Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy

Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1, COL3A1, FN1, TGFB1, and PDGFA. We treated seven mdx mice with 60 mg/kg/day nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1, Col3a1, Tgfb1, and Pdgfa. Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients.España, Ministerio de Economía y Competitividad BFU2016-74975-PEspaña, Instituto Ramón y Cajal PI13/0134

Preservation of critical quality attributes of mesenchymal stromal cells in 3D bioprinted structures by using natural hydrogel scaffolds

Three dimensional (3D) bioprinting is an emerging technology that enables complex spatial modeling of cell-based tissue engineering products, whose therapeutic potential in regenerative medicine is enormous. However, its success largely depends on the definition of a bioprintable zone, which is specific for each combination of cell-loaded hydrogels (or bioinks) and scaffolds, matching the mechanical and biological characteristics of the target tissue to be repaired. Therefore proper adjustment of the bioink formulation requires a compromise between: (i) the maintenance of cellular critical quality attributes (CQA) within a defined range of specifications to cell component, and (ii) the mechanical characteristics of the printed tissue to biofabricate. Herein, we investigated the advantages of using natural hydrogel-based bioinks to preserve the most relevant CQA in bone tissue regeneration applications, particularly focusing on cell viability and osteogenic potential of multipotent mesenchymal stromal cells (MSCs) displaying tripotency in vitro, and a phenotypic profile of 99.9% CD105(+)/CD45,(-) 10.3% HLA-DR,(+) 100.0% CD90,(+) and 99.2% CD73(+)/CD31(-) expression. Remarkably, hyaluronic acid, fibrin, and gelatin allowed for optimal recovery of viable cells, while preserving MSC's proliferation capacity and osteogenic potency in vitro. This was achieved by providing a 3D structure with a compression module below 8.8 +/- 0.5 kPa, given that higher values resulted in cell loss by mechanical stress. Beyond the biocompatibility of naturally occurring polymers, our results highlight the enhanced protection on CQA exerted by bioinks of natural origin (preferably HA, gelatin, and fibrin) on MSC, bone marrow during the 3D bioprinting process, reducing shear stress and offering structural support for proliferation and osteogenic differentiation

Higher independent mobility to school among adolescents: A secondary analysis using cross-sectional data between 2010 and 2017 in Spanish youth

The PACO Study was supported by the Spanish Ministry of Economy, Industry and Competitiveness and the European Regional Development Fund (DEP2016-75598-R, MINECO/FEDER, UE), and Spanish Ministry of Education and Vocational Training (FPU17/03934). This study has been partially funded by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades, European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR. This study is part of a PhD thesis conducted in the Official Doctoral Program in Biomedicine of the University of Granada, SpainThe team would like to acknowledge the support of the following Spanish research centres and local/regional public institutions in providing data used in this study: Auguria, Agenda 21, University of Cádiz, University of Valencia, Autonomous University of Barcelona, University of Zaragoza, La Biciclante, La Ciclería, City Council of Zaragoza, University Carlos III and University of Granada.Aim: To describe and to analyse the associations between independent mobility to school (IM) with gender and age in Spanish youth aged 6–18 years old from 2010 to 2017. Moreover, to study the changes in the rates of IM from 2010 to 2017 by gender and age. Methods: Cross-sectional data were obtained from 11 Spanish studies. The study sample comprised 3460 children and 1523 adolescents. Logistic regressions models (IM with gender and age) and multilevel logistic regressions (IM with time period) were used. Results: Boys had higher odds ratio (OR) of IM than girls in children (OR = 1.86; CI: 1.50–2.28, p < 0.01). Adolescents showed higher IM than children: 12–14 years old (OR: 6.30; CI: 1.65–23.97) and 14–16 years old (OR: 7.33; CI: 1.18–45.39) had higher IM than 6–8 years old for boys (all, p < 0.05). Moreover, 12–14 years old (OR: 4.23; CI: 1.01–17.81) had higher IM than 6–8 years old for girls (p < 0.001). IM was not associ- ated with the time period. Conclusion: The IM is higher in boys and in adolescents, highlighting the relevance to promote IM strategies targeting girls and children. In these strategies is essential the support of researchers, public health practitioners and families to achieve positive results.Spanish Ministry of Economy, Industry and Competitiveness and the European Regional Development Fund, Grant/Award Number: DEP2016-75598-RSpanish Ministry of Education and Vocational Training, Grant/Award Number: FPU17/03934Funding for open access charge: Universidad de Granada / CBU

Is independent mobility influenced by age and gender in primary school children from Granada?

