Inflammatory markers and bone mass in children with overweight/obesity: the role of muscular fitness

Objectives To examine which inflammatory markers are associated with bone mass and whether this association varies according to muscular fitness in children with overweight/obesity. Methods Plasma interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), epidermal growth factor, vascular endothelial growth factor A (VEGF), and C-reactive protein were analyzed in 55 children aged 8–11 years. A muscular fitness score was computed. Bone mineral content (BMC) of the total body-less head (TBLH) and lumbar spine (LS) were assessed using dual-energy x-ray absorptiometry. Results IL-6 (β = −0.136) and VEGF (β = −0.099) were associated with TBLH BMC, while TNF-α (β = −0.345) and IL-1β (β = 0.212) were associated with LS BMC (P < 0.05). The interaction effect of muscular fitness showed a trend in the association of VEGF with TBLH BMC (P = 0.122) and TNF-α with LS BMC (P = 0.057). Stratified analyses by muscular fitness levels showed an inverse association of VEGF with TBLH BMC (β = −0.152) and TNF-α with LS BMC (β = −0.491) in the low-fitness group, while no association was found in the high-fitness group. Conclusion IL-6, VEGF, TNF-α, and IL-1β are significantly associated with bone mass. Higher muscular fitness may attenuate the adverse effect of high VEGF and TNF-α on bone mass

Muscular fitness mediates the association between 25-hydroxyvitamin D and areal bone mineral density in children with overweight/obesity

The association between vitamin D [25(OH)D] and bone health has been widely studied in children. Given that 25(OH)D and bone health are associated with muscular fitness, this could be the cornerstone to understand this relationship. Hence, the purpose of this work was to examine if the relation between 25(OH)D and areal bone mineral density (aBMD) was mediated by muscular fitness in children with overweight/obesity. Eighty-one children (8-11 years, 53 boys) with overweight/obesity were included. Body composition was measured with dual energy X-ray Absorptiometry (DXA), 25(OH)D was measured in plasma samples and muscular fitness was assessed by handgrip and standing long jump tests (averaged z-scores were used to represent overall muscular fitness). Simple mediation analyses controlling for sex, years from peak height velocity, lean mass and season were carried out. Our results showed that muscular fitness z-score, handgrip strength and standing long jump acted as mediators in the relationship between 25(OH)D and aBMD outcomes (percentages of mediation ranged from 49.6% to 68.3%). In conclusion, muscular fitness mediates the association of 25(OH)D with aBMD in children with overweight/obesity. Therefore, 25(OH)D benefits to bone health could be dependent on muscular fitness in young ages

The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice

Positive allosteric modulators of cc-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are small molecules that decrease deactivation of AMPARs via an allosteric site. These molecules keep the receptor in an active state. Interestingly, this type of modulator has been proposed for treating cognitive decline in ageing, dementias, and Alzheimer's disease (AD). S 47445 (8-cyclopropyl-3[2-(3-fluorophenyflethy1]-7,8-dihydro-3H-[1,3]oxazino[6,5-g][1,2,3]benzotriazine-4,9-dione) is a novel AMPAR positive allosteric modulator (AMPA-PAM). Here, the mechanisms by which S 47445 could improve synaptic strength and connectivity were studied and compared between young and old mice. A single oral administration of S 47445 at 10 mg/kg significantly increased long-term potentiation (LTP) in CA3-CA1 hippocampal synapses in alert young mice in comparison to control mice. Moreover, chronic treatment with S 47445 at 10 mg/kg in old alert animals significantly counteracted the deficit of LTP due to age. Accordingly, chronic treatment with S 47445 at 10 mg/kg seems to preserve synaptic cytoarchitecture in old mice as compared with young control mice. It was shown that the significant decreases in number and size of pre-synaptic buttons stained for VGlutl, and post-synaptic dendritic spines stained for spinophilin, observed in old mice were significantly prevented after chronic treatment with 10 mg/kg of S 47445. Altogether, by its different effects on LTP, VGlutl-positive particles, and spinophilin, S 47445 is able to modulate both the structure and function of hippocampal excitatory synapses known to be involved in learning and memory processes. These results open a new window for the treatment of specific age-dependent cognitive decline and dementias such as AD. (C) 2017 The Authors. Published by Elsevier Ltd

Suppressive ability against Rosellinia Necatrix of agricultural soils

Comunicación a congreso internacionalThe use of organic soil amendments to enhance the suppressiveness of natural soils has been proposed as an additional strategy to control plant diseases. Avocado is one of the main subtropical crops in southern Spain and white root rot, caused by the fungus Rosellinia necatrix, one of the most serious problems. Previous studies on this pathosystem have shown that application of composted almond shells caused a change in soil microbial communities of both population and functional level. In this work, evaluation of the suppressive capacity of almond shells amended soils have performed. “In vitro” assays using two different susceptible plants, Persea americana (avocado) and Triticum aestivum (wheat), indicate a clear relationship between soil microbial communities and suppressiveness. Addition of composted almond shells to the agricultural soil resulted in increased suppressiveness against R. necatrix, directly associated to microbial components, since suppressiveness was reduced when the soil was pasteurized, and partially recovered when the pasteurized soil was complemented with field soil. Different strains producing antifungal compounds were correlated with suppressiveness by molecular approaches.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tech. Plan Nacional I+D+I from Ministerio de Economía (MINECO,Spain) (AGL2011-30354-C02-01) and co-financed by FEDER funds (EU). C. Vida was supported by a PhD fellowship from the FPI program of MINECO

Differences in brain volume between metabolically healthy and unhealthy overweight and obese children: the role of fitness

The aim of this study was to examine whether metabolically healthy overweight/obese children have greater global and regional gray matter volumes than their metabolically unhealthy peers. We further examined the association between gray matter volume and academic achievement, along with the role of cardiorespiratory fitness in these associations. A total of 97 overweight/obese children (10.0 +/- 1.2 years) participated. We classified children as metabolically healthy/unhealthy based on metabolic syndrome cut-offs. Global and regional brain volumes were assessed by magnetic resonance imaging. Academic achievement was assessed using the Woodcock-Munoz standardized test. Cardiorespiratory fitness was assessed by the 20 m shuttle run test. Metabolically healthy overweight/obese (MHO) children had greater regional gray matter volume compared to those who were metabolically unhealthy (MUO) (all p 0.05). The findings of the present study support that metabolically healthy overweight/obese children have greater gray matter volume compared to those that are metabolically unhealthy, which is in turn related to better academic achievement. However, cardiorespiratory fitness seems to explain, at least partially, these findings.The ActiveBrains project was funded by the Spanish Ministry of Economy and Competitiveness and the 'Fondo Europeo de Desarrollo Regional (FEDER)' (DEP2013-47540, DEP2016-79512-R, DEP2017-91544-EXP and RYC-2011-09011). CC-S are supported by the Government of Andalusian, Integrated Territorial Initiative 2014-2020 for the province of Cadiz (PI-0002-2017) and the Spanish Ministry of Science and Innovation (FJC2018-037925-I). IE-C are supported by the Alicia Koplowitz Foundation and the Spanish Ministry of Economy and Competitiveness (RTI2018-095284-J-100). JHM and JM-G are supported by the Spanish Ministry of Education, Culture and Sport (FPU15/02645 and FPU14/06837, respectively). JVR is supported by a grant from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33396). PH was supported by a grant from the Strategic Research Area Health Care Science, Karolinska Institutet/Umea University. Additional funding was obtained from the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Scientific Excellence Unit on Exercise and Health (UCEES). Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades and European Regional Development Funds (ref. SOMM17/6107/UGR). In addition, funding was provided by the SAMID III network, RETICS, funded by the PN I + D + I 2017-2021 (Spain), ISCIII-Sub-Directorate General for Research Assessment and Promotion, the European Regional Development Fund (ERDF) (Ref. RD16/0022), the EXERNET Research Network on Exercise and Health in Special Populations (DEP2005-00046/ACTI) and the European Union's 2020 research and innovation program under grant agreement No 667302

Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5′-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (with support from NIH P41-GM103311)grants from Alexion and FEIOMM, by Instituto de Salud Carlos III (grants PI18-00803 and PI18-01235)co-funding from FEDER and by Junta de Andalucía (grant PI-0207-2016)GM-N is supported by the predoctoral program from Instituto de Salud Carlos III (FI17/00178) and by the Research Initiation Grants for Official Master Students program from the University of Granada (2017)PJR is a Ramon y Cajal Researcher from the MINECO (RYC-2015-18383) at GENyO and University of Granada

Effects of an exercise program on cardiometabolic and mental health in children with overweight or obesity: a secondary analysis of a randomized clinical trial

