RESUMO
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.
Assuntos
Paralisia Cerebral/genética , Proteínas F-Box/genética , Tubulina (Proteína)/genética , Proteínas Supressoras de Tumor/genética , beta Catenina/genética , Animais , Paralisia Cerebral/patologia , Ciclina D/genética , Citoesqueleto/genética , Drosophila/genética , Exoma/genética , Matriz Extracelular/genética , Feminino , Adesões Focais/genética , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Mutação/genética , Neuritos/metabolismo , Neuritos/patologia , Fatores de Risco , Análise de Sequência de DNA , Transdução de Sinais/genética , Sequenciamento do Exoma , Proteína rhoB de Ligação ao GTP/genéticaRESUMO
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.
Assuntos
Compostos de Alumínio/uso terapêutico , Substitutos Ósseos/uso terapêutico , Compostos de Cálcio/uso terapêutico , Incisivo/anormalidades , Óxidos/uso terapêutico , Equipe de Assistência ao Paciente , Silicatos/uso terapêutico , Raiz Dentária/anormalidades , Adulto , Necrose da Polpa Dentária/terapia , Combinação de Medicamentos , Seguimentos , Cimentos de Ionômeros de Vidro/uso terapêutico , Humanos , Masculino , Planejamento de Assistência ao Paciente , Periodontite Periapical/terapia , Bolsa Periodontal/terapia , Preparo de Canal Radicular/métodos , Retalhos Cirúrgicos/cirurgiaRESUMO
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.
Assuntos
Taquicardia Ventricular , Adenosina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ablação por Cateter , Desfibriladores Implantáveis , Eletrocardiografia , Humanos , Prognóstico , Taquicardia Ventricular/classificação , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/terapiaRESUMO
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.