Trabajar comportamientos saludables y fomentar la autonomía en niños desde el centro educativo es fundamental. El presente estudio pretende analizar las relaciones entre la movilidad independiente con edad y género en niños de 6 a 12 años de Granada. Un total de 1143 niños de Granada participaron en el estudio cumplimentando un cuestionario sobre hábitos de movilidad al centro educativo. Para analizar las asociaciones se usaron regresiones logísticas. Los chicos presentaron un mayor porcentaje de movilidad independiente que las chicas. Se encontraron diferencias significativas en el porcentaje de movilidad independiente entre todos los grupos de edad por género. Trabajar comportamientos saludables desde la etapa de primaria podría aumentar la autonomía de los niños españoles.Nowadays, a significant percentage of children do not accumulate the recommended amount of daily physical activity. The present study aims to analyze the relationships between independent mobility with age and gender in Spanish children aged 6 to 12 years old from Granada. A total of 1143 children from Granada participated in the study by completing a questionnaire on mobility habits at the school. To analyze the associations, logistic regressions were used. Boys presented higher levels of independent mobility than girls. Significant differences were found in the percentage of independent mobility between all age groups by gender. Working healthy behaviors since the primary school could increase the autonomy of Spanish children

Convergent Validation of a Self-Reported Commuting to and from School Diary in Spanish Adolescents

The aim of this study was to examine the convergent validity of self-reported diary times for commuting to and from school with device-measured positional data (Global Positioning System; GPS) in Spanish adolescents. Methods: Cross-sectional data were obtained from four Spanish public secondary schools in 2021, comprising 47 adolescents and 141 home-school and school-home trips. Participants self-reported the time they left and arrived at home and school through a commuting diary. They wore a GPS device recording the objective time during three trips (i.e., one home-school trip and two school-home trips). Agreement between commuting diary and GPS data regarding home-school trips and school-home trips was evaluated using Bland-Altman plots. Results: Total commuting time differed by 1 min (95% limits of agreement were 16.1 min and -18.1 min) between subjective and objective measures (adolescents reported 0.8 more minutes in home-school trips and 1 more minute in school-home trips compared to objective data). Passive commuters reported 0.7 more minutes and active commuters reported 1.2 more minutes in the total commuting time compared to objective data. Conclusions: Self-reported commuting diaries may be a useful tool to obtain commuting times of adolescents in epidemiological research or when tools to measure objective times are not feasible.Spanish Ministry of Economy, Industry and Competitiveness and the European Regional Development Fund (DEP2016-75598-R, MINECO/FEDER, UE)Spanish Ministry of Education and Vocational Training (FPU17/03934, FPU18/04251)University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence, Unit of Excellence on Exercise and Health (UCEES)Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades, European Regional Development Fund (ERDF), ref. SOMM17/6107/UGRInstituto de Salud Carlos III through the fellowship CP20/00178 European Social Fun

The Effect of a School-Based Intervention on Children’s Cycling Knowledge, Mode of Commuting and Perceived Barriers: A Randomized Controlled Trial

The low rates of active commuting to/from school in Spain, especially by bike, and the wide range of cycling interventions in the literature show that this is a necessary research subject. The aims of this study were: (1) to assess the feasibility of a school-based cycling intervention program for adolescents, (2) to analyse the effectiveness of a school-based cycling intervention program on the rates of cycling and other forms of active commuting to/from school (ACS), and perceived barriers to active commuting in adolescents. A total of 122 adolescents from Granada, Jaén and Valencia (Spain) participated in the study. The cycling intervention group participated in a school-based intervention program to promote cycling to school during Physical Education (PE) sessions in order to analyse the changes in the dependent variables at baseline and follow up of the intervention. Wilcoxon, Signs and McNemar tests were undertaken. The association of the intervention program with commuting behaviour, and perceived barriers to commuting, were analysed by binary logistic regression. There were improvements in knowledge at follow-up and the cycling skill scores were medium-low. The rates of cycling to school and active commuting to/from school did not change, and only the “built environment (walk)” barrier increased in the cycling group at follow-up. School-based interventions may be feasibly effective tools to increase ACS behaviour, but it is necessary to implement a longer period and continue testing further school-based cycling interventions.Spanish GovernmentEuropean Commission DEP2016-75598-RUniversity of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES)Junta de AndaluciaEuropean Regional Development Fund (ERDF), "R&D research staff contract, within the framework of the Spanish National Youth Guarantee" - Junta de AndaluciaEuropean Social Fund (ESF)Spanish Government FPU18/04251 FPU17/0393

