Stroke Steadiness as a Determinant Factor of Performance in 100 m Freestyle in Young Swimmers.

The classical kinematic variables in swimming are based on the calculation of mean values. Stroke steadiness determines the relationship between the duration of all consecutive strokes throughout a test. The aims of the current investigation were to examine differences in stroke-to-stroke steadiness according to swimmers' performance level on both body sides (breathing and non-breathing) and to analyse the interrelationship with kinematics during a 100 m front-crawl test. Thirty-two young, experienced swimmers voluntarily participated in the present study and were divided into two groups, national level (n = 15) and local level (n = 17), according to their competitive status within the national age-rankings. All participants performed a 100 m maximal test in a 50 m pool where they were laterally recorded. Kinematic variables such as mean velocity, stroke rate, stroke length, and stroke index, as well as long-term steadiness and short-term steadiness, were calculated. The two 50 m sections were analysed independently. Significant differences were observed between the two groups in the classical kinematic variables and in stroke steadiness (p < 0.05). In addition, stroke steadiness showed moderately high correlations with velocity (r = [-0.61-(-0.749)]) and stroke index (r = [-0.356-(-0.582)]). Maintaining a more stable inter-stroke period appears to be a determinant of performance in young, high-level national swimmers.

Assessment of Intercostal Muscle Near-Infrared Spectroscopy for Estimating Respiratory Compensation Point in Trained Endurance Athletes.

This study aimed to assess the reliability and validity of estimating the respiratory compensation point (RCP) in trained endurance athletes by analyzing intercostal muscles' NIRS-derived tissue oxygenation dