Prevalência e fatores associados à sintomatologia depressiva em idosos residentes no Nordeste do Brasil

OBJETIVO: Analisar a influência de fatores sociodemográficos, de saúde física, capacidade funcional e função cognitiva sobre a sintomatologia depressiva de idosos do município de Santa Cruz, no Rio Grande do Norte. MÉTODOS: Estudo com delineamento transversal de base populacional, incluindo 310 idosos, acima de 60 anos, residentes na zona urbana da cidade, nos quais se aplicou a Escala de Depressão Geriátrica (GDS-15).Aanálise estatística foi realizada com nível de significância p = 0,05, com cálculo da respectiva odds ratio (OR) na regressão logística binária. RESULTADOS: Encontrou-se uma prevalência de 25,5% de sujeitos considerados casos de depressão, nos quais, a partir de análise multivariada, verificou-se associação significativa com idade acima de 75 anos (p = 0,046), analfabetismo (p = 0,037), má percepção de saúde (p < 0,001) e dependência para atividades instrumentais da vida diária (AIVD) (p = 0,001). CONCLUSÕES: As variáveis idade acima de 75 anos, analfabetismo, má percepção de saúde e dependência para AIVD estiveram associadas de forma independente à presença de sintomatologia depressiva nos idosos da nossa população. Os autores discutem que a identificação de fatores que influenciam o surgimento de sintomas depressivos em idosos constitui passo fundamental para o planejamento das ações que visem reduzir os efeitos dessa enfermidade na qualidade de vida dessas pessoas.

Redefining the MED13L syndrome

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.

Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3'-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-d pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

Searching for therapeutic strategies in a mouse modelo of Machado-Joseph disease: targeting proteostases

Tese de Doutoramento em Ciências da Saúde

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.

Cardiomiopatia hipertrófica tratada por técnica intervencionista de redução septal

Mulher de 75 anos com cardiomiopatia hipertrófica obstrutiva, com dispnéia classe IV, refratária ao tratamento clínico, apresentava contra-indicações relativas para abordagens cirúrgica e de implante de marcapasso. Realizou-se procedimento intervencionista para injeção seletiva de álcool absoluto no 1º ramo septal da artéria interventricular anterior. O infarto septal provocado acompanhou-se de liberação enzimática, elevação de ST e bloqueio de ramo direito do feixe de His. Não houve complicações inesperadas, e o gradiente da via ejetiva de ventrículo esquerdo, de 66mmHg, foi imediatamente abolido. Controle ecocardiográfico evidencia manutenção desse resultado, até o momento, dois meses após o procedimento, em correspondência a marcante alívio sintomático.

Pre-clinical trials for Machado-Joseph Disease: Hypothesis-based and hypothesis-free therapeutic approaches

Tese de Doutoramento em Ciências da Saúde

Intra-His bundle block: clinical, electrocardiographic, and electrophysiologic characteristics

OBJECTIVE: To assess the clinical, electrocardiographic, and electrophysiologic characteristics of patients (pt) with intra-His bundle block undergoing an electrophysiologic study (EPS). METHODS: We analyzed the characteristics of 16 pt with second-degree atrioventricular block and symptoms of syncope or dyspnea, or both, undergoing conventional EPS. RESULTS: Intra-His bundle block was documented in 16 pt during an EPS. In 15 (94%) pt, the atrioventricular block was recorded in sinus rhythm; 4 (25%) pt had intra-His Wenckebach phenomenon, which correlated with Mobitz I (MI) atrioventricular block on the electrocardiogram. Seven (44%) pt had 2:1 atrioventricular block, 2 of whom were asymptomatic (12.5%). One (6%) pt had intra- and infra-His bundle block. Clinically, 11 (68%) pt had syncope or presyncope, 3 (18%) had dyspnea on exertion, and 2 (12.5%) were asymptomatic. Eight (50%) pt had bundle-branch block as follows: 4 (25%) pt had left bundle-branch block, and 4 (25%) had right bundle-branch block. Left anterosuperior divisional block was observed in 3 pt (19%), 2 of whom with associated right bundle-branch block. CONCLUSION: Intra-His bundle block was observed in 11% of the pt with second-degree atrioventricular block, syncope or presyncope, or both, it being the most frequent clinical presentation. Intra-His bundle block was more common in the elderly (> 60 years) and among females. The most frequent electrocardiographic presentations were second-degree Mobitz I or type 2:1 atrioventricular block.