RESUMEN
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
Asunto(s)
Parálisis Cerebral/genética , Proteínas F-Box/genética , Tubulina (Proteína)/genética , Proteínas Supresoras de Tumor/genética , beta Catenina/genética , Animales , Parálisis Cerebral/patología , Ciclina D/genética , Citoesqueleto/genética , Drosophila/genética , Exoma/genética , Matriz Extracelular/genética , Femenino , Adhesiones Focales/genética , Predisposición Genética a la Enfermedad , Genoma Humano/genética , Humanos , Masculino , Mutación/genética , Neuritas/metabolismo , Neuritas/patología , Factores de Riesgo , Análisis de Secuencia de ADN , Transducción de Señal/genética , Secuenciación del Exoma , Proteína de Unión al GTP rhoB/genéticaRESUMEN
This article is a case report of the successful interdisciplinary management of a maxillary lateral incisor with a deep palatogingival groove. The tooth presented with severe periodontal destruction owing to the deep extension of the groove up to the root apex. The groove was meticulously diagnosed and treated by endodontic and subsequent periodontal surgery leading to complete resolution of the pathological process.
Asunto(s)
Compuestos de Aluminio/uso terapéutico , Sustitutos de Huesos/uso terapéutico , Compuestos de Calcio/uso terapéutico , Incisivo/anomalías , Óxidos/uso terapéutico , Grupo de Atención al Paciente , Silicatos/uso terapéutico , Raíz del Diente/anomalías , Adulto , Necrosis de la Pulpa Dental/terapia , Combinación de Medicamentos , Estudios de Seguimiento , Cementos de Ionómero Vítreo/uso terapéutico , Humanos , Masculino , Planificación de Atención al Paciente , Periodontitis Periapical/terapia , Bolsa Periodontal/terapia , Preparación del Conducto Radicular/métodos , Colgajos Quirúrgicos/cirugíaRESUMEN
Idiopathic ventricular tachycardia is a defined set of tachycardias when structural or pathological cause has been ruled out for the same. This paper tries to define and classify these arrhythmias to organize a logical therapeutic approach to deal with them. 60-80% of the idiopathic tachycardias originate from the right ventricular outflow tract (RVOT) and in 10% from the left ventricular outflow tract (LVOT). Outflow tract tachycardias have either LBBB or RBBB morphology with early R wave transition in chest leads. Adenosine, beta blockers and calcium channel blockers is the common medical treatment. Radiofrequency ablation is however the treatment of choice. Verapamil sensitive left ventricular tachycardia (ILVT) and propranolol sensitive left ventricular tachycardia (IPVT) are the other two forms recognized. RF ablation seems ideal for long-term management of ILVT and implantable cardioverter defibrillator (ICD) for IPVT. Inherited channelopathies include catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome and long QT syndrome where there is an inherited disorder in the ion-exchange channels of the cell-membrane leading to tachycardia. Prognosis in these is variable; CPVT, in particular, has a malignant course when untreated. RF ablation and placement of an ICD are important in the overall management of specific arrhythmia.
Asunto(s)
Taquicardia Ventricular , Adenosina/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Ablación por Catéter , Desfibriladores Implantables , Electrocardiografía , Humanos , Pronóstico , Taquicardia Ventricular/clasificación , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiología , Taquicardia Ventricular/terapiaRESUMEN
Rhabdomyosarcoma (RMS) cell lines were transduced with an adenoviral vector containing the wild-type p53 (wtp53) cDNA (Ad-p53) and then exposed to four cytotoxic agents: actinomycin D, vincristine, 5-fluorouracil and bleomycin. Potentiation of cytotoxicity following wild-type p53 expression varied from 0- to 20-fold for different drugs and between cell lines. It appeared that alveolar RMS cells (n = 2) were more susceptible to p53-mediated chemosensitization than embryonal RMS cells (n = 3), although this was independent of pax3-FKHR expression. Overall, cells that were most chemosensitive prior to Ad-p53 exposure were those that were most susceptible to p53 potentiation of cytotoxicity. The different results obtained with these RMS cell lines does not appear to be related to expression of pax3-FKHR, p21, Bax or Bcl-2 but may in part be due to differential regulation of p53 target genes, such as MDM2. In conclusion, exogenous wild-type expression selectively chemosensitizes RMS cells to cytotoxic agents. However, expression of transcriptionally active wtp53 does not predict a chemosensitive phenotype.