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Gene regulation in embryonic stem cells (ESCs) has been extensively studied at the epigenetic-transcriptional level, but not at the posttranscriptional level. Pumilio (Pum) proteins are among the few known translational regulators required for stem-cell maintenance in invertebrates and plants. Here we report the essential function of two murine Pum proteins, Pum1 and Pum2, in ESCs and early embryogenesis. Pum1/2 double-mutant ESCs display severely reduced self-renewal and differentiation, and Pum1/2 double-mutant mice are developmentally delayed at the morula stage and lethal by embryonic day 8.5. Remarkably, Pum1-deficient ESCs show increased expression of pluripotency genes but not differentiation genes, whereas Pum2-deficient ESCs show decreased pluripotency markers and accelerated differentiation. Thus, despite their high homology and overlapping target messenger RNAs (mRNAs), Pum1 promotes differentiation while Pum2 promotes self-renewal in ESCs. Pum1 and Pum2 achieve these two complementary aspects of pluripotency by forming a negative interregulatory feedback loop that directly regulates at least 1,486 mRNAs. Pum1 and Pum2 regulate target mRNAs not only by repressing translation, but also by promoting translation and enhancing or reducing mRNA stability of different target mRNAs. Together, these findings reveal distinct roles of individual mammalian Pum proteins in ESCs and their essential functions in ESC pluripotency and embryogenesis.
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Desarrollo Embrionario/genética , Proteínas de Unión al ARN/genética , Animales , Diferenciación Celular/genética , Autorrenovación de las Células/genética , Regulación de la Expresión Génica , Mamíferos , Ratones , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Estabilidad del ARN/genética , ARN Mensajero/genéticaRESUMEN
PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment. RESULTS: There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged. CONCLUSION: BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.
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Antineoplásicos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Hidroxicloroquina/efectos adversos , Imidazoles/efectos adversos , Mácula Lútea/patología , Melanoma/tratamiento farmacológico , Oximas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Enfermedades de la Retina , Adulto , Anciano , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Imidazoles/uso terapéutico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Masculino , Melanoma/genética , Persona de Mediana Edad , Oximas/uso terapéutico , Células Fotorreceptoras/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Enfermedades de la Retina/inducido químicamente , Enfermedades de la Retina/patología , Epitelio Pigmentado de la Retina/patologíaAsunto(s)
Inmunosupresores/uso terapéutico , Oclusión de la Arteria Retiniana/diagnóstico , Síndrome de Susac/complicaciones , Anciano , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Oclusión de la Arteria Retiniana/tratamiento farmacológico , Oclusión de la Arteria Retiniana/etiología , Síndrome de Susac/diagnóstico , Síndrome de Susac/tratamiento farmacológico , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: To describe in detail the retinal phenotype of LAMP2-associated Danon disease. METHODS: Three LAMP2-positive patients from two unrelated families were studied with spectral-domain optical coherence tomography and with short-wavelength and near-infrared fundus autofluorescence (FAF) imaging. Visual function was measured with full-field electroretinography and chromatic perimetry. A patient with choroideremia was also studied for comparison. RESULTS: A 45-year-old LAMP2-heterozygous woman, her 21-year-old hemizygous son, and an unrelated heterozygous 60-year-old woman had normal visual acuities. Central spectral-domain optical coherence tomographies were grossly normal in the younger two patients (mother and son). The oldest patient showed a tenuous interdigitation signal, interruptions of the inner segment ellipsoid zone band, and parafoveal outer nuclear layer thinning. Quantitatively, all patients had shorter than normal ellipsoid zone to retinal pigment epithelium distance in pericentral retina, normal at the foveola. A speckled hypoautofluorescence pattern on short-wavelength FAF contrasted with grossly abnormal near-infrared FAF in the heterozygous carriers. The oldest patient had reduced full-field electroretinography amplitudes (to â¼50% of normal) for rod- and cone-mediated responses and her perimetry showed severe rod dysfunction but substantial cone function. A disproportionate loss of the near-infrared FAF compared with the short-wavelength FAF, predominantly outer segment changes, and severe rod dysfunction with preserved cone function was similarly documented in a 9-year-old choroideremia hemizygous patient. CONCLUSION: A disproportionate loss of the near-infrared FAF signal compared with the short-wavelength FAF signal, outer segment abnormalities, and severe rod dysfunction but relatively preserved cone vision suggests a stereotypical pattern of primary retinal pigment epithelial or parallel retinal pigment epithelial + photoreceptor disease in Danon disease.
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Coroideremia , Enfermedad por Depósito de Glucógeno de Tipo IIb , Degeneración Retiniana , Femenino , Humanos , Epitelio Pigmentado de la Retina , Coroideremia/complicaciones , Coroideremia/diagnóstico , Coroideremia/genética , Agudeza Visual , Electrorretinografía , Tomografía de Coherencia Óptica/métodos , Pigmentos Retinianos , Angiografía con FluoresceínaRESUMEN
PURPOSE: To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 (CEP290-LCA) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition. METHODS: This is a retrospective review of records of five patients with CEP290-LCA. Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths. RESULTS: All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals. CONCLUSIONS: We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.
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Amaurosis Congénita de Leber , Humanos , Amaurosis Congénita de Leber/diagnóstico , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/patología , Retina , Cemento de Fosfato de Zinc , Epitelio Pigmentado de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Mutación , Antígenos de Neoplasias/genética , Proteínas del Citoesqueleto/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
PURPOSE: To describe in detail the phenotype of a patient with enhanced S-cone syndrome. METHODS: We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory to steroid treatment, and a negative uveitic workup. The patient underwent a complete ophthalmic examination, full-field electroretinograms (ffERG), automatic static perimetry and multimodal imaging with spectral domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy (AOSLO). RESULTS: Spectral domain optical coherence tomography demonstrated cystoid macular edema and a hyperthick, delaminated midperipheral retina. Fluorescein angiography did not demonstrate macular leakage. Rod-mediated ffERGs were undetectable, and there was a supernormal response to short-wavelength stimuli compared with photopically matched longer wavelengths of light consistent with enhanced S-cone syndrome. Gene screening was positive for compound heterozygous mutations NR2E3: a known (c.119-2 A>C) and a novel (c.119-1G>A) mutation. By perimetry, sensitivities were normal or above normal for short-wavelength stimuli; there was no detectable rod-mediated vision. AOSLO demonstrated higher than normal cone densities in the perifoveal retina and evidence for smaller outer segment cone diameters. CONCLUSION: Evidence for supernumerary cones (at least twice the normal complement) by AOSLO and spectral domain optical coherence tomography was associated with supernormal S-cone sensitivities and electroretinogram responses confirming previous in vivo findings in postmortem human specimens. Smaller than normal cones in enhanced S-cone syndrome may represent "hybrid" photoreceptors analogous to the rd7/rd7 murine model of the disease.
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Enfermedades Hereditarias del Ojo , Degeneración Retiniana , Trastornos de la Visión , Adolescente , Enfermedades Hereditarias del Ojo/diagnóstico por imagen , Enfermedades Hereditarias del Ojo/fisiopatología , Humanos , Masculino , Degeneración Retiniana/diagnóstico por imagen , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/fisiopatologíaRESUMEN
Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells (RGCs). Recent studies have implicated pro-inflammatory microglia, macrophages, and A1 astrocytes in the pathogenesis of neurodegenerative diseases. The role of pro-inflammatory, neurotoxic A1 astrocytes in glaucoma is just beginning to be explored. Using a mouse model of glaucoma, we demonstrate that ocular hypertension is sufficient to trigger production of C1q, interleukin-1α (IL-1α), and tumor necrosis factor α (TNF-α), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulation of these cytokines occurs first in CD11b+ CD11c+ cells followed by CD11b+ CD11c- cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduces A1 astrocyte transformation and RGC death. Together, these results highlight a neuroinflammatory mechanism of glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.
