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1.
Hum Mol Genet ; 25(21): 4787-4803, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28173139

RESUMEN

ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harboring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells. The mechanisms that underlie selective neuronal vulnerability and neurodegeneration in the central nervous system upon Atrx mutation or deletion are unknown. To interrogate the cellular specificity of Atrx for its retinal neuroprotective functions, we employed a combination of temporal and lineage-restricted conditional ablation strategies to generate five different conditional knockout mouse models, and subsequently identified a non-cell-autonomous requirement for Atrx in bipolar cells for inhibitory interneuron survival in the retina. Atrx-deficient retinal bipolar cells exhibit functional, structural and molecular alterations consistent with impairments in neuronal activity and connectivity. Gene expression changes in the Atrx-null retina indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of ATRX in the forebrain and retina may contribute to similar neuropathological processes underlying cognitive impairment and visual dysfunction in ATR-X syndrome.


Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Talasemia alfa/genética , Animales , Cromatina , Modelos Animales de Enfermedad , Interneuronas/metabolismo , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Proteínas Nucleares/genética , Retina/metabolismo , Células Bipolares de la Retina/metabolismo , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Talasemia alfa/metabolismo
2.
J ISAKOS ; 8(5): 318-324, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37127091

RESUMEN

OBJECTIVES: To determine whether magnetic resonance imaging (MRI) with metal artifact reduction sequencing is superior to conventional knee MRI in the evaluation of an injured anterior cruciate ligament (ACL) graft, where visualisation on conventional MRI can be limited by the metal artifact from fixation devices. METHODS: Eighteen patients underwent conventional MRI sequence (proton density fat saturated [PDFS]) and two types of metal artifact reduction sequencing MRI (WARP, slice encoding for metal artifact correction (SEMAC); Siemens) following a secondary injury to their ACL reconstructed knee. Six raters with experience in knee MRI evaluation reviewed sagittal PDFS, WARP, and SEMAC sequences, providing semi-quantitative grades for visualisation and diagnostic confidence assessing the ACL, posterior cruciate ligament , menisci, tibial and femoral tunnel margins, and articular cartilage. Intra-class correlation coefficients for inter-rater reliability were evaluated. The 6-rater mean scores for the visualisation and diagnostic confidence derived from each sequence were compared using the Friedman test for multiple paired samples. RESULTS: No statistically significant difference in the ACL visualisation among the sequences was found (p â€‹= â€‹0.193). Further, a subgroup analysis was performed in cases evaluated as "moderately blurry" or "indistinct ACL visualisation" on PDFS (58% of cases). SEMAC significantly improved diagnostic confidence in ACL visualisation (p â€‹= â€‹0.041) and ACL graft rupture (p â€‹= â€‹0.044) compared to PDFS. There was no statistically significant difference in the inter-observer reliability between sequences. The WARP sequence added 2.84 â€‹± â€‹0.69 â€‹min, while SEMAC added 2.95 â€‹± â€‹0.40 â€‹min to the standard knee MRI scan time. CONCLUSION: use of the SEMAC metal reduction sequence significantly improved diagnostic accuracy and confidence in the detection of ACL graft rupture in cases where the ACL was moderately blurry or indistinct on the PDFS sequence. This sequence should be considered as an adjunct to conventional PDFS in cases where graft visualisation is limited by the metal artifact from fixation devices. LEVEL OF EVIDENCE: III.


Asunto(s)
Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Humanos , Artefactos , Reproducibilidad de los Resultados , Articulación de la Rodilla/cirugía , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/diagnóstico , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/métodos
3.
Neuroscience ; 452: 169-180, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33197500

RESUMEN

Mutation of the α-thalassemia/mental retardation syndrome X-linked protein, ATRX, causes intellectual disability and is associated with pleiotropic defects including ophthalmological abnormalities. We have previously demonstrated that Atrx deficiency in the mouse retina leads to the selective loss of inhibitory interneurons and inner retinal dysfunction. Onset of the amacrine cell neurodegenerative phenotype in Atrx-deficient retinas occurs postnatally after neuronal specification, and coincides with eye opening. Given this timing, we sought to interrogate the influence of light-dependent visual signaling on Atrx-mediated neuronal survival and function in the mouse retina. Retina-specific Atrx conditional knockout (cKO) mice were subjected to light deprivation using two different paradigms: (1) a dark-rearing regime, and (2) genetic deficiency of metabotropic glutamate receptor 6 (mGluR6) to block the ON retinal signaling pathway. Scotopic electroretinography was performed for adult dark-reared Atrx cKO mice and controls to measure retinal neuron function in vivo. Retinal immunohistochemistry and enumeration of amacrine cells were performed for both light deprivation paradigms. We observed milder normalized a-wave, b-wave and oscillatory potential (OP) deficits in electroretinograms of dark-reared Atrx cKO mice compared to light-exposed counterparts. In addition, amacrine cell loss was partially limited by genetic restriction of retinal signaling through the ON pathway. Our results suggest that the temporal features of the Atrx cKO phenotype are likely due to a combined effect of light exposure upon eye opening and coincident developmental processes impacting the retinal circuitry. In addition, this study reveals a novel activity-dependent role for Atrx in mediating post-replicative neuronal integrity in the CNS.


Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X , Proteína Nuclear Ligada al Cromosoma X , Talasemia alfa , Animales , Ratones , Ratones Endogámicos C57BL , Retina , Proteína Nuclear Ligada al Cromosoma X/genética
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