Synergistic activation of AMPK prevents from polyglutamine-inducedtoxicity inCaenorhabditis elegans

11 páginas, 4 figuras. Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.phrs.2020.105105.Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKβ1. In addition, we used an RNAi strategy to silence the expression of the second AMPKβ subunit in worms, namely aakb-2/AMPKβ2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKβ2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.We thank the CGC, funded by the NIH Office of ResearchInfrastructure Programs (P40 OD010440), for worm strains. [...] RPVMis aMiguel Servet type IIresearcher (CPII16/00004) funded by Institutode Salud Carlos III (ISCIII, Madrid, Spain). Grants from the ISCIII wereused to perform this work (PI14/00949 and PI17/00011). All grantsfrom ISCIII are co-financed by the European Development RegionalFund”A way to achieve Europe”(ERDF). JBY holds a grant from theGeneralitat Valenciana and the European Social Fund (ACIF/2019/249). Some equipment used in this work has been funded in partnershipbetween the Generalitat Valenciana (Conselleria de Sanitat I SalutPública, Valencian Community, Spain) and European Funds (ERDF/FSE), through the call "Improvement of research infrastructures for rarediseases”CV FEDER 2014-2020. This work has been partially supportedby a grant from the Fundació Telemarató de la TV3 (Reference 559),which covered the work of MDS. The funds from the ISCIII are partiallysupported by the European Regional Development Fund. RPVM is also aMarie Curie fellow (CIG322034, EU). This work has been partiallysupported by a grant from the CIBERER (ACCI2016), a grant from theFundación Ramón Areces (CIVP19S8119) and anAyuda Miguel Gilgrantto RPVM (VII Convocatoria Ayudas a la Investigación MHER, 2019Peer reviewe

Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. Methods: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. Results: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). Conclusions: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials

Genetic and constitutional factors are major contributors to substantia nigra hyperechogenicity

9 páginas, 2 figuras, 4 tablasHyperechogenicity of substantia nigra (SNh) is a frequent finding in amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and other movement disorders (MD) patients, but its meaning is unclear. To ascertain the contribution of different factors to SNh area, we measured it in 108 ALS, 102 PD, 91 other MD patients and 91 healthy controls. Demographical data were collected in all patients and controls. In ALS patients, we also recorded clinical variables, performed genetic analysis and measured baseline levels of ferritin. After family history and genetic testing, ALS patients were classified as familial (15) or sporadic (93). ALS, PD and other MD patients had a larger SNh area than controls. Left SNh and male gender, but not age, associated with larger SNh area in both patients and controls. Familial ALS patients showed larger SNh area than sporadic ones and familial ALS was the only clinical variable in the multivariate analysis to be associated with larger SNh area in ALS patients. Our results suggest that SNh associates with genetic and constitutional factors (male gender, handedness), some of which predispose to certain neurodegenerative diseases. This evidence supports the idea of SNh as an inborn marker of unspecific neuronal vulnerability.The research leading to these results has received funding from Instituto de Investigación Sanitaria La Fe (2013/0332, PI JFVC/TS), from Instituto de Salud Carlos III (ISCIII, PI12/0946, PI TS) and from Ministerio de Economía, Industria y Competitividad (SAF2014-59469-R, PI: JPT). The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED, group 209) are initiatives from the ISCIII.Peer reviewe

Incidence and clinical outcomes of the different neovascular forms of age-related macular degeneration in Valencia (Spain)