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Receptor del Péptido 1 Similar al Glucagón/agonistas , Inflamación/patología , Hipertensión Ocular/complicaciones , Neuronas Retinianas/patología , Animales , Astrocitos/patología , Antígeno CD11b/metabolismo , Muerte Celular , Complemento C1q/metabolismo , Femenino , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Interleucina-1alfa/metabolismo , Presión Intraocular , Masculino , Ratones Endogámicos C57BL , Hipertensión Ocular/fisiopatología , Células Ganglionares de la Retina/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Purpose: To determine the therapeutic window for gene augmentation for Leber congenital amaurosis (LCA) associated with mutations in LCA5. Methods: Five patients (ages 6-31) with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5gt/gt mouse model and the efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal day 5 (P5) (early, n = 11 eyes), P15 (mid, n = 14), and P30 (late, n = 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease. Results: Patients with LCA5-LCA showed a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted sensitivity loss. The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became nondetectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue. Conclusions: LCA5-LCA is a particularly severe form of LCA that was recapitulated in the Lca5gt/gt mouse. Gene augmentation resulted in structural and functional rescue in the Lca5gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all patients with LCA5-LCA, at a level equivalent to that observed in rescued Lca5gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA.
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Dependovirus/genética , Proteínas del Ojo/genética , Terapia Genética , Amaurosis Congénita de Leber/terapia , Proteínas Asociadas a Microtúbulos/genética , Retina/fisiopatología , Adulto , Animales , Niño , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Terapia Genética/métodos , Vectores Genéticos , Humanos , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Imagen Óptica , Fenotipo , Pupila/fisiología , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Pruebas del Campo Visual , Campos Visuales/fisiología , Adulto JovenRESUMEN
Achromatopsia is an inherited retinal degeneration characterized by the loss of cone photoreceptor function. In this issue of the JCI, Moshiri et al. characterize a naturally occurring model of the disease in the rhesus macaque caused by homozygous mutations in the phototransduction enzyme PDE6C. Using retinal imaging, and electrophysiologic and biochemical methods, the authors report a clinical phenotype nearly identical to the human condition. These findings represent the first genetic nonhuman primate model of an inherited retinal disease, and provide an ideal testing ground for the development of novel gene replacement, gene editing, and cell replacement therapies for cone dystrophies.
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Defectos de la Visión Cromática , Animales , Humanos , Luz , Macaca mulatta , Retina , Células Fotorreceptoras Retinianas ConosRESUMEN
Importance: Novel oral anticoagulation and antiplatelet therapies have become a mainstay of treatment for thromboembolic disease. However, the safety profile of these medications has not been completely characterized. Objective: To determine the risk of developing intraocular hemorrhages with novel oral antithrombotic therapy compared with that of traditional antithrombotic agents. Design, Setting, and Participants: In this retrospective cohort study, a large national insurance claims database was used to generate 2 parallel analyses. All patients with incident use of dabigatran etexilate or rivaroxaban between January 1, 2010, and September 30, 2015, were compared with patients with incident use of warfarin sodium. Similarly, patients with new use of prasugrel hydrochloride were compared with those with new use of clopidogrel bisulfate. Both analyses required the patient to be in the insurance plan for at least 24 months prior to initiation of therapy and excluded patients with any previous diagnosis of intraocular hemorrhages or any prescription for the comparator medications. Furthermore, the antiplatelet analysis required a diagnosis of acute coronary syndrome or a myocardial infarction within 60 days of initiation of pharmacologic therapy. The anticoagulant analysis excluded patients with end-stage renal disease, renal transplants, and those with heart valve disease. Main Outcomes and Measures: Incident intraocular hemorrhages at 90 and 365 days. Multivariate Cox proportional hazards regression models were used to compare the hazard ratio (HR) of developing an intraocular hemorrhage in individuals taking novel agents compared with those taking traditional medications. Results: A total of 146â¯137 patients taking warfarin (76â¯714 women and 69â¯423 men; mean [SD] age, 69.8 [11.8] years) were compared with 64â¯291 patients taking dabigatran or rivaroxaban (31â¯576 women and 32â¯715 men; mean [SD] age, 67.6 [11.7] years). Cox proportional hazards regression revealed a decreased hazard for developing an intraocular hemorrhage with dabigatran or rivaroxaban at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03), but not at 90 days (HR, 0.73; 95% CI, 0.22-2.63; P = .13). A total of 103â¯796 patients taking clopidogrel (37â¯578 women and 66â¯218 men; mean [SD] age, 68.0 [11.3] years) were compared with 8386 patients taking prasugrel (1988 women and 6380 men; mean [SD] age, 61.0 [9.6] years) and no increased hazard for developing an intraocular hemorrhage with prasugrel was seen at 90 days (HR, 0.75; 95% CI, 0.29-1.92; P = .55) or 365 days (HR, 1.19; 95% CI, 0.69-2.04; P = .53). Conclusions and Relevance: These results suggest a decreased risk of intraocular hemorrhage associated with novel direct thrombin inhibitors and direct factor Xa inhibitors, but no difference for P2Y12 inhibitors compared with traditional vitamin K anticoagulation and antiplatelet therapy, respectively.
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Dabigatrán/efectos adversos , Hemorragia del Ojo/inducido químicamente , Medición de Riesgo/métodos , Rivaroxabán/efectos adversos , Tromboembolia/prevención & control , Warfarina/efectos adversos , Administración Oral , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Antitrombinas/administración & dosificación , Antitrombinas/efectos adversos , Relación Dosis-Respuesta a Droga , Hemorragia del Ojo/epidemiología , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Pennsylvania/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Warfarina/administración & dosificaciónRESUMEN
PURPOSE: To describe early structural and functional retinal changes in a patient with Cohen syndrome. METHODS: A 13-month-old Caucasian girl of Irish and Spanish ancestry was noted to have micrognathia and laryngomalacia at birth, which prompted a genetic evaluation that revealed biallelic deletions in COH1 (VPS13B) (a maternally inherited 60-kb deletion involving exons 26-32 and a paternally inherited 3.5-kb deletion within exon 17) consistent with Cohen syndrome. She underwent a complete ophthalmic examination, full-field flash electroretinography and retinal imaging with spectral domain optical coherence tomography. RESULTS: Central vision was central, steady, and maintained. There was bilateral myopic astigmatic refractive error. Fundus exam was notable for dark foveolar pigmentation, but no obvious abnormalities of either eye. Spectral domain optical coherence tomography cross sections through the fovea revealed a normal appearing photoreceptor outer nuclear layer but loss of the interdigitation signal between the photoreceptor outer segments and the apical retinal pigment epithelium. Retinoschisis involving the inner nuclear layer of both eyes and possible ganglion cell layer thinning were also noted. There was a detectable electroretinogram with similarly reduced amplitudes of rod- (white, 0.01 cd.s.m-2) and cone-mediated (3 cd.s.m-2, 30 Hz) responses. CONCLUSION: Photoreceptor outer segment abnormalities and retinoschisis may represent the earliest structural retinal change detected by spectral domain optical coherence tomography in patients with Cohen syndrome, suggesting a complex pathophysiology with primary involvement of the photoreceptor cilium and disorganization of the structural integrity of the inner retina.
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Dedos/anomalías , Eliminación de Gen , Discapacidad Intelectual/patología , Microcefalia/patología , Hipotonía Muscular/patología , Miopía/patología , Obesidad/patología , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/patología , Retinosquisis/patología , Proteínas de Transporte Vesicular/genética , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Femenino , Dedos/patología , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Microcefalia/complicaciones , Microcefalia/genética , Hipotonía Muscular/complicaciones , Hipotonía Muscular/genética , Miopía/complicaciones , Miopía/genética , Obesidad/complicaciones , Obesidad/genética , Pronóstico , Células Fotorreceptoras Retinianas Conos/metabolismo , Degeneración Retiniana/complicaciones , Degeneración Retiniana/genética , Retinosquisis/complicaciones , Retinosquisis/genéticaRESUMEN
Purpose: To describe the retinal phenotype of pediatric patients with mutations in the retinol dehydrogenase 12 (RDH12) gene. Methods: Twenty-one patients from 14 families (ages 2-17 years) with RDH12-associated inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted chromatic full-field stimulus testing (FST) and transient pupillometry. Results: Visual acuity ranged from 20/40 to light perception. There was parafoveal depigmentation or atrophic maculopathies accompanied by midperipheral intraretinal pigment migration. SD-OCT revealed foveal thinning in all patients and detectable but thinned outer nuclear layer (ONL) at greater eccentricities from the fovea. Photoreceptor outer segment (POS) signals were only detectable in small pockets within the central retina. Measurable kinetic visual fields were limited to small (<5-10°) central islands of vision. Electroretinograms were reported as undetectable or severely reduced in amplitude. FST sensitivities to a 467 nm stimulus were rod-mediated and reduced on average by â¼2.5 log units. A thinned central ONL colocalized with severely reduced to nondetectable cone-mediated sensitivities. Pupillometry confirmed the psychophysically measured abnormalities. Conclusions: RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. Severely abnormal POS but detectable ONL in the pericentral and peripapillary retina suggest these regions may become targets for gene therapy.
