De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome.

OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.

[Evaluation of a schoolbased intervention to promote smokefree areas]. / Evaluación de una intervención de promoción de espacios sin humo en el ámbito educativo.

OBJECTIVE: To determine the effect of an intervention in secondary schools on visible tobacco use, the prevalence and intensity of smoking, and the attitudes and behaviors of teachers and students. METHODS: We performed a quasiexperimental study in 18 public secondary schools that carried out the program and in 18 that did not (control group). Information was obtained on visible tobacco use and the number of ashtrays and smokefree posters through direct observation. Data were collected on tobacco use, the number of heavy smokers, smoking in schools, opinions on smokefree schools, smoking in front of the students, and attempts to quit smoking through questionnaires to teachers and students in the third year of compulsory secondary education (15-year-olds) and in the final year of secondary school (18-year-olds). RESULTS: Visible tobacco use was lower in the intervention group (27.9 vs. 45.6%) and twice as many posters were displayed. No differences were found in the prevalence of daily tobacco use, but the percentage of heavy smokers was lower in teachers and students in the intervention group. Smoking was lower in students in the third year of compulsory secondary education in schools carrying out the program. Opinions about smokefree schools were favorable in both groups. CONCLUSIONS: The program contributed to reducing visible tobacco use and in decreasing the number of heavy smokers among teachers and students.

Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys.

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans.

Limited role of Sirt1 in cancer protection by dietary restriction.

Dietary restriction (DR) has multiple beneficial effects, the two most prominently studied being an increased longevity and an increased cancer protection. Mammalian Sirt1 is a protein deacetylase that has been linked to DR. To explore the relation between Sirt1 and DR, we have examined here DR-induced cancer protection in mice overexpressing Sirt1 (2-3 fold) under its own regulatory elements (Sirt1-tg mice). In particular, we have subjected p53­deficient mice, carrying or not the Sirt1-tg allele, to every-other-day fasting (EOD), which is a type of DR that significantly delays cancer onset. As expected, EOD extended the survival of p53-heterozygous (p53 (+/-) ) mice. However, the extension of survival of p53-heterozygous mice by EOD was the same in the presence or absence of the Sirt1-tg allele. These results suggest that Sirt1 has a limited role in mediating cancer protection by DR in mammals.

Evaluación de una intervención de promoción de espacios sin humo en el ámbito educativo / Evaluation of a schoolbased intervention to promote smokefree areas

Objetivo: Conocer el efecto de un programa sobre el consumo visible de tabaco en los institutos de enseñanza secundaria (IES), la prevalencia y la intensidad del consumo del alumnado y el profesorado, y sus actitudes y conductas respecto al consumo en el centro. Métodos: Estudio casi experimental en 18 IES que realizaron el programa y en 18 que no lo realizaron (grupo control). Por observación directa se registró el consumo visible, la existencia de ceniceros y de carteles de «espacio libre de humo». Por encuesta al profesorado y al alumnado de 3.o de ESO y 2.o de Bachillerato, se recogieron datos de consumo de tabaco, grandes fumadores, consumo en el recinto escolar y opinión sobre la prohibición de fumar; a los profesores también se les preguntó sobre el consumo delante de los alumnos y sobre los intentos de dejar de fumar. Resultados: En el grupo de intervención había menor consumo en las zonas observadas (el 27,9 frente al 45,6%) y el doble de carteles. No hubo diferencias en la prevalencia de consumo diario, pero sí en el porcentaje de grandes fumadores, que fue menor en el profesorado y el alumnado del grupo de intervención; también eran menos los alumnos de 3.o de ESO que fumaban en el centro. La opinión sobre la prohibición de fumar en el centro era favorable en los dos grupos. Conclusiones: El programa contribuyó a la reducción del consumo visible y del número de cigarrillos/día consumidos por profesorado y alumnado(AU)

Objective: To determine the effect of an intervention in secondary schools on visible tobacco use, the prevalence and intensity of smoking, and the attitudes and behaviors of teachers and students. Methods: We performed a quasiexperimental study in 18 public secondary schools that carried out the program and in 18 that did not (control group). Information was obtained on visible tobacco use and the number of ashtrays and smokefree posters through direct observation. Data were collected on tobacco use, the number of heavy smokers, smoking in schools, opinions on smokefree schools, smoking in front of the students, and attempts to quit smoking through questionnaires to teachers and students in the third year of compulsory secondary education (15-year-olds) and in the final year of secondary school (18-year-olds). Results: Visible tobacco use was lower in the intervention group (27.9 vs. 45.6%) and twice as many posters were displayed. No differences were found in the prevalence of daily tobacco use, but the percentage of heavy smokers was lower in teachers and students in the intervention group. Smoking was lower in students in the third year of compulsory secondary education in schools carrying out the program. Opinions about smokefree schools were favorable in both groups. Conclusions: The program contributed to reducing visible tobacco use and in decreasing the number of heavy smokers among teachers and students(AU)