Sphingolipid extracts enhance gene delivery of cationic lipid vesicles into retina and brain

[EN]The aim was to evaluate relevant biophysic processes related to the physicochemical features and gene transfection mechanism when sphingolipids are incorporated into a cationic niosome formulation for non-viral gene delivery to central nervous system. For that, two formulations named niosphingosomes and niosomes devoid of sphingolipid extracts, as control, were developed by the oil-in water emulsion technique. Both formulations and the corresponding complexes, obtained upon the addition of the reporter EGFP plasmid, were physicochemically and biologically characterized and evaluated. Compared to niosomes, niosphingosomes, and the corresponding complexes decreased particle size and increased superficial charge. Although there were not significant differences in the cellular uptake, cell viability and transfection efficiency increased when human retinal pigment epithelial (ARPE-19) cells were exposed to niosphingoplexes. Endocytosis via caveolae decreased in the case of niosphingoplexes, which showed higher co-localization with lysosomal compartment, and endosomal escape properties. Moreover, niosphingoplexes transfected not only primary central nervous system cells, but also different cells in mouse retina, depending on the administration route, and brain cortex. These preliminary results suggest that niosphingosomes represent a promising non-viral vector formulation purposed for the treatment of both retinal and brain diseases by gene therapy approach.This work was supported by the Basque Country Government (Department of Education, University and Research, Consolidated Groups IT907-16) . Additional funding was provided by the CIBER of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , an initiative of the Carlos III Health Institute (ISCIII) . I.V.B. and M.S.R. thank the University of the Basque Country (UPV/EHU) for the granted postdoctoral fellowship (ESPDOC19/47) and the granted pre-doctoral fellowship (PIF17/79) , respectively. Authors wish to thank the intel-lectual and technical assistance from the ICTS "NANBIOSIS," more specifically by the Drug Formulation Unit (U10) of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the University of Basque Country (UPV/EHU) . Technical and human sup-port provided by SGIKER (UPV/EHU) is also gratefully acknowledged

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.Funding: This study has been supported: (i) by MICINN (SAF2009-11847 and SAF2015-68580-C2-1-R), CIBERNED (CB06/05/0089) and “Fundación Eugenio Rodríguez Pascual”, to JFR; (ii) by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin, to CJH; and (iii) by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), to PM. Carmen Rodríguez-Cueto was a predoctoral fellow supported by FPI Program-Ministry of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Active commuting to school and associated health indicators: evaluation protocol of the PACO study Cycle and Walk to School and its implementation in secondary school