Importance: Childhood obesity is a risk factor associated with type 2 diabetes, cardiovascular disease, and mental disorders later in life. Investigation of the parallel effects of a defined exercise program on cardiometabolic and mental health in children with overweight or obesity may provide new insights on the potential benefits of exercise on overall health. Objective: To investigate the effects of a 20-week exercise program on cardiometabolic and mental health in children with overweight or obesity. Design, Setting, and Participants: This secondary analysis of a parallel-group randomized clinical trial was conducted in Granada, Spain, from November 1, 2014, to June 30, 2016. Data analyses were performed between February 1, 2020, and July 14, 2022. Children with overweight or obesity aged 8 to 11 years were eligible, and the study was performed in an out-of-school context. Intervention: The exercise program included 3 to 5 sessions/wk (90 min/session) of aerobic plus resistance training for 20 weeks. The wait-list control group continued with their usual routines. Main Outcomes and Measures: Cardiometabolic outcomes as specified in the trial protocol included body composition (fat mass, fat-free mass, and visceral adipose tissue), physical fitness (cardiorespiratory, speed-agility, and muscular), and traditional risk factors (waist circumference, blood lipid levels, glucose levels, insulin levels, and blood pressure). Cardiometabolic risk score (z score) was calculated based on age and sex reference values for levels of triglycerides, inverted high-density lipoprotein cholesterol, and glucose, the mean of systolic and diastolic blood pressure, and waist circumference. An additional cardiometabolic risk score also included cardiorespiratory fitness. Mental health outcomes included an array of psychological well-being and ill-being indicators. Results: The 92 participants included in the per-protocol analyses (36 girls [39%] and 56 boys [61%]) had a mean (SD) age of 10.0 (1.1) years. The exercise program reduced the cardiometabolic risk score by approximately 0.38 (95% CI, -0.74 to -0.02) SDs; decreased low-density lipoprotein cholesterol level by -7.00 (95% CI, -14.27 to 0.37) mg/dL (to convert to mmol/L, multiply by 0.0259), body mass index (calculated as weight in kilograms divided by height in meters squared) by -0.59 (95% CI, -1.06 to -0.12), fat mass index by -0.67 (95% CI, -1.01 to -0.33), and visceral adipose tissue by -31.44 (95% CI, -58.99 to -3.90) g; and improved cardiorespiratory fitness by 2.75 (95% CI, 0.22-5.28) laps in the exercise group compared with the control group. No effects were observed on mental health outcomes. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, an aerobic plus resistance exercise program improved cardiometabolic health in children with overweight or obesity but had no effect on mental health. Trial Registration: ClinicalTrials.gov Identifier: NCT02295072.This project was supported with grants DEP2013-47540, DEP2016-79512-R, DEP2017-91544-EXP, and RYC-2011-09011 from the Spanish Ministry of Economy and Competitiveness and the Fondo Europeo de Desarrollo Regional (FEDER) and by grant PID2020-120249RB-I00 from the MCIN/AEI /10.13039/501100011033. Additional funding was obtained from the Andalusian Operational Programme supported with grant B-CTS-355-UGR18 from the European Regional Development Fund (FEDER in Spanish). Dr Cardenas-Sanchez is supported by grant FJC2018-037925-I from the Spanish Ministry of Science and Innovation and by a grant from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No 101028929. Dr Migueles is supported by grant FPU15/02645 from the Spanish Ministry of Education, Culture and Sport, and grant 2012–00036 from the Swedish Research Council for Health, Working Life and Welfare. Dr Torres-Lopez is supported by grant FPU17/04802 from the Spanish Ministry of Science, Innovation and Universities. Dr Rodriquez-Ayllon was funded by grant DEP2017-91544-EXP from the Ramón Areces Foundation. Additional support was obtained from grant ALICIAK-2018 from the Alicia Koplowitz Foundation, University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence, Unit of Excellence on Exercise, Nutrition and Health, the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades; and grant DEP2005-00046/ACTI from the EXERNET Research Network on Exercise and Health in Special Populations. This research was supported by grant CB22/03/00058 from the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea–European Regional Development Fund

Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases

Objectives: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. Methods: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 – December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal- 5′-phosphate (PLP) and genetic study of ALPL gene. Results: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). Conclusions: This new algorithm was effective in detecting previously undiagnosed cases ofHPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.Instituto de Salud Carlos III grants PI21-01069 co-funded by the European Regional Development Fund (FEDER) and by Junta de Andalucía grant PI-0268-2019Operational Programme for Youth Employment of the Junta de Andalucía with Ref: POEJ_04/2022-12Instituto de Salud Carlos III with co-funding by FEDER (CD20/00022)(FI19/00118 and CM21/00221) from Instituto de Salud CarlosPostdoctoral fellowship from the Junta de Andalucía (RH-0141-2020

Systemic effects of hypophosphatasia characterization of two novel variants in the ALPL gene

IntroductionHypophosphatasia (HPP) is an inborn metabolic error caused by mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP) and leading to decreased alkaline phosphatase (ALP) activity. Although the main characteristic of this disease is bone involvement, it presents a great genetic and clinical variability, which makes it a systemic disease.MethodsPatients were recruited based on biochemical assessments. Diagnosis was made by measuring serum ALP and pyridoxal 5-phosphate levels and finally by Sanger sequencing of the ALPL gene from peripheral blood mononuclear cells. Characterization of the new variants was performed by transfection of the variants into HEK293T cells, where ALP activity and cellular localization were measured by flow cytometry. The dominant negative effect was analyzed by co-transfection of each variant with the wild-type gene, measuring ALP activity and analyzing cellular localization by flow cytometry.ResultsTwo previously undescribed variants were found in the ALPL gene: leucine 6 to serine missense mutation (c.17T&gt;C, L6S) affecting the signal peptide and threonine 167 deletion (c.498_500delCAC, T167del) affecting the vicinity of the active site. These mutations lead mainly to non-pathognomonic symptoms of HPP. Structural prediction and modeling tools indicated the affected residues as critical residues with important roles in protein structure and function. In vitro results demonstrated low TNSALP activity and a dominant negative effect in both mutations. The results of the characterization of these variants suggest that the pleiotropic role of TNSALP could be involved in the systemic effects observed in these patients highlighting digestive and autoimmune disorders associated with TNSALP dysfunction.ConclusionsThe two new mutations have been classified as pathogenic. At the clinical level, this study suggests that both mutations not only lead to pathognomonic symptoms of the disease, but may also play a role at the systemic level

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution