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‣ Genotype-phenotype correlation in Brazillian Rett syndrome patients; Correlação genótipo-fenótipo em pacientes brasileiras com síndrome de Rett

LIMA, Fernanda T. de; BRUNONI, Decio; SCHWARTZMAN, José Salomão; POZZI, Maria Cristina; KOK, Fernando; JULIANO, Yara; PEREIRA, Lygia da Veiga
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.10207%
BACKGROUND: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. PURPOSE: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. METHOD: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. RESULTS: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. CONCLUSION: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/phenotype correlations, guiding the implementation of mutation searching programs.; INTRODUÇÃO: A síndrome de Rett é uma grave doença do neurodesenvolvimento ligada ao X dominante, causada por mutações no gene MECP2. OBJETIVOS: Identificar mutações de ponto no gene MECP2 e estabelecer uma correlação entre as principais mutações encontradas e o fenótipo. MÉTODO: Avaliação clínica de 105 pacientes...

‣ Mudanças em subgrupos de monócitos durante infecção aguda pelo vírus da imunodeficiência símia (SIV); expansão de uma população inédita de células CD14+CD16- com um fenótipo atípico CCR2-; Changes in monocyte subsets during the simian immunodeficiency virus (SIV) acute infection; surge of a novel subpopulation of CD14+CD16- cells with an atypical CCR2- phenotype

Gama, Lucio
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 08/07/2011 Português
Relevância na Pesquisa
27.044285%
Monócitos podem ser classificados em três subgrupos de acordo com o nível de expressão dos marcadores CD14 e CD16. Monócitos clássicos são os mais abundantes no sangue. Eles expressam um fenótipo CD14+CD16-CCR2+, conferindo a eles a habilidade de migrar rapidamente a sítios inflamatórios, através da resposta à quimiocina CCL2 (CC chemokine ligand 2). Aqui apresentamos a identificação e caracterização de uma expansão de um novo subgrupo de monócitos durante a infecção por SIV e HIV. Essas células são indistinguíveis dos monócitos clássicos quanto à expressão de CD14 e CD16; porém não expressam CCR2 de superfície. A análise do transcriptoma de células selecionadas confirmou que elas representam uma subpopulação distinta que expressa níveis mais baixos de citocinas inflamatórias e marcadores de ativação que as CCR2+. Elas exibem fagocitose alterada e quimiotaxia deficiente em resposta a CCL2 e CCL7, além de serem refratárias à infecção por SIV e apresentarem atividade antiproliferativa. Nós as denominamos monócitos clássicos atípicos CCR2- (ACC monocytes), e acreditamos que elas têm um papel importante na patogenia da AIDS, possivelmente refletindo uma resposta anti-inflamatória contra a excessiva imunoativação observada durante a infecção por SIV e HIV. Tratamento antirretroviral leva a um declínio dessa subpopulação tanto em macacos como seres humanos...

‣ Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome

Vieira, Gustavo H.; Rodriguez, Jayson D.; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F.; Carvalho, Daniel R.; Duarte, Andréa de Rezende; Santos, Suely R.; Souza, Deise H. de; Dupont, Barbara R.; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, A
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 148-154
Português
Relevância na Pesquisa
36.78875%
Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. © 2012 Macmillan Publishers Limited All rights reserved.

‣ Genotype-phenotype correlation in Brazillian Rett syndrome patients

Lima,Fernanda T. de; Brunoni,Decio; Schwartzman,José Salomão; Pozzi,Maria Cristina; Kok,Fernando; Juliano,Yara; Pereira,Lygia da Veiga
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2009 Português
Relevância na Pesquisa
47.10207%
BACKGROUND: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. PURPOSE: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. METHOD: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. RESULTS: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. CONCLUSION: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/phenotype correlations, guiding the implementation of mutation searching programs.

‣ Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia

Torres,N.; Mello,M.P.; Germano,C.M.R.; Elias,L.L.K.; Moreira,A.C.; Castro,M.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2003 Português
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36.830156%
Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). We determined by allele-specific PCR the frequency of microconversion in the CYP21A2 gene in 50 Brazilian patients with the classical (salt wasting: SW and simple virilizing: SV) forms and nonclassical (NC) form of CAH-21OH and correlated genotype with phenotype. Genotypes were classified into three mutation groups (A, B, and C) based on the amount of enzymatic activity in in vitro studies using adrenal cells. In 94 unrelated alleles, we diagnosed 76% of the affected alleles after screening for 7 microconversions. The most frequent point mutations observed in this series were I172N (19%), V281L (18%), and IVS2,A/C>G,-12 (15%). In the SW form, the most frequent mutation was IVS2,A/C>G,-12 (38%), in the SV form it was I172N (53%), and in the NC form it was V281L (57.7%). We observed a good correlation between genotype and phenotype. Discordance between genotype and phenotype was found in one SV patient with a mild mutation in one of the alleles (R356W/V281L). However, we cannot rule out the presence of an additional mutation in these alleles. We also observed a good correlation of genotype with 17alpha-hydroxyprogesterone, testosterone...

‣ Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele

Polizzi,Angela; Tesse,Riccardina; Santostasi,Teresa; Diana,Anna; Manca,Antonio; Logrillo,Vito Paolo; Cazzato,Maria Domenica; Pantaleo,Maria Giuseppa; Armenio,Lucio
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2011 Português
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36.691545%
Cystic fibrosis (CF) is caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. We ascertained five patients with a novel complex CFTR allele, with two mutations, H939R and H949L, inherited in cis in the same exon of CFTR gene, and one different mutation per patient inherited in trans in a wide population of 289 Caucasian CF subjects from South Italy. The genotype-phenotype relationship in patients bearing this complex allele was investigated. The two associated mutations were related to classical severe CF phenotypes.

‣ Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas

Sieber, O. M.; Lamlum, H.; Crabtree, M. D.; Rowan, A. J.; Barclay, E.; Lipton, L.; Hodgson, S.; Thomas, H. J. W.; Neale, K.; Phillips, R. K. S.; Farrington, S. M.; Dunlop, M. G.; Mueller, H. J.; Bisgaard, M. L.; Bulow, S.; Fidalgo, P.; Albuquerque, C.; Sc
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called “multiple” adenoma patients, have a phenotype like AAPC, with 3–99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

‣ Mutations of the Selenoprotein N Gene, Which Is Implicated in Rigid Spine Muscular Dystrophy, Cause the Classical Phenotype of Multiminicore Disease: Reassessing the Nosology of Early-Onset Myopathies

Ferreiro, Ana; Quijano-Roy, Susana; Pichereau, Claire; Moghadaszadeh, Behzad; Goemans, Nathalie; Bönnemann, Carsten; Jungbluth, Heinz; Straub, Volker; Villanova, Marcello; Leroy, Jean-Paul; Romero, Norma B.; Martin, Jean-Jacques; Muntoni, Francesco; Voit
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
Português
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47.23356%
Multiminicore disease (MmD) is an autosomal recessive congenital myopathy characterized by the presence of multiple, short core lesions (known as “minicores”) in most muscle fibers. MmD is a clinically heterogeneous condition, in which four subgroups have been distinguished. Homozygous RYR1 mutations have been recently identified in the moderate form of MmD with hand involvement. The genes responsible for the three other forms (including the most prevalent phenotype, termed the “classical” phenotype) remained, so far, unknown. To further characterize the genetic basis of MmD, we analyzed a series of 62 patients through a combined positional/candidate-gene approach. On the basis of clinical and morphological data, we suspected a relationship between classical MmD and the selenoprotein N gene (SEPN1), which is located on chromosome 1p36 (RSMD1 locus) and is responsible for the congenital muscular dystrophy with rigid spine syndrome (RSMD). A genomewide screening, followed by the analysis of 1p36 microsatellite markers in 27 informative families with MmD, demonstrated linkage to RSMD1 in eight families. All showed an axial myopathy with scoliosis and respiratory failure, consistent with the most severe end of the classical MmD spectrum; spinal rigidity was evident in some...

‣ De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.

Allanson, J E; Hennekam, R C; Ireland, M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1997 Português
Relevância na Pesquisa
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Classical de Lange syndrome presents with a striking face, pronounced growth and mental retardation, and variable limb deficiencies. Over the past five years, a mild variant has been defined, with less significant psychomotor retardation, less marked pre- and postnatal growth deficiency, and an uncommon association with major malformations, although mild limb anomalies may be present. We have evaluated 43 subjects with de Lange syndrome, 30 with classical features, aged from birth to 21 years, and 13 with the mild phenotype, aged from 18 months to 30 years. In addition to assessment of gestalt and facial change with time, detailed craniofacial measurements have been obtained on each subject and composite pattern profiles compiled. The characteristic face of classical de Lange syndrome is present at birth and changes little throughout life, although there is some lengthening of the face with age and the jaw becomes squared. In mild de Lange syndrome, the characteristic classical appearance may be present at birth, but in some subjects it may be two or three years before the typical face is obvious. In general, the overall impression is less striking, perhaps because of increased facial expression and greater alertness. With age, the face loses the characteristic appearance...

‣ The expanding phenotype of laminin α2 chain (merosin) abnormalities: case series and review

Jones, K.; Morgan, G.; Johnston, H.; Tobias, V.; Ouvrier, R.; Wilkinson, I.; North, K.
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
Publicado em /10/2001 Português
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Initial reports of patients with laminin α2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin α2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin α2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin α2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin α2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported)...

‣ P-glycoprotein overexpression cannot explain the complete doxorubicin-resistance phenotype in rat glioblastoma cell lines.

Huet, S.; Schott, B.; Robert, J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1992 Português
Relevância na Pesquisa
27.044285%
We have associated pharmacological studies to a semi-quantitative evaluation of P-glycoprotein(s) expression, to establish if classical multidrug resistance (MDR) could account for the complete resistance phenotype exhibited by progressively doxorubicin-resistant rat glioblastoma cells. Three resistant variants (C6 0.001, C6 0.1 and C6 0.5) of the C6 glioblastoma cell line (C6 S) were selected by long-term culture in the presence of three concentrations of doxorubicin (0.001, 0.1 and 0.5 microgram.ml-1 respectively). The degree of doxorubicin resistance was respectively 7, 33 and 400, and all the cell variants were cross-resistant to m-AMSA, etoposide and vincristine. Doxorubicin incorporation was reduced similarly in all resistant cells, irrespective of the level of resistance. When exposed to their respective doxorubicin IC50, the 7-fold resistant cells had the same intracellular drug incorporation as the sensitive cells, whereas the 33-fold and 400-fold resistant cells could incorporate respectively 3.7 and 17 times more drug. The ratio of doxorubicin exposures required for 50% DNA synthesis inhibition and 50% growth inhibition was dependent on the degree of resistance; this ratio was 12.8 in C6 S, 11.6 in C6 0.001, 6.3 in C6 0.1 and 1.8 in C6 0.5. P-glycoprotein(s) overexpression was of the same magnitude as the resistance factor in variants C6 0.001 and C6 0.1...

‣ Sequential expression of macrophage anti-microbial/inflammatory and wound healing markers following innate, alternative and classical activation

Menzies, F M; Henriquez, F L; Alexander, J; Roberts, C W
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /06/2010 Português
Relevância na Pesquisa
36.65365%
The present study examines the temporal dynamics of macrophage activation marker expression in response to variations in stimulation. We demonstrate that markers can be categorized as ‘early’ (expressed most abundantly at 6 h post-stimulation) or ‘late’ (expressed at 24 h post-stimulation). Thus nos2 and p40 (IL-12/IL-23) are early markers of innate and classical activation, while dectin-1 and mrc-1 are early markers and fizz1 (found in inflammatory zone-1) and ym1 are late markers of alternative activation. Furthermore, argI is a late marker of both innate and alternative activation. The ability of interferon (IFN)-γ to alter these activation markers was studied at both the protein level and gene level. As reported previously, IFN-γ was able to drive macrophages towards the classical phenotype by enhancing nos2 gene expression and enzyme activity and p40 (IL-12/IL-23) gene expression in lipopolysaccharide (LPS)-stimulated macrophages. IFN-γ antagonized alternative macrophage activation, as evident by reduced expression of dectin-1, mrc-1, fizz1 and ym1 mRNA transcripts. In addition, IFN-γ antagonized arginase activity irrespective of whether macrophages were activated innately or alternatively. Our data explain some apparent contradictions in the literature...

‣ Rediscovery by Whole Genome Sequencing: Classical Mutations and Genome Polymorphisms in Neurospora crassa

McCluskey, Kevin; Wiest, Aric E.; Grigoriev, Igor V.; Lipzen, Anna; Martin, Joel; Schackwitz, Wendy; Baker, Scott E.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em 01/09/2011 Português
Relevância na Pesquisa
27.03517%
Classical forward genetics has been foundational to modern biology, and has been the paradigm for characterizing the role of genes in shaping phenotypes for decades. In recent years, reverse genetics has been used to identify the functions of genes, via the intentional introduction of variation and subsequent evaluation in physiological, molecular, and even population contexts. These approaches are complementary and whole genome analysis serves as a bridge between the two. We report in this article the whole genome sequencing of eighteen classical mutant strains of Neurospora crassa and the putative identification of the mutations associated with corresponding mutant phenotypes. Although some strains carry multiple unique nonsynonymous, nonsense, or frameshift mutations, the combined power of limiting the scope of the search based on genetic markers and of using a comparative analysis among the eighteen genomes provides strong support for the association between mutation and phenotype. For ten of the mutants, the mutant phenotype is recapitulated in classical or gene deletion mutants in Neurospora or other filamentous fungi. From thirteen to 137 nonsense mutations are present in each strain and indel sizes are shown to be highly skewed in gene coding sequence. Significant additional genetic variation was found in the eighteen mutant strains...

‣ Staphylococcus aureus small colony variants show common metabolic features in central metabolism irrespective of the underlying auxotrophism

Kriegeskorte, André; Grubmüller, Stephanie; Huber, Claudia; Kahl, Barbara C.; von Eiff, Christof; Proctor, Richard A.; Peters, Georg; Eisenreich, Wolfgang; Becker, Karsten
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 21/10/2014 Português
Relevância na Pesquisa
27.102073%
In addition to the classical phenotype, Staphylococcus aureus may exhibit the small colony-variant (SCV) phenotype, which has been associated with chronic, persistent and/or relapsing infections. SCVs are characterized by common phenotypic features such as slow growth, altered susceptibility to antibiotic agents and pathogenic traits based on increased internalization and intracellular persistence. They show frequently auxotrophies mainly based on two different mechanisms: (i) deficiencies in electron transport as shown for menadione- and/or hemin-auxotrophs and (ii) thymidylate biosynthetic-defective SCVs. To get a comprehensive overview of the metabolic differences between both phenotypes, we compared sets of clinically derived menadione-, hemin- and thymidine-auxotrophic SCVs and stable site directed mutants exhibiting the SCV phenotype with their corresponding isogenic parental strains displaying the normal phenotype. Isotopologue profiling and transcriptional analysis of central genes involved in carbon metabolism, revealed large differences between both phenotypes. Labeling experiments with [U-13C6]glucose showed reduced 13C incorporation into aspartate and glutamate from all SCVs irrespective of the underlying auxotrophism. More specifically...

‣ Phenotype Shift from Atypical Scrapie to CH1641 following Experimental Transmission in Sheep

Simmons, Marion M.; Moore, S. Jo; Lockey, Richard; Chaplin, Melanie J; Konold, Timm; Vickery, Christopher; Spiropoulos, John
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 24/02/2015 Português
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The interactions of host and infecting strain in ovine transmissible spongiform encephalopathies are known to be complex, and have a profound effect on the resulting phenotype of disease. In contrast to classical scrapie, the pathology in naturally-occurring cases of atypical scrapie appears more consistent, regardless of genotype, and is preserved on transmission within sheep homologous for the prion protein (PRNP) gene. However, the stability of transmissible spongiform encephalopathy phenotypes on passage across and within species is not absolute, and there are reports in the literature where experimental transmissions of particular isolates have resulted in a phenotype consistent with a different strain. In this study, intracerebral inoculation of atypical scrapie between two genotypes both associated with susceptibility to atypical forms of disease resulted in one sheep displaying an altered phenotype with clinical, pathological, biochemical and murine bioassay characteristics all consistent with the classical scrapie strain CH1641, and distinct from the atypical scrapie donor, while the second sheep did not succumb to challenge. One of two sheep orally challenged with the same inoculum developed atypical scrapie indistinguishable from the donor. This study adds to the range of transmissible spongiform encephalopathy phenotype changes that have been reported following various different experimental donor-recipient combinations. While these circumstances may not arise through natural exposure to disease in the field...

‣ Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

Liu, Yudong; Holdbrooks, Andrew T.; Meares, Gordon P.; Buckley, Jessica A.; Benveniste, Etty N.; Qin, Hongwei
Fonte: AAI Publicador: AAI
Tipo: Artigo de Revista Científica
Português
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37.005664%
The JAK/STAT pathway is critical for development, regulation, and termination of immune responses, and dysregulation of the JAK/STAT pathway, that is, hyperactivation, has pathological implications in autoimmune and neuroinflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) regulates STAT3 activation in response to cytokines that play important roles in the pathogenesis of neuroinflammatory diseases, including IL-6 and IL-23. We previously demonstrated that myeloid lineage–specific deletion of SOCS3 resulted in a severe, nonresolving atypical form of experimental autoimmune encephalomyelitis (EAE), characterized by lesions, inflammatory infiltrates, elevated STAT activation, and elevated cytokine and chemokine expression in the cerebellum. Clinically, these mice exhibit ataxia and tremors. In this study, we provide a detailed analysis of this model, demonstrating that the atypical EAE observed in LysMCre-SOCS3fl/fl mice is characterized by extensive neutrophil infiltration into the cerebellum and brainstem, increased inducible NO synthase levels in the cerebellum and brainstem, and prominent axonal damage. Importantly, infiltrating SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, NO, TNF-α, and IL-1β. Kinetic studies demonstrate that neutrophil infiltration into the cerebellum and brainstem of LysMCre-SOCS3fl/fl mice closely correlates with atypical EAE clinical symptoms. Ab-mediated depletion of neutrophils converts the atypical phenotype to the classical EAE phenotype and...

‣ Pathogenic Mycobacterium bovis strains differ in their ability to modulate the proinflammatory activation phenotype of macrophages

Andrade, Marcelle R. M.; Amaral, Eduardo Pinheiro; Ribeiro, Simone C. M.; Almeida, Fabricio M.; Peres, Tanara V.; Lanes, Veronica; Lima, Maria Regina D'Imperio; Lasunskaia, Elena B.
Fonte: BIOMED CENTRAL LTD; LONDON Publicador: BIOMED CENTRAL LTD; LONDON
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.691545%
Background: Tuberculosis, caused by Mycobacterium tuberculosis or Mycobacterium bovis, remains one of the leading infectious diseases worldwide. The ability of mycobacteria to rapidly grow in host macrophages is a factor contributing to enhanced virulence of the bacteria and disease progression. Bactericidal functions of phagocytes are strictly dependent on activation status of these cells, regulated by the infecting agent and cytokines. Pathogenic mycobacteria can survive the hostile environment of the phagosome through interference with activation of bactericidal responses. To study the mechanisms employed by highly virulent mycobacteria to promote their intracellular survival, we investigated modulating effects of two pathogenic M. bovis isolates and a reference M. tuberculosis H37Rv strain, differing in their ability to multiply in macrophages, on activation phenotypes of the cells primed with major cytokines regulating proinflammatory macrophage activity. Results: Bone marrow- derived macrophages obtained from C57BL/6 mice were infected by mycobacteria after a period of cell incubation with or without treatment with IFN-gamma, inducing proinflammatory type-1 macrophages (M1), or IL-10, inducing anti-inflammatory type-2 cells (M2). Phenotypic profiling of M1 and M2 was then evaluated. The M. bovis strain MP287/03 was able to grow more efficiently in the untreated macrophages...

‣ Diagnóstico clínico e laboratorial da fibrose cística : métodos clássicos e novas perspectivas = Clinical and laboratorial diagnosis of cystic fibrosis: classical methods and new perspectives; Clinical and laboratorial diagnosis of cystic fibrosis : classical methods and new perspectives

Maria de Fátima Corrêa Pimenta Servidoni
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/07/2014 Português
Relevância na Pesquisa
37.205957%
A Fibrose Cística (FC) é uma doença genética autossômica recessiva, comum em caucasianos. Tem incidência de 1: 2.500 a 1: 6.000 nascidos vivos e 1: 25 em portadores sãos na Europa e EUA e no Brasil a incidência estimada é de 1:10.000 nascidos vivos. É causada pela presença de dois genes CFTR (do inglês Cystic Fibrosis Transmembrane Conductance Regulator) mutados, que codificam uma proteína também denominada CFTR. A CFTR é o principal canal de Cloro (Cl-), é expressa na membrana apical das células epiteliais dos tratos respiratório e digestório (pâncreas, fígado e intestino), nas glândulas sudoríparas e salivares, e no aparelho reprodutor masculino. Regula o transporte de iôns e de água.O comprometimento ou a ausência da função da CFTR promove a desidratação das mucosas com produção de um muco viscoso com consequente obstrução das vias respiratórias e ductos das glândulas exócrinas determinando o fenótipo da FC. O grau de função da CFTR será determinante da gravidade da doença. Até à data, já foram descritas cerca de 2000 mutações no gene CFTR. A F508del é a mutação mais prevalente, está presente em 85% dos pacientes a nível mundial e em 65% no Brasil. As mutações podem ser classificadas em 6 grupos de acordo com o defeito molecular e celular e determina o fenótipo da FC. Pode ser classificado em: clássico e não-clássico. O clássico é o mais conhecido e frequente e apresenta sintomas graves. O não-clássico ocorre em cerca de 15% dos doentes e apresenta sintomas mais brandos...

‣ Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3.

Havel, R J; Kotite, L; Kane, J P; Tun, P; Bersot, T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1983 Português
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Familial dysbetalipoproteinemia has been reported to be associated uniquely with an apolipoprotein E phenotype (E2/2) that occurs in approximately 1% of all persons. We have observed the typical clinical and biochemical characteristics of this disorder in five members of a family, in all of whom the apolipoprotein E phenotype, as determined by isoelectric focusing electrophoresis, is E3/3. The disorder is present in three generations of the family: the proband, her mother, and three of the proband's five children. The proband's husband, father of all five children, also has apolipoprotein E phenotype E3/3, as do his two unaffected children. As in normal persons with phenotype E3/3, the apolipoprotein E of affected members appears to have a single residue of cysteine. When incorporated with egg lecithin into discoidal complexes, the apolipoprotein E from affected members was taken up normally into perfused livers of estradiol-treated rats, in which a high level of LDL receptors is expressed. When isoelectric focusing electrophoresis was carried out over a narrow range of pH (5-7), each of the apolipoprotein E isoforms of affected members was observed as a doublet, even after reduction of dimers of the protein with 2-mercaptoethanol and treatment with neuraminidase to minimize the content of sialylated forms of the protein. Doublets were also observed in the apolipoprotein E-2 of patients with classical dysbetalipoproteinemia...

‣ Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype.

de Vries, B B; Fryns, J P; Butler, M G; Canziani, F; Wesby-van Swaay, E; van Hemel, J O; Oostra, B A; Halley, D J; Niermeijer, M F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1993 Português
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A special subphenotype of the fragile X syndrome is reported which is characterised by extreme obesity with a full, round face, small, broad hands/feet, and regional skin hyperpigmentation. It resembles the Prader-Willi syndrome (PWS) and might therefore be named 'Prader-Willi-like'. Unlike the PWS, these PW-like fragile X patients lack the neonatal hypotonia with feeding problems during infancy followed by hyperphagia from toddlerhood. We describe five new fragile X patients and present a clinical update of three previously described patients with the PW-like phenotype. In one family, segregation of either the classical Martin-Bell or the PW-like phenotype was observed and in another family there was repeated transmission of the PW-like phenotype. Previously, one of the patients had been misdiagnosed as having classical PWS, based on clinical findings. Molecular studies of the FMR-1 gene showed the typical full mutations as seen in fragile X syndrome males. Molecular analysis of the 15q11-13 region, which is deleted in the majority of classical PWS patients, did not show any detectable abnormalities. In a group of 26 patients with suspected Prader-Willi syndrome but without detectable molecular abnormalities of chromosome 15, one fragile X patient was found. These clinical and molecular findings illustrate the necessity to perform DNA analysis of the FMR-1 gene in mentally retarded patients presenting with a PW phenotype but without the PWS specific cytogenetic/molecular abnormalities of chromosome 15.