Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle.

Background Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands. Scope of review The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time. Major conclusions Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.post-print3250 K

Impact of multimorbidity on disability and quality of life in the Spanish older population

Background Population aging is closely related to high prevalence of chronic conditions in developed countries. In this context, health care policies aim to increase life span cost-effectively while maintaining quality of life and functional ability. There is still, however, a need for further understanding of how chronic conditions affect these health aspects. The aim of this paper is to assess the individual and combined impact of chronic physical and mental conditions on quality of life and disability in Spain, and secondly to show gender trends. Methods Cross-sectional data were collected from the COURAGE study. A total of 3,625 participants over 50 years old from Spain were included. Crude and adjusted multiple linear regressions were conducted to detect associations between individual chronic conditions and disability, and between chronic conditions and quality of life. Separate models were used to assess the influence of the number of diseases on the same variables. Additional analogous regressions were performed for males and females. Results All chronic conditions except hypertension were statistically associated with poor results in quality of life and disability. Depression, anxiety and stroke were found to have the greatest impact on outcomes. The number of chronic conditions was associated with substantially lower quality of life [ß for 4+ diseases: -18.10 (-20.95,-15.25)] and greater disability [ß for 4+ diseases: 27.64 (24.99,30.29]. In general, women suffered from higher rates of multimorbidity and poorer results in quality of life and disability. Conclusions Chronic conditions impact greatly on quality of life and disability in the older Spanish population, especially when co-occurring diseases are added. Multimorbidity considerations should be a priority in the development of future health policies focused on quality of life and disability. Further studies would benefit from an expanded selection of diseases. Policies should also deal with gender idiosyncrasy in certain cases

Gender gap in STEM: a cross-sectional study of primary school students’ self-perception and test anxiety in mathematics

Contribution: Significant gender differences are observed on primary school students’ perception of self-efficacy and test anxiety in mathematics. Girls perceive themselves to be significantly worse than boys in mathematics and report higher test anxiety toward mathematics exams. Gender differences in self-efficacy become more pronounced as students grow up, and test anxiety increases for all students. However, the present study shows that teachers’ do not perceive differences in self-efficacy in mathematics between boys and girls. Background: The low presence of women in science, technology, engineering, and mathematics (STEM) might be explained by the attitude of young students toward mathematics. Different studies show that girls are less interested in STEM areas than boys during secondary school. A study on the reasons for this fact pointed out that the early years of education can provide a relevant insight to reverse the situation. Research Questions: Is there any age-dependent gender difference in primary school students in aspects related to mathematics? Are teachers aware of students’ perceptions? Methodology: This work presents a study of over 2000 primary school students (6–12 years old) and 200 teachers in Aragón (Spain). The study consists of a survey on aspects that influence the experience of female and male students with mathematics and Spanish language for comparison purposes and teacher’s awareness of students’ perception. Findings: The present study shows that during primary school, girls are more likely to experiment a negative attitude toward mathematics than boys as they grow up, and teachers may not perceive girls’ situation. La baja presencia de mujeres en ciencia, tecnología, la ingeniería y las matemáticas (STEM) podrían explicarse por la actitud de las niños y niñas hacia las matemáticas. Diferentes estudios muestran que las niñas están menos interesadas en las áreas STEM que niños cuando cursan educación secundaria. Además, un estudio sobre los motivos para este hecho señaló que los primeros años de educación podrían proporcionar una visión relevante para revertir la situación. Por ello, este trabajo parte de las siguientes preguntas de investigación, ¿Existe alguna diferencia de género que sea dependiente de la edad en estudiantes de educación primaria en aspectos relacionados con las matemáticas? ¿Conoce el profesorado la autopercepción de sus estudiantes? Las principales contribuciones de este trabajo son que las diferencias significativas de género se observan en la percepción de autoeficacia de los estudiantes de primaria y ansiedad ante los exámenes en matemáticas. Las niñas se perciben a sí mismas significativamente peor que los niños en matemáticas e indican mayor ansiedad ante los exámenes de matemáticas. Las diferencias de género en la autoeficacia se vuelven más pronunciada a medida que los estudiantes crecen, mientras que la ansiedad ante los exámenes aumenta para todos los estudiantes. Pese a estos resultados, el presente estudio muestra que los profesores no perciben diferencias en la autoeficacia en matemáticas entre niños y niñas. Este estudio se basa en las encuestas realizadas a más de 2000 escolares (6-12 años) y 200 profesores en Aragón (España). El estudio consiste en una encuesta a los estudiantes sobre aspectos que pueden influir en la experiencia de los niños y niñas con las matemáticas, así como con la lengua española para disponer de una materia que permita establecer comparaciones y una encuesta al profesor que incluye cuestiones sobre su percepción de los estudiantes. El principal hallazgo del estudio es que, durante la escuela primaria, es más probable que las niñas experimenten una actitud negativa hacia matemáticas que los niños a medida que crecen, y que los maestros pueden no ser conscientes de la situación de las niñas

