensaio Radioligante , Ratos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Deleção de Sequência/fisiologia , Células Tumorais Cultivadas , Bexiga Urinária , Colágeno Tipo XVII
10.
Mol Biol Cell ; 4(9): 871-84, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8257791

RESUMO

The alpha 6 beta 4 integrin is structurally distinct from all the other known integrins because the cytoplasmic domain of beta 4 is unusually large and contains four type III fibronectin-like modules toward its C-terminus. To examine the function of the beta 4 cytoplasmic tail, we have expressed full-length and truncated human beta 4 cDNAs in rat bladder epithelial 804G cells, which form hemidesmosome-like adhesions in vitro. The cDNA encoded wild-type beta 4 subunit associated with endogenous alpha 6 and was recruited at the cell surface within hemidesmosome-like adhesions. A recombinant form of beta 4, lacking almost the entire cytoplasmic domain associated with alpha 6, reached the cell surface but remained diffusely distributed. A beta 4 molecule lacking almost the entire extracellular portion did not associate with alpha 6 but was correctly targeted to the hemidesmosome-like adhesions. Thus, the cytoplasmic portion of beta 4 contains sequences that are required and may be sufficient for the assembly of the alpha 6 beta 4 integrin into hemidesmosomes. To localize these sequences we examined the properties of additional mutant forms of beta 4. A truncated beta 4 subunit, lacking the most C-terminal pair of type III fibronectin homology domains, was incorporated into hemidesmosome-like adhesions, but another recombinant beta 4 molecule, lacking both pairs of type III fibronectin repeats, was not. Finally a recombinant beta 4 molecule, which was created by adjoining the region of the cytoplasmic domain including all type III repeats to the transmembrane segment, was efficiently recruited in hemidesmosome-like adhesions. Taken together these results suggest that the assembly of the alpha 6 beta 4 integrin into hemidesmosomes is mediated by a 303-amino acid region of beta 4 tail that comprises the first pair of type III fibronectin repeats and the segment between the second and third repeats. These data imply a function of a specific segment of the beta 4 cytoplasmic domain in interaction with cytoskeletal components of hemidesmosomes.


Assuntos
Antígenos de Superfície/metabolismo , Citoesqueleto/metabolismo , Desmossomos/metabolismo , Integrinas/metabolismo , Animais , Antígenos de Superfície/biossíntese , Sequência de Bases , Linhagem Celular , Citoesqueleto/ultraestrutura , Primers do DNA , DNA Complementar/metabolismo , Desmossomos/ultraestrutura , Epitélio/metabolismo , Expressão Gênica , Genes myc , Humanos , Integrina alfa6beta4 , Integrinas/biossíntese , Substâncias Macromoleculares , Dados de Sequência Molecular , Mutagênese Insercional , Ratos , Transfecção , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária
11.
Cancer Res ; 52(14): 3918-23, 1992 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-1617667

RESUMO

Using a polymerase chain reaction-single strand conformation polymorphism approach we analyzed 96 human primary breast tumors for the presence of mutations in exons 2, 5, 6, 7, 8, and 9 of the p53 gene. These exons have been shown to comprise highly conserved sequences and the portion including exons 5 through 9 is believed to be the target for over 90% of the acquired mutations in human cancer. Eighteen tumors of the 96 (18.7%) tested showed reproducibly a variant band indicative of a mutation. Most (15 tumors) of the mutations were single nucleotide substitutions and G:C to A:T transitions were prevalent (6 tumors), G:C to T:A transversions came next (4 tumors), and guanines were always on the nontranscribed strand. Concomitant loss of the wild type allele and mutation of the other copy was observed in only 3 of 18 mutated cases; this is consistent with the heterogeneous cellular composition of breast tumors. Furthermore p53 mutations were correlated to estrogen and/or progesterone receptor negative tumors, thus indicating their relationships to aggressive breast cancer. No association could be observed with DNA amplification events in these tumors.


Assuntos
Neoplasias da Mama/genética , Éxons/genética , Genes p53/genética , Mutação/genética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Análise Mutacional de DNA , Feminino , Amplificação de Genes , Humanos , Reação em Cadeia da Polimerase
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