RESUMO
Lenz microphthalmia syndrome and oculo-facio-cardio-dental syndrome (OFCD) are allelic X-linked syndromes and similarly characterized by ocular, distinctive facial morphology, cardiac, dental malformations and intellectual disability. We report a seven-month-old boy with congenital glaucoma, complex cardiac defect, dextrocardia and cerebral white matter hypoplasia suggestive of Lenz microphthalmia/OFCD syndrome. Molecular testing revealed a novel missense mutation (c.G1619A; p.R540Q) in BCOR. This boy might be the third male patient with a BCOR mutation based on literature search. Previously, Xenopus studies showed that BCOR is required for vertebrate laterality determination. Our finding provides additional support that the manifestations of defective lateral patterning and dextrocardia are associated with Lenz microphthalamia/OFCD syndrome.
Assuntos
Anoftalmia/genética , Catarata/congênito , Defeitos dos Septos Cardíacos/genética , Microftalmia/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Sequência de Aminoácidos , Anoftalmia/diagnóstico , Catarata/diagnóstico , Catarata/genética , Análise Mutacional de DNA , Evolução Fatal , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Defeitos dos Septos Cardíacos/diagnóstico , Humanos , Lactente , Masculino , Microftalmia/diagnóstico , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
In this study, we investigated the protective role of silenced iNOS expression in neuron death in the nigrostriatal pathway in a 6-OHDA animal model of Parkinson's disease (PD). The animal model was established by intrastriatal infusion of a single dose of 6-OHDA. Silencing of iNOS expression was established by intrastriatal infusion of adenovirus-carried iNOS-targeted small interfering RNA (siRNA). Apomorphine-induced rotation behavior was measured. Expression of iNOS, OX-42, and TH; levels of DA, DOPAC, and HVA in the striatum; and the levels of p53 phosphorylation, Bax, and cleaved caspase-3 (CC3) in the substantia nigra were measured. We demonstrated that co-infusion of 6-OHDA with adenovirus expressing siRNA of iNOS blocked the activation of microglia, iNOS transcription, and p53-Bax-CC3 apoptotic cascade as well as significantly blocking 6-OHDA-induced decreases in DA, DOPAC, HVA, and TH levels and effectively decreased rotation number. Our study highlighted the role of iNOS in the neurodegeneration of nigrostriatal dopaminergic neurons in the 6-OHDA animal model of PD and suggested that the microglial activation-iNOS-p53-Bax-CC3 apoptotic pathway plays a key role in the neurodegeneration in the 6-OHDA model.
Assuntos
Óxido Nítrico Sintase Tipo II/genética , Oxidopamina/toxicidade , Transtornos Parkinsonianos/genética , RNA Interferente Pequeno/genética , Adenoviridae/genética , Animais , Antiparkinsonianos/farmacologia , Apomorfina/farmacologia , Apoptose/fisiologia , Linhagem Celular , Corpo Estriado/citologia , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Humanos , Rim/citologia , Macrófagos/citologia , Masculino , Camundongos , Microglia/citologia , Microglia/metabolismo , Atividade Motora/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Wistar , Simpatolíticos/toxicidade , Proteína Supressora de Tumor p53/metabolismoRESUMO
To investigate the involvement of the nucleus accumbens (NAc) in cognitive impairment and the therapeutic effects of brain-derived neurotrophic factor (BDNF) in an animal model of cognitive deficit, we infused BDNF into the NAc of cognitively impaired aged rats. Cognition was evaluated by Morris water maze test. Structural synaptic plasticity was measured by Golgi staining. Brain tissue homogenization was used to measure the changes in signal molecules. Cultured PC-12 cells expressing tyrosine kinase receptor (Trk) B/p75 neurotrophin receptor (p75(NTR)), p75(NTR) or TrkA/p75(NTR) receptors were used for BDNF stimulation assays. Significant decreases in the levels of BDNF, phosphatidylinositol-3-kinase (PI3K) and integrin-linked kinase (ILK) activity, protein kinase B (Akt) Ser47³ phosphorylation, dendritic branching, and density of dendritic spines on medium spiny neurons were observed in the NAc. Importantly, infusion of BDNF restored cognition, synaptic plasticity, and cell signaling. In cultured PC-12 cells, BDNF activated PI3K/Akt signaling through the TrkB receptor, whereas stimulation of ILK/Akt occurred through TrkA/p75(NTR) heteroreceptor. Our study suggested that the decreased BDNF level and its downstream signaling as well as loss of synaptic plasticity in the NAc are associated with cognitive impairments in aged rats. The BDNF-activated PI3K-Akt and ILK-Akt signaling play a key role in structural synaptic plasticity. Our study also suggested that BDNF could be a mechanism-based treatment for dementia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Cognição/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Sinapses/metabolismoRESUMO
OBJECTIVE: To explore the clinical features, diagnosis, treatment and prognosis of endometrial carcinoma in young, middle-aged and elderly women. METHODS: We retrospectively analyzed the clinical data of 82 cases of endometrial carcinoma in young, middle-aged women and 33 cases of endometrial cacinoma in elderly women. RESULTS: The rates of adenocarcinoma in young, middle-aged and elderly groups were 74.4% and 75.5%, respectively. The young,middle-aged and elderly patients with Stage I endometrial cancer were 64.6% and 69.7%, and those with Stage III and IV were 15.9% and 15.2%, respectively. The histological Grade 1 carcinoma of endometrium in young,middle-aged and elderly women were 70.7% and 60.6%, respectively. The young, middle-aged women without myometrial invasion were more than the elderly women (42.8% vs 15.6%, P < 0.01). The young, middle-aged women with myometrial invasion more than half of myometrial wall were less than the elderly women (10.4% vs 40.6%, P < 0.01). The rate of chemical treatment after the surgery in the elderly women was more than that of the young, middle-aged women (P < 0.05). The 5-year survival rate of the young, middle-aged women was obviously higher than that of the elderly women (92.79% vs 72.21%, P < 0.05). CONCLUSION: Adenocarcinoma and well-differentiated cells are the main pathological characteristics of endometrial carcinoma both in the young, middle-aged and the elderly women. Most young, middle-aged and el-derly patients can be diagnosed and treated in the early stage. Early diagnosis and reasonable treatment can improve the prognosis. The prognosis of the young, middle-aged patients is obviously better than that of the elderly patients, and the myometrial invasion depth may be the main difference.
