Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Med Genet A ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052936

RESUMO

Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis. Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development.

2.
Cell Tissue Res ; 373(1): 149-160, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29869713

RESUMO

Misfolded α-synuclein accumulates in histological inclusions constituting "Lewy pathology" found in idiopathic Parkinson disease, Parkinson disease dementia and dementia with Lewy body. The mechanism inducing α-synuclein misfolding is still unknown. The misfolded molecules form oligomers that organize into fibrils. α-Synuclein fibrils, in vitro, are capable of initiating an auto-replicating process, transforming normal molecules into misfolded molecules that aggregate. Fibrils can cross the neuronal membrane and recruit α-synuclein molecules in connected neurons. Such properties of seeding and propagation, shared with prion proteins, belong to "tissular propagons". Lewy bodies isolate harmful species from the cytoplasm and have been thought to be protective. In PRKN gene mutations, however, the absence of Lewy bodies is not associated with a more aggressive course. In idiopathic Parkinson disease, the proportion of neurons with Lewy bodies in the substantia nigra remains stable despite the progression of neuronal loss. This stable proportion suggests that Lewy bodies are eliminated at the rate at which neurons are lost because Lewy bodies cause, or invariably accompany, neuronal loss. Experimentally, cellular death selectively occurs in inclusion-bearing neurons. This set of data indicates that α-synuclein misfolding is the essential mechanism causing the lesions of Parkinson disease and dementia with Lewy body. Lewy pathology is a direct and visible evidence of α-synuclein misfolding and, as such, is an accurate marker for assessing the presence of α-synuclein misfolding even if the inclusions themselves may not be as directly causative as the molecules they accumulate.


Assuntos
Corpos de Lewy/patologia , Sistema Nervoso/patologia , Neuroproteção , Neurotoxinas/toxicidade , alfa-Sinucleína/metabolismo , Animais , Humanos , Corpos de Lewy/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos
3.
Birth Defects Res ; 110(7): 598-602, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29356416

RESUMO

BACKGROUND: The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism. CASE: A targeted exome sequencing of morbid genes causing cerebral malformations identified novel RTTN compound heterozygous mutations in a family where three pregnancies were terminated because a severe fetal microcephaly was diagnosed. An autopsy performed on the second sib showed moderate growth restriction and a microcephaly with simplified gyral pattern. The histopathological study discovered a malformed cortical plate. CONCLUSIONS: The present study confirms the involvement of RTTN gene mutations in microcephaly with simplified gyral pattern and describes the observed abnormal neuropathological findings.


Assuntos
Encéfalo/patologia , Proteínas de Transporte/genética , Microcefalia/genética , Mutação , Proteínas de Ciclo Celular , Humanos , Microcefalia/patologia
5.
Medicine (Baltimore) ; 93(24): 318-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25500701

RESUMO

Dermatomyositis (DM) is a major clinical subset of autoimmune myositis (AIM). The characteristic DM rash (Gottron papules, heliotrope rash) and perifascicular atrophy at skeletal muscle biopsy are regarded as specific features for this diagnosis. However, new concepts are challenging the current definition of DM. A modified Bohan and Peter classification of AIM was proposed in which the core concept was the inclusion of the diagnostic significance of overlap connective tissue disease features. In this clinical classification, a DM rash in association with myositis in the absence of overlap features indicates a diagnosis of pure DM. However, overlap features in association with myositis allow a diagnosis of overlap myositis (OM), irrespective of the presence or absence of the DM rash. Perifascicular atrophy may be present in both pure DM and OM. Recently, the presence of perifascicular atrophy in myositis without a DM rash was proposed as diagnostic of a novel entity, adermatopathic DM. We conducted the present study to evaluate these new concepts to further differentiate pure DM from OM.Using the modified Bohan and Peter classification, we performed a follow-up study of a longitudinal cohort of 100 consecutive adult French Canadian patients with AIM, including 44 patients with a DM phenotype, defined as a DM rash, and/or DM-type calcinosis, and/or the presence of perifascicular atrophy on muscle biopsy. A detailed evaluation was performed for overlap features, the extent and natural history of the DM rash, adermatopathic DM, DM-specific and overlap autoantibodies by protein A immunoprecipitation on coded serum samples, and associations with cancer and survival.Two distinct subsets were identified in patients with a DM phenotype: pure DM (n = 24) and OM with DM features, or OMDM (n = 20). In pure DM, the DM rash was a dominant finding. It was the first disease manifestation, was always present at the time of myositis diagnosis, and was associated with a high cutaneous score and chronicity. Concurrent heliotrope rash and Gottron papules (positive predictive value [PPV] 91%), as well as the V-sign and/or shawl sign (PPV 100%), were diagnostic of pure DM. Anti-Mi-2, anti-MJ, and anti-p155 autoantibodies were present in 50% of pure DM patients and were restricted to this subset (PPV 100%). Cancer was present in 21% of pure DM patients. The 15-year survival was excellent (92%).In contrast, in patients with OMDM, the first manifestation was proximal muscle weakness or other skeletal muscle-related complaints. The DM rash appeared at diagnosis or at follow-up, was associated with a low cutaneous extent score and was transient. Adermatopathic DM, which was absent in pure DM, was highly predictive (PPV 100%) of OMDM. Overlap autoantibodies (including anti-Jo-1, anti-PL-7, anti-PM-Scl, anti-U1RNP, and/or anti-U5-RNP) were found in 70% of OMDM patients. OMDM was not associated with cancer, but the 15-year survival was significantly decreased (65%).Perifascicular atrophy occurred as commonly in OMDM (n = 6/20, 30%) as in pure DM (n = 4/24, 17%) patients. These 6 OMDM patients had adermatopathic DM at myositis diagnosis, and only 1 of them developed a DM rash at follow-up, emphasizing the lack of specificity of perifascicular atrophy for pure DM.In conclusion, using the modified Bohan and Peter classification of AIM allowed identification of OMDM, a new clinical subset of OM. Furthermore, identification of OMDM allowed recognition of pure DM as a new entity that was distinct from OMDM or from OM without DM features. However, the absolute specificity of a DM rash and perifascicular muscle atrophy for the diagnosis of pure DM was lost. The distinctive clinical manifestations and autoantibody profiles presented are proposed as diagnostic criteria to differentiate pure DM from OMDM.


Assuntos
Dermatomiosite/diagnóstico , Miosite/diagnóstico , Adolescente , Adulto , Idoso , Atrofia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Dermatomiosite/patologia , Diagnóstico Diferencial , Exantema/diagnóstico , Exantema/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/patologia , Pele/patologia , Adulto Jovem
6.
J Cutan Med Surg ; 18(3): 206-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24800711

RESUMO

BACKGROUND: Deep dermatophytosis of genital skin is a rare clinical manifestation of infection by a common group of pathogens. OBJECTIVE: We emphasize the importance of clinical suspicion and the use of accurate diagnostic methods in the evaluation of deep dermatophytosis. METHODS: We report a single case of tinea pubis, kerion type, caused by Trichophyton mentagrophytes in an immunocompetent host. RESULTS: A 54-year-old female presented with a suppurative infection of the vulva and pubis that was unresponsive to empirical antibiotic therapy. T. mentagrophytes was isolated. Oral itraconazole was initiated on the basis of clinical suspicion and continued for a total of 6 weeks. CONCLUSION: Accurate diagnosis and treatment of deep dermatophytosis of genital skin rests upon proper identification of the pathogen. Prompt initiation of treatment with an oral antifungal agent, such as itraconazole, should be undertaken in order to avoid irreversible scarring alopecia.


Assuntos
Antifúngicos/uso terapêutico , Itraconazol/uso terapêutico , Tinha do Couro Cabeludo/tratamento farmacológico , Tinha do Couro Cabeludo/microbiologia , Doenças da Vulva/tratamento farmacológico , Doenças da Vulva/microbiologia , Feminino , Humanos , Pessoa de Meia-Idade , Tinha do Couro Cabeludo/patologia , Doenças da Vulva/patologia
7.
J Cell Physiol ; 226(7): 1907-14, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21506121

RESUMO

Our hypothesis is that the development of lesional areas of skin in patients with systemic sclerosis (SSc) originates from the selection of profibrotic cell subpopulations within their non-lesional skin areas, due to their greater resistance to apoptosis. Sensitivity to apoptosis of early-stage or late-stage SSc fibroblasts as well as of healthy cells was compared using extrinsic or intrinsic apoptotic pathway-inducers. Subpopulations of non-lesional SSc cells and healthy cells obtained after repeated Fas-induced apoptosis were compared with respect to their fibrotic parameters such as collagen and MMP secretion. Only late-stage lesional SSc cells were more resistant to Fas-induced apoptosis than their non-lesional counterparts isolated from the same patient. This result correlated with an increase in the levels of the anti-apoptotic proteins cFLIPs and cIAP in lesional cells compared to non-lesional cells. Healthy and non-lesional cell populations could be selected to generate a subpopulation that was more resistant to apoptosis. However, only the late-stage non-lesional SSc fibroblast populations showed a significant decrease in MMP secretion, one of parameters of the fibrosis. Our results show that resistance to apoptosis is an important characteristic of the late-stage lesional SSc fibroblast phenotype. We thus hypothesized that a selection of specific fibroblast subpopulations from late-stage non-lesional SSc skin areas could be at the origin of lesional populations. These cells should become independent of any exogenous stimuli and can induce or maintain SSc skin lesions.


Assuntos
Apoptose , Proteína Ligante Fas/metabolismo , Fibroblastos/enzimologia , Metaloproteinases da Matriz Secretadas/metabolismo , Esclerodermia Difusa/enzimologia , Transdução de Sinais , Pele/enzimologia , Adulto , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo , Fibroblastos/patologia , Fibrose , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/patologia , Pele/patologia , Receptor fas/metabolismo
8.
J Pathol ; 217(4): 534-42, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19086038

RESUMO

We set out to examine the pathophysiological mechanisms of fibrosis in diffuse systemic sclerosis (SSc) using a tissue engineering approach. Skin fibroblasts were isolated from lesional skin of SSc patients with a disease duration of less than 1 year (early-stage SSc) or more than 10 years (late-stage SSc). Fibroblasts were also isolated from non-lesional skin and compared with normal fibroblasts isolated from healthy adults. Cells were cultured using a tissue engineering method to reconstruct a human dermis, and histologically observed. Dermal thickness was measured, as it reflects the global and intrinsic capacity of cells to reconstitute matrix. Collagen I, MMP-1, and MMP activity were evaluated. Cells were treated with TGFbeta1 or CTGF during dermis formation to study their fibrogenic role. Clinical severity of skin involvement was measured by a modified Rodnan score. Thickness of the dermis generated with non-lesional early-stage SSc fibroblasts was similar to normal cells. In contrast, reconstructed dermis from lesional early-stage SSc fibroblasts and non-lesional late-stage SSc cells was thinner, while lesional late-stage SSc fibroblasts made a thicker dermis. Dermis was always thicker when produced with TGFbeta1-treated cells, except when lesional late-stage SSc fibroblasts from patients with high Rodnan skin scores were used. CTGF did not affect dermal thickness. Measurements of collagen I and collagenases in the culture medium of the various reconstructed dermis could explain some of the changes observed. We conclude that the fibrotic phenotype of SSc fibroblasts varies with disease duration and with severity of skin involvement, and this is clearly visualized during in vitro dermis reconstruction.


Assuntos
Escleroderma Sistêmico/patologia , Pele/patologia , Adulto , Idoso , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Colágeno Tipo I/análise , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Progressão da Doença , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Masculino , Metaloproteinase 1 da Matriz/análise , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinases da Matriz/análise , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Engenharia Tecidual/métodos , Fator de Crescimento Transformador beta1/farmacologia
9.
J Exp Med ; 204(2): 253-8, 2007 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-17242164

RESUMO

Compelling evidence suggests that the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell-mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.


Assuntos
Citocinas/metabolismo , Células Epiteliais/metabolismo , Hipersensibilidade/etiologia , Imunidade Inata/imunologia , Mastócitos/imunologia , Análise de Variância , DNA Complementar/genética , Ensaio de Imunoadsorção Enzimática , Humanos , Reação em Cadeia da Polimerase , Receptores de Citocinas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA