miRNAs in protection and regeneration of dopaminergic midbrain neurons

PD is the second most frequent neurodegenerative disorder affecting over 3 % of the population older than 80 years of age. Although PD is a system disorder which affects most regions of the brain, the progressive demise of the nigrostriatal projections and the inability of this system to regenerate are mainly responsible for the functional deficits observed. The etiology underlying PD is not finally resolved. Recent studies suggest that gene expression regulators might contribute to a large variety of disease states. miRNAs are small non-coding RNAs that are important for the post-transcriptional regulation of gene expression. Alterations in miRNA function have been reported in different neurodegenerative diseases including PD. Furthermore, miRNAs are auspicious therapeutic targets, as the manipulation of their expression might be neuroprotective or could induce the regeneration of neurons. In the present study the miRNAome of developing PMN cultures was analyzed and it was demonstrated that the major changes occur during early development. In order to analyze miRNA expression changes during degeneration and spontaneous regeneration of the murine nigrostriatal system a small RNA sequencing of the midbrain of the 6-OHDA mouse model for PD was performed and revealed novel sets of miRNAs involved in degeneration and regeneration of DA neurons in vivo. Taken together, miRNAs play an important role in development, maintenance and degeneration of DA neurons in vivo and in vitro and thus are promising targets for a better understanding of PD pathophysiology and the development of new therapeutic strategies

The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

The homeostasis of iron is of fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation of iron can be observed during aging and both are shared characteristics of several neurodegenerative diseases. Iron-mediated generation of reactive oxygen species (ROS) may lead to protein aggregation and cellular toxicity. The process of misfolding and aggregation of neuronal proteins such as α-synuclein, Tau, amyloid beta (Aβ), TDP-43 or SOD1 is a common hallmark of many neurodegenerative disorders and iron has been shown to facilitate protein aggregation. Thus, both, iron and aggregating proteins are proposed to amplify their detrimental effects in the disease state. In this review, we give an overview on effects of iron on aggregation of different proteins involved in neurodegeneration. Furthermore, we discuss the proposed mechanisms of iron-mediated toxicity and protein aggregation emphasizing the red-ox chemistry and protein-binding properties of iron. Finally, we address current therapeutic approaches harnessing iron chelation as a disease-modifying intervention in neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis

miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons.

Parkinson’s disease (PD) is the second-most-frequent neurodegenerative disorder worldwide. One major hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra. Glial cell line-derived neurotrophic factor (GDNF) potently increases DA neuron survival in models of PD; however, the underlying mechanisms are incompletely understood. MicroRNAs (miRNAs) are small, non-coding RNAs that are important for post-transcriptional regulation of gene expression. Using small RNA sequencing, we show that GDNF specifically increases the expression of miR-182-5p and miR-183-5p in primary midbrain neurons (PMNs). Transfection of synthetic miR-182-5p and miR-183-5p mimics leads to increased neurite outgrowth and mediates neuroprotection of DA neurons in vitro and in vivo, mimicking GDNF effects. This is accompanied by decreased expression of FOXO3 and FOXO1 transcription factors and increased PI3K-Akt signaling. Inhibition of endogenous miR-182-5p or miR-183-5p in GDNF-treated PMNs attenuated the pro-DA effects of GDNF. These findings unveil an unknown miR-mediated mechanism of GDNF action and suggest that targeting miRNAs is a new therapeutic avenue to PD phenotypes

The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders

Acord transformatiu CRUE-CSICThis work was supported by an NIHR Professorship (to M.A.K.). M.A.K. has received funding from the Sir Jules Thorn Award for Biomedical Research and Wellcome Trust. B.P.-D. was supported by Instituto de Salud Carlos III, PI 18/01319 and PI21/00248, and has received funding from Beca José Castillejos (CAS14/00328). K.J.P. was supported by an MRC Clinician-Scientist Fellowship (511015) and was supported by the Dystonia Medical Research Foundation and Fight for Sight. S.S.M. has received funding from the Winston Churchill Memorial trust and Cerebral Palsy Alliance.Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Protocol d'atenció i acompanyament al naixement a Catalunya

Acompanyament al naixement; Voluntats de la dona; Atenció al nadóBirth support; Women's wills; Newborn careAcompañamiento en el nacimiento; Voluntades de la mujer; Atención al recién nacidoL’Organització Mundial de la Salut, l’any 2018 va proposar una sèrie d’actuacions per a l’atenció al moment del part, que tenen per lema ‘Atenció per a una experiència positiva en el naixement’. En aquest document s’actualitza el ‘Protocol del part, puerperi i atenció al nadó’, document elaborat pel Departament de Salut, publicat l’any 2003 i actualitzat l’any 2019 com a ‘Protocol d’atenció i acompanyament al naixement’, seguint les recomanacions de l’OMS, així com totes aquelles basades en l’evidència científica, amb el màxim respecte a les opinions i voluntats de les dones gestants i amb l’objectiu d’ajudar-les a elles i a les seves famílies a tenir una experiència positiva en el part. Les activitats de promoció de la salut i prevenció de la malaltia són l’eix vertebrador d’aquest protocol i de tots els que es coordinen des del Servei de Salut Maternoinfantil de la Sub-direcció de Promoció de la Salut de l’Agència de Salut Pública de Catalunya del Departament de Salut. En aquest sentit, cal ressaltar la seva relació amb el Protocol del seguiment de l’embaràs a Catalunya (3a. edició) que es va presentar el 2018, amb el qual comparteix principis i enfocament. El protocol s’estructura en tres capítols en relació a les etapes (prepart, part i puerperi), recollint en el tercer, l’atenció la nadó. Cada capítol té diversos apartats en les activitats a realitzar, la informació a donar i el registre, entre d’altres. Es recull, després, la bibliografia i una sèrie de annexos amb eines pràctiques

Disease-related cortical thinning in presymptomatic granulin mutation carriers

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.info:eu-repo/semantics/publishedVersio

Identification of potential invasive alien species in Spain through horizon scanning

Invasive alien species have widespread impacts on native biodiversity and ecosystem services. Since the number of introductions worldwide is continuously rising, it is essential to prevent the entry, establishment and spread of new alien species through a systematic examination of future potential threats. Applying a three-step horizon scanning consensus method, we evaluated non-established alien species that could potentially arrive, establish and cause major ecological impact in Spain within the next 10 years. Overall, we identified 47 species with a very high risk (e.g. Oreochromis niloticus, Popillia japonica, Hemidactylus frenatus, Crassula helmsii or Halophila stipulacea), 61 with high risk, 93 with moderate risk, and 732 species with low risk. Many of the species categorized as very high or high risk to Spanish biodiversity are either already present in Europe and neighbouring countries or have a long invasive history elsewhere. This study provides an updated list of potential invasive alien species useful for prioritizing efforts and resources against their introduction. Compared to previous horizon scanning exercises in Spain, the current study screens potential invaders from a wider range of terrestrial, freshwater, and marine organisms, and can serve as a basis for more comprehensive risk analyses to improve management and increase the efficiency of the early warning and rapid response framework for invasive alien species. We also stress the usefulness of measuring agreement and consistency as two different properties of the reliability of expert scores, in order to more easily elaborate consensus ranked lists of potential invasive alien species.This work is one of the main results of the InvaNET network (RED2018-102571-T, RED2022-134338-T, https://invasiber.org/InvaNET/), financially supported by MCIN/AEI/10.13039/501100011033. We thank Guido Jones, funded by the Cabildo de Tenerife under the TFinnova Programme supported by MEDI and FDCAN, for revising the English.Peer reviewe

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Informe final del escaneo de horizonte sobre futuras especies exóticas invasoras en España

73 p.La introducción de especies exóticas invasoras (EEI) es una de las principales causas de la pérdida de biodiversidad a nivel global, que provoca grandes costes socioeconómicos. Sin embargo, el número de nuevas introducciones continúa creciendo año tras año. Por lo tanto, urge identificar posibles futuras EEI con el objetivo de diseñar e implementar medidas que prevengan y mitiguen los efectos negativos de su introducción. Así, el objetivo de este estudio es prospectar qué especies exóticas no establecidas en España podrían llegar fácilmente en los próximos 10 años, establecerse y causar importantes impactos ecológicos. Para ello, se ha realizado un escaneo de horizonte, siguiendo la metodología establecida en trabajos previos, siendo el primero para el conjunto de las especies exóticas invasoras en España. Se añadieron en el análisis especies que no son autóctonas de España, incluyendo los archipiélagos de Canarias y Baleares, y que no están establecidas en España. Un total de 39 científicos, expertos en distintos grupos taxonómicos y ecosistemas, ha evaluado 933 especies. Con el objetivo de analizar el acuerdo entre las evaluaciones individuales de los expertos y su consistencia, se llevaron a cabo dos análisis de fiabilidad complementarios, cuyos resultados se discuten en este informe. Como resultado del escaneo, se obtuvo una lista priorizada de 105 especies (46 con riesgo muy alto y 59 con riesgo alto). La mayoría de estas especies (84,8%), sin embargo, no están incluidas actualmente en el Catálogo Español de Especies Exóticas Invasoras. Por lo tanto, se recomienda la realización de un análisis de riesgo más detallado de estas especies y, si se confirma el riesgo alto, la solicitud de su incorporación en dicho catálogo o en el Listado de especies alóctonas susceptibles de competir con las especies silvestres autóctonas, alterar su pureza genética o los equilibrios ecológicos. Del mismo modo, se propone la realización de escaneos de horizonte específicos para los archipiélagos de Canarias y Baleares, ya que muchas de las especies autóctonas de la Península no lo son de las islas y podrían tener un gran impacto si allí se introdujeran. Este informe también analiza la afinidad taxonómica (i.e. filo) y funcional (i.e. productor primario, depredador, omnívoro, herbívoro o filtrador) de las especies de la lista priorizada, su origen geográfico y las principales vías de introducción. Por último, discute los mecanismos de impacto de dichas especies.Ministerio de Ciencia e Innovació