Self-adaptive quality requirement elicitation process for legacy systems: a case study in healthcare

Legacy systems need to be continuously maintained and reengineered to improve their provision of services and improve quality attributes. An approach that promises to improve quality attributes and reduce human maintenance tasks is the self-adaptive approach, where software systems modify their own behaviour. However, there is little guidance in the literature on how to migrate to a self-adaptive system and evaluate which features should be designed/implemented with self-adaptive behaviour. In this paper, we describe a process called Self-Adaptive Quality Requirement Elicitation Process (SAQEP), a process that allows eliciting quality attribute requirements from legacy system stakeholders and specify which of these requirements can be taken account to be implemented in a self-adaptation system. The SAQEP has been applied to elicit the self-adaptive quality requirements of a legacy system in a Mexican hospital. We also discuss our experience applying this approach.We would like to thank Instituto Nacional de Rehabilitacion (INR) for providing access to their system and staff, specially to Marco Antonio Nuñez Gaona. This work was partially funded by The Royal Academy of Engineering (NRCP1516/1/39) and The Royal Society (NI150203) hrough the Newton fund scheme

Impacts of Creatine Supplementation on Running Anaerobic Sprint Performance Test (RAST) Power and Velocity in Youth Soccer Players

Creatine supplementation commonly enhances short-term, high-intensity effort performance such the soccer-specific ability to perform repeated sprints. Research in this regard is both generally sparse but specifically more so in youth athletes. PURPOSE: to determine the effect of 28 days of creatine monohydrate supplementation on running anaerobic sprint performance (RAST) power and velocity in youth soccer players. METHODS: Sixteen male youth soccer players were randomized in double-blinded, parallel-group fashion to either 28 days of creatine supplementation (CRE; 15.9±0.35y) or an equivalently-dosed dextrose (PLA; 15.5±0.54y; 0.3g/kg/d loading dose for the first seven days, followed by 0.03g/kg/d for the remaining period), whereby they maintained their typical diet and training routines throughout the study. Furthermore, all subjects measured their weight and performed two RAST tests both prior to (PRE) and following (POST) supplementation, consisting of 10 second rest intervals between six maximal 35m runs. RAST peak and mean values for power and velocity were determined via a Speed Test FIT CEFISE photocell system. Due to the data’s distribution, individual appropriate within- and between-group nonparametric analyses were employed to assess PRE-to-POST supplementation mean and peak power (mP and pP) and velocity (mV and pV) at a significance level of p\u3c.05. RESULTS: Neither power parameter (mP and pP) nor pV differed PRE-to-POST or between groups (p\u3e.05). Nevertheless, nonparametric analyses revealed statistically significant mV differences (p=.025), whereby post-supplementation CRE was greater (23.7±1.64km/h) compared to both PRE in either group (CRE-PRE: 22.9±1.81km/h; PLA-PRE: 22.1±0.638km/h) and relative to PLA post-supplementation (22.2±1.15km/h). CONCLUSION: Although creatine supplementation did not meaningfully enhance RAST-associated power nor peak velocity, it did enhance mean velocity in youth soccer athletes. Notwithstanding our limited ability to claim a creatine-mediated performance advantage in this and similar demographics, future research should corroborate and further support these data by employing a standardized training protocol to eliminate additional extraneous variables

Retinal Structure in RPE65-Associated Retinal Dystrophy

PURPOSE: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals. METHODS: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5–24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V_{30}). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated. RESULTS: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was −300.63 µm/year, and −1.17 mm^{2}/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V_{30}. CONCLUSIONS: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.

Inherited photoreceptor degeneration causes the death of melanopsin-positive retinal ganglion cells and increases their coexpression of brn3a

Purpose: To study the population of intrinsically photosensitive retinal ganglion cells (melanopsin-expressing RGCs, m+RGCs) in P23H-1 rats, a rat model of inherited photoreceptor degeneration. Methods: At postnatal (P) times P30, P365, and P540, retinas from P23H dystrophic rats (line 1, rapid degeneration; and line 3, slow degeneration) and Sprague Dawley (SD) rats (control) were dissected as whole-mounts and immunodetected for melanopsin and/or Brn3a. The dendritic arborization of m+RGCs and the numbers of Brn3a+RGCs and m+RGCs were quantified and their retinal distribution and coexpression analyzed. Results: In SD rats, aging did not affect the population of Brn3a+RGCs or m+RGCs or the percentage that showed coexpression (0.27%). Young P23H-1 rats had a significantly lower number of Brn3a+RGCs and showed a further decline with age. The population of m+RGCs in young P23H-1 rats was similar to that found in SD rats and decreased by 22.6% and 28.2% at P365 and P540, respectively, similarly to the decrease of the Brn3a+RGCs. At these ages the m+RGCs showed a decrease of their dendritic arborization parameters, which was similar in both the P23H-1 and P23H-3 lines. The percentage of coexpression of Brn3a was, however, already significantly higher at P30 (3.31%) and increased significantly with age (10.65% at P540). Conclusions: Inherited photoreceptor degeneration was followed by secondary loss of Brn3a+RGCs and m+RGCs. Surviving m+RGCs showed decreased dendritic arborization parameters and increased coexpression of Brn3a and melanopsin, phenotypic and molecular changes that may represent an effort to resist degeneration and/or preferential survival of m+RGCs capable of synthesizing Brn3a

Recessive dystrophic epidermolysis bullosa: the origin of the c.6527insC mutation in the Spanish population

This work was supported by grants from the Spanish Ministry of Science and Innovation (MICINN) (SAF2007-61019 and SAF 2010-16976), INTRA ⁄08 ⁄714.1 and INTRA ⁄09 ⁄758 from the Biomedical Network Research Centre on Rare Diseases (CIBERER) and S2010 ⁄BMD-2420 (CELLCAM) from Comunidad de Madrid

Tracing the retina to analyze the integrity and phagocytic capacity of the retinal pigment epithelium

We have developed a new technique to study the integrity, morphology and functionality of the retinal neurons and the retinal pigment epithelium (RPE). Young and old control albino (Sprague-Dawley) and pigmented (Piebald Virol Glaxo) rats, and dystrophic albino (P23H-1) and pigmented (Royal College of Surgeons) rats received a single intravitreal injection of 3% Fluorogold (FG) and their retinas were analyzed from 5 minutes to 30 days later. Retinas were imaged in vivo with SD-OCT and ex vivo in flat-mounts and in cross-sections. Fifteen minutes and 24 hours after intravitreal administration of FG retinal neurons and the RPE, but no glial cells, were labeled with FG-filled vesicles. The tracer reached the RPE 15 minutes after FG administration, and this labeling remained up to 30 days. Tracing for 15 minutes or 24 hours did not cause oxidative stress. Intraretinal tracing delineated the pathological retinal remodelling occurring in the dystrophic strains. The RPE of the P23H-1 strain was highly altered in aged animals, while the RPE of the RCS strain, which is unable to phagocytose, did not accumulate the tracer even at young ages when the retinal neural circuit is still preserved. In both dystrophic strains, the RPE cells were pleomorphic and polymegathic