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Oxidorreductasas de Alcohol/genética , Mutación , Degeneración Retiniana/genética , Células Fotorreceptoras Retinianas Bastones/fisiología , Adolescente , Niño , Preescolar , Adaptación a la Oscuridad , Electrorretinografía , Femenino , Humanos , Masculino , Fenotipo , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Pruebas del Campo Visual , Campos Visuales/fisiologíaRESUMEN
The authors describe a case of presumed endogenous fungal endophthalmitis in an immunocompetent pediatric patient with acute lymphoblastic leukemia. A 15-year-old boy with a history of high-risk B-cell acute lymphoblastic leukemia status post-chemotherapy presented with acute changes in vision in his left eye. Fundus examination revealed a white bi-lobed chorioretinal lesion with overlying vitritis and associated subretinal fluid. Magnetic resonance imaging of the brain revealed small ring-enhancing lesions in the right parietal and left occipital lobes. Blood, cerebrospinal fluid, aqueous, and vitreous cultures were all negative. Bone marrow and vitreous cytology were negative for malignant cells. The patient was treated for presumed fungal endophthalmitis with systemic and intravitreal voriconazole, followed by pars plana vitrectomy with intravitreal voriconazole and amphotericin B injections. The chorioretinal lesion resolved and visual acuity recovered to 20/20. Chorioretinal infiltrates in a patient with leukemia may require treatment even in the absence of a definitive diagnostic test result. Intervention should be guided by risk analysis and clinical judgment. [J Pediatr Ophthalmol Strabismus. 2017;54:e42-e46.].
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Endoftalmitis/terapia , Infecciones Fúngicas del Ojo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Vitrectomía/métodos , Voriconazol/administración & dosificación , Adolescente , Antifúngicos/administración & dosificación , Biopsia , Endoftalmitis/diagnóstico , Endoftalmitis/microbiología , Infecciones Fúngicas del Ojo/diagnóstico , Infecciones Fúngicas del Ojo/microbiología , Humanos , Inyecciones Intravítreas , Imagen por Resonancia Magnética , Masculino , Agudeza VisualRESUMEN
Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the "POAGome." We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-ß signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-ß signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.
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Biología Computacional/métodos , Glaucoma de Ángulo Abierto , Presión Intraocular/fisiología , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Células Ganglionares de la Retina/patologíaAsunto(s)
Sistemas CRISPR-Cas , Química , Premio Nobel , Animales , Historia del Siglo XXI , HumanosRESUMEN
We previously demonstrated that the Kaposi's sarcoma-associated herpesvirus polyadenylated nuclear RNA contains a 79-nt cis-acting element, the ENE, which allows intronless polyadenylated transcripts to accumulate to high nuclear levels by protecting them from rapid degradation. We proposed a model based on the predicted structure of the ENE in which a U-rich internal loop hybridizes with the 3'-polyadenylate (polyA) tail to sequester it from exonucleolytic attack. We have tested this model by mutational analysis of the ENE. Point mutations in the predicted U-rich internal loop and in the flanking stems abolish the ENE's ability to (i) interact with the polyA tail, (ii) inhibit deadenylation in vitro, and (iii) stabilize transcripts in vivo. In all but one case, compensatory mutations in the flanking stems restore ENE activities, demonstrating the importance of these stems and uncovering a unique role for the loop-proximal G-C base pair in the lower stem. Increasing the U content of the U-rich internal loop surprisingly decreases stability in vivo but does not affect deadenylation in vitro, comparable to the effects of deleting certain "unstructured" regions of the ENE. Taken together, our data support the formation of the proposed ENE secondary structure in vivo and argue that the specific ENE structure inhibits rapid RNA decay in cis by engaging in a limited set of base-pairing interactions with the polyA tail.