El presente estudio ha sido financiado por el Ministerio de Economía, Industria y Competitividad del Gobierno de España y el Fondo Europeo de Desarrollo Regional (DEP2016- 75598-R, MINECO/FEDER, UE). Se recibe una ayuda del Ministerio de Ciencia, Innovacioìn y Universidades del Gobierno de EspanÞa (FPU17/03934; FPU18/04251). Además, este estudio ha sido parcialmente financiado por la Universidad de Granada, Plan Propio de Investigación 2016, Acciones de excelencia: Unidades de excelencia; Unidad de Excelencia en Ejercicio y Salud (UCEES), y por la Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades, Fondo Europeo de Desarrollo Regional (FEDER), ref. SOMM17 / 6107 / UGR.Es fundamental elaborar un protocolo de evaluación para garantizar rigor y homogeneidad en cualquier estudio de investigación. Asimismo, se requieren consideraciones específicas si la investigación se desarrolla en contexto educativo y en diferentes centros educativos. Este trabajo tiene como objetivo describir el protocolo de evaluación del estudio de investigación titulado: Estudio PACO “Pedalea y Anda al Colegio”. Además, se aportan recomendaciones globales y aplicaciones prácticas en el contexto educativo. El principal objetivo del estudio PACO es fomentar el comportamiento de desplazamiento activo entre estudiantes de Educación Secundaria Obligatoria para mejorar los niveles de actividad física y otros indicadores de salud asociados. Por ello, el protocolo de evaluación incluye la metodología e instrumentos específicos para evaluar en los adolescentes variables como: 1) modo de desplazamiento al centro educativo y otros factores psicosociales asociados a dicho desplazamiento mediante el cuestionario PACO alumnos, 2) barreras familiares para el desplazamiento activo al centro educativo mediante el cuestionario PACO familias, 3) características antropométricas (peso, talla, perímetro de cintura y de cuello), 4) niveles de actividad física y gasto energético evaluados mediante acelererometría y 5) características de la ruta real casa-colegio registradas mediante Sistema de Posicionamiento Global. La transparencia en la metodología y logística necesaria para evaluar dichas variables en contexto educativo, es la clave para garantizar el rigor y la homogeneidad en futuras implementaciones, ya sean estas realizadas por investigadores o docentes. Finalmente, los datos obtenidos, serán fiables y relevantes para implementar estrategias educativas que fomenten la salud integral de los adolescentes.It is essential to develop an evaluation protocol to develop rigor and homogeneity in any research study. Likewise, some considerations are specifically needed if the research is carried out in an educational context and in different schools. This work aims to describe y the evaluation protocol of the research study entitled: PACO Study “Cycle and Walk to School”. In addition, it provides global recommendations and practical applications in the educational context. The main objective of the PACO Study is to promote the behaviour of active commuting among students of Compulsory Secondary Education to improve their physical activity levels and other associated health indicators. For this reason, the evaluation protocol includes the specific methodology and instruments for evaluating variables such as: 1) mode of commuting to school and other psychosocial factors associated with active commuting through the PACO student questionnaire, 2) family barriers to active commuting to school through the PACO families questionnaire, 3) anthropometric characteristics (weight, height, waist and neck circumference), 4) levels of physical activity and energy expenditure evaluated by accelerometry and 5) characteristics of the real home-school route through a Global Positioning System. The transparency in the methodology and logistic necessary to evaluate the variables in the educational context is key to evaluate the rigor and homogeneity in future implementations, whether they are carried out by researchers or teachers. Finally, the obtained data will be reliable and relevant to implement educational strategies in order to promote an integral health of the adolescents.Ministerio de Economía, Industria y Competitividad del Gobierno de España y el Fondo Europeo de Desarrollo Regional (DEP2016- 75598-R, MINECO/FEDER, UE)Ministerio de Ciencia, Innovacioìn y Universidades del Gobierno de España (FPU17/03934; FPU18/04251).Universidad de Granada Plan Propio de Investigación 2016, Acciones de excelencia: Unidades de excelencia; Unidad de Excelencia en Ejercicio y Salud (UCEES)Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades, Fondo Europeo de Desarrollo Regional (FEDER), ref. SOMM17 / 6107 / UG

Clinical features and outcomes of Streptococcus anginosus group infective Endocarditis: a multicenter matched cohort study

[EN] Background. Although Streptococcus anginosus group (SAG) endocarditis is considered a severe disease associated with abscess formation and embolic events, there is limited evidence to support this assumption. Methods. We performed a retrospective analysis of prospectively collected data from consecutive patients with definite SAG endocarditis in 28 centers in Spain and Italy. A comparison between cases due to SAG endocarditis and viridans group streptococci (VGS) or Streptococcus gallolyticus group (SGG) was performed in a 1:2 matched analysis. Results. Of 5336 consecutive cases of definite endocarditis, 72 (1.4%) were due to SAG and matched with 144 cases due to VGS/ SGG. SAG endocarditis was community acquired in 64 (88.9%) cases and affected aortic native valve in 29 (40.3%). When comparing SAG and VGS/SGG endocarditis, no significant differences were found in septic shock (8.3% vs 3.5%, P = .116); valve disorder, including perforation (22.2% vs 18.1%, P = .584), pseudoaneurysm (16.7% vs 8.3%, P = .108), or prosthesis dehiscence (1.4% vs 6.3%, P = .170); paravalvular complications, including abscess (25% vs 18.8%, P = .264) and intracardiac fistula (5.6% vs 3.5%, P = .485); heart failure (34.7% vs 38.9%, P = .655); or embolic events (41.7% vs 32.6%, P = .248). Indications for surgery (70.8% vs 70.8%; P = 1) and mortality (13.9% vs 16.7%; P = .741) were similar between groups. Conclusions. SAG endocarditis is an infrequent but serious condition that presents a prognosis similar to that of VGS/SGG.This work was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0005), co‐financed by the European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligent Growth 2014–2020. We thank CERCA Programme/Generalitat de Catalunya for institutional support. J. M. M. received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–2021