RESUMEN
PURPOSE: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. METHODS: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. RESULTS: We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual. CONCLUSION: These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.
Asunto(s)
Encéfalo/metabolismo , Reparación de la Incompatibilidad de ADN/genética , Exoma/genética , Enfermedades Genéticas Congénitas/genética , Encéfalo/patología , Enfermedades Genéticas Congénitas/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.
Asunto(s)
Proteínas de Unión al ADN/genética , Salud de la Familia , Pérdida Auditiva/genética , Proteínas Mitocondriales/genética , Mutación/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Complejo II de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Pérdida Auditiva/complicaciones , Heterocigoto , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Músculo Esquelético/ultraestructura , Adulto JovenRESUMEN
Keratosis obturans (KO) and external auditory canal cholesteatoma (EACC) are two distinct keratinaceous lesions of the external ear. This article reviews the signs, symptoms, pathophysiology, workup, and treatment of each. Patients with either pathology can often be managed in the clinic with debridement; however, EACC is more likely to involve osteonecrosis and require more extensive operative management if disease is not confined to the canal on account of the bony erosion characteristic of cholesteatoma. If required for extensive disease, surgical approaches to both pathologies are similar.
Asunto(s)
Colesteatoma , Enfermedades del Oído , Queratosis , Humanos , Conducto Auditivo Externo/diagnóstico por imagen , Conducto Auditivo Externo/cirugía , Enfermedades del Oído/diagnóstico , Enfermedades del Oído/cirugía , Colesteatoma/diagnóstico , Colesteatoma/cirugía , Queratosis/diagnóstico , Queratosis/patología , Queratosis/cirugía , Estudios RetrospectivosRESUMEN
We present the first case of a head and neck oncological procedure accomplished in a Jehovah's Witness using the Ultracision Harmonic Scalpel (Ethicon, Cincinnati, OH). Jehovah's Witnesses present a serious challenge to the head and neck cancer surgeon due to their refusal to accept transfusion of any blood products. However, our experience reinforces the view that surgical management of head and neck cancer is possible in these patients. We show the Harmonic Scalpel, an ultrasonic tissue dissector, to be a useful surgical tool in obviating the need for blood transfusion. Preoperative optimisation, intra-operative surgical and anaesthetic techniques are also fully discussed.
Asunto(s)
Pérdida de Sangre Quirúrgica/prevención & control , Carcinoma de Células Escamosas/cirugía , Testigos de Jehová , Neoplasias de la Boca/cirugía , Instrumentos Quirúrgicos , Transfusión Sanguínea , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Boca/patología , Cuidados Preoperatorios , Colgajos Quirúrgicos , Resultado del TratamientoRESUMEN
Endovascular stenting has been successfully employed in the management of aortic aneurysms; however, its use in managing peripheral arterial conditions remains questionable. We review the utility of endovascular technique in the management of peripheral arterial conditions like aneurysms, pseudoaneurysms and arterio-venous fistulas in the emergency setting. Though long term data about graft patency rates is not yet available, the endovascular approach appears to be a useful minimally invasive technique in situations where open repair is either difficult or not feasible.