Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Fidelidade de Troquéis de Gesso, Obtidos a Partir de Moldes de Vários Elastômeros, Através de Duas Diferentes Técnicas de Moldagem.

As restaurações fixas são rotineiramente fabricadas sobre um modelo de gesso, obtidos a partir do molde de um dente preparado. A precisão na adaptação destas é influênciada diretamente pelas propriedades dos materiais de moldagem empregado. Qualquer que seja o elastomêro eleito, o método mais confiável para se avaliar o seu desempenho em conduzir a modelos de gesso fiéis, parece ser aquele no qual é empregado um coroa-padrão que se adapta com precisão a um troquel apropriado. Este trabalho tem por objetivo avaliar se dentre as técnicas da dupla moldagem (com alívio de 1 e 2 mm) e a do casquete, existe uma mais adequada ou se ambas apresentam adequações suficiente e semelhantes. Foram empregados cinco elastômeros (Express, Impregum F, Imprint, Permlastic e President), os moldes foram obtidos empregando-se um dispositivo de moldagem idealizado por ARAÚJO e JÖRGENSEN6 e vazados com gesso especial tipo IV (Vel-Mix). A coroa-padrão foi posicionada nos troquéis e avaliada, quanto à sua precisão de adaptação, em um microscópio de medição de profundidade. Os resultados estatístico mostraram que a técnica do casquete apresentou melhores resultados para os materiais Impregum F e Imprint, vindos a seguir o Express e o President (ambos com alívio de 2 mm) e o Express (alívio de 1 mm); o Permlastic e o Express, na técnica do casquete, apresentaram piores resultados que os anteriores, mas semelhantes entre si, sendo o President (casquete) semelhante à este último; o President (alívio de 1 mm), foi o que apresentou pior resultado.Fixed restorations are usually produced on gypsum dies obtained from a prepared tooth mold and its precise adaptation is directly influenced by the properties of the impression materials. The objective of this study was to compare the performance of five impression materials and different methods of impression. Materials were tested using the putty-wash method being the first impression realeased in 1 or 2 mm (for Express and President) and the individual resin tray shell (Express, Impregum F, Imprint, Permlastic e Predident). The deviced used by ARAÚJO; JÖRGENSEN6 and the Vel-Mix (type IV) gypsum were used. The adaptation of one standard-crown to the dies was analysed with a depth measuring microscope. The results showed that Impregum F and Imprint (with a shell) gave the best results, followed by Express and President (putty/wash 2 mm) and Express (putty/wash 1 mm). The results with Permlastic and Express (shell) were less satisfactory and the difference between them wasnt statistically significant. Express (shell) was not statistically different from the President (shell), and the worse result was given by the President (putty/wash - 1 mm) when compared to all the others

Fidelidade de Troquéis de Gesso, Obtidos a Partir de Moldes de Vários Elastômeros, Através de Duas Diferentes Técnicas de Moldagem.

As restaurações fixas são rotineiramente fabricadas sobre um modelo de gesso, obtidos a partir do molde de um dente preparado. A precisão na adaptação destas é influênciada diretamente pelas propriedades dos materiais de moldagem empregado. Qualquer que seja o elastomêro eleito, o método mais confiável para se avaliar o seu desempenho em conduzir a modelos de gesso fiéis, parece ser aquele no qual é empregado um coroa-padrão que se adapta com precisão a um troquel apropriado. Este trabalho tem por objetivo avaliar se dentre as técnicas da dupla moldagem (com alívio de 1 e 2 mm) e a do casquete, existe uma mais adequada ou se ambas apresentam adequações suficiente e semelhantes. Foram empregados cinco elastômeros (Express, Impregum F, Imprint, Permlastic e President), os moldes foram obtidos empregando-se um dispositivo de moldagem idealizado por ARAÚJO e JÖRGENSEN6 e vazados com gesso especial tipo IV (Vel-Mix). A coroa-padrão foi posicionada nos troquéis e avaliada, quanto à sua precisão de adaptação, em um microscópio de medição de profundidade. Os resultados estatístico mostraram que a técnica do casquete apresentou melhores resultados para os materiais Impregum F e Imprint, vindos a seguir o Express e o President (ambos com alívio de 2 mm) e o Express (alívio de 1 mm); o Permlastic e o Express, na técnica do casquete, apresentaram piores resultados que os anteriores, mas semelhantes entre si, sendo o President (casquete) semelhante à este último; o President (alívio de 1 mm), foi o que apresentou pior resultado.Fixed restorations are usually produced on gypsum dies obtained from a prepared tooth mold and its precise adaptation is directly influenced by the properties of the impression materials. The objective of this study was to compare the performance of five impression materials and different methods of impression. Materials were tested using the putty-wash method being the first impression realeased in 1 or 2 mm (for Express and President) and the individual resin tray shell (Express, Impregum F, Imprint, Permlastic e Predident). The deviced used by ARAÚJO; JÖRGENSEN6 and the Vel-Mix (type IV) gypsum were used. The adaptation of one standard-crown to the dies was analysed with a depth measuring microscope. The results showed that Impregum F and Imprint (with a shell) gave the best results, followed by Express and President (putty/wash – 2 mm) and Express (putty/wash – 1 mm). The results with Permlastic and Express (shell) were less satisfactory and the difference between them wasn’t statistically significant. Express (shell) was not statistically different from the President (shell), and the worse result was given by the President (putty/wash - 1 mm) when compared to all the others

O ângulo funcional mastigatório de Planas (AFMP) e a finalização ortodôntica

As chaves de oclusão devem estar presentes em uma oclusão ideal, portanto na correta finalização ortodôntica. Esses parâmetros são estáticos, porém a oclusão deve também ser analisada dinamicamente. Objetivo: A proposta desse trabalho é ilustrar, utilizando três casos clínicos, as chaves estáticas e dinâmicas e os ajustes que são preconizados para a obtenção do Ângulo Funcional Mastigatório de Planas (AFMP) iguais. Relato de Caso: foram relatados 3 casos clínicos diferentes, com graus de dificuldade de tratamento:  um Classe I com diastemas e giroversões; Classe I com uma sobremordida acentuada, e Classe III, subdivisão direita com mordida aberta anterior. Os casos foram detalhados quanto à finalização demonstrando a oclusão estática, e ajustes para obtenção de adequada oclusão dinâmica. Conclusão: Ajustes oclusais, após tratamento ortodôntico, melhoram a estabilidade oclusal e funcional, proporcionando um equilíbrio dentário e permitindo ao paciente uma mastigação bilateral

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field