Objetivo Analizar la incidencia y los resultados visuales de cada uno de los subtipos de lesión neovascular en pacientes con degeneración macular asociada la edad (DMAE). Material y métodos Revisión retrospectiva de pacientes con DMAE neovascular tratados en el Hospital Universitario y Politécnico la Fe de Valencia por un mismo retinólogo (RGP) desde diciembre de 2012 hasta julio del 2015. Se registraron las formas anatómicas del complejo neovascular, así como el número de tratamientos intravítreos administrados y el cambio de visión obtenido con este. Resultados Fueron incluidos 174 ojos de 156 pacientes con una edad media de 79,9 años y un seguimiento de al menos 4 meses. El 40,8% presentaban neovascularización coroidea (NVC) tipo 1; el 12%, tipo 2; el 31%, tipo 3; el 14,4% presentaban formas mixtas y el 1,7%, vasculopatía polipoidea. La agudeza visual inicial media era de 0,32 y de 0,38 a los 24 meses, habiendo recibido una media de 9,3 inyecciones. Las formas neovasculares tipo 2, 3 y mixtas mostraron un resultado visual significativamente inferior a las tipo 1, no existiendo significación estadística en la vasculopatía polipoidea. Conclusiones La NVC tipo 1 fue la más observada, y además se relacionó con un mejor pronóstico visual, en comparación con el resto de lesiones neovasculares, en pacientes tratados con ranibizumab.Objective To analyse the incidence and outcomes of the different neovascular subtypes in age-related macular degeneration (AMD). Material and methods A retrospective review was carried out on patients with neovascular AMD treated in the University and Polytechnic Hospital la Fe in Valencia by the same retinal physician (RGP) between December 2012 and July 2015. The anatomic classification of the neovascular lesions was recorded, as well as the number of intravitreal treatments administered and the change in visual acuity (VA) obtained throughout the follow-up. Results A total number of 174 eyes of 156 patients (mean age: 79.9 years) with a minimum follow-up of 4 months were included. The anatomic classification of choroidal neovascularisation (CNV) showed the presence of type 1 lesions in 40,8%, type 2 lesions in 12%, type 3 lesions in 31%, and mixed lesions in 14.4%, with 1.7% showing polypoidal choroidal vasculopathy features. Overall, the mean baseline VA was 0,32, improving to 0,38 at 24 months, after having received a mean of 9.3 injections. Type 2, 3, and mixed forms showed a visual result significantly lower than type 1, but there was no significant difference in the polypoidal vasculopathy. Conclusions Type 1 CNV was the most common finding, and was associated with a better visual prognosis, compared to the other neovascular lesions.Sin financiaciónNo data JCR 20180.230 SJR (2018) Q3, 91/127 OphthalmologyNo data IDR 2018UE

Metformin intake associates with better cognitive function in patients with Huntington's disease.

Huntington's disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD. Herein we report statistical analyses of a sample population of participants in the Enroll-HD database, a world-wide observational study on HD, to assess the effect of metformin intake in HD patients respect to cognitive status using linear models. This cross-sectional study shows for the first time that the use of metformin associates with better cognitive function in HD patients

Exploring the efficacy of dialectical behaviour therapy and methylphenidate on emotional comorbid symptoms in adults with attention Deficit/Hyperactivity disorder: Results of the COMPAS multicentre randomised controlled trial

This study evaluated the efficacy of dialectical behaviour group therapy (GPT) vs. individual clinical management (CM) and methylphenidate (MPH) vs. placebo (PLB) on emotional symptoms in adults with ADHD. This longitudinal multicentre RCT compared four groups (GPT+MPH, GPT+PLB, CM+MPH, and CM+PLB) over five assessment periods, from baseline to week 130. Emotional symptomatology was assessed using SCL-90-R subscales. Of 433 randomized participants, 371 remained for final analysis. At week 13, GPT+MPH group showed smaller anxiety reductions than CM groups, but differences disappeared at subsequent assessments. Emotional symptom improvements were significantly predicted by reduction in core ADHD symptoms in all groups except GPT+MPH group. The unexpected lack of between-group differences may be explained by a 'floor effect', different intervention settings (group vs. individual), and psychotherapy type. Multiple regression analyses suggest a more specific effect of combined interventions (GPT+MPH). Implications for clinical practice are discussed.German Federal Ministry of Education and Research (01GV0605, 01GV0606)11.3 Q1 JCR 20222.139 Q1 SJR 2022No data IDR 2022UE

Cognitive results among the HD patients and controls ^a.

<p>Cognitive results among the HD patients and controls <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179283#t002fn001" target="_blank">^a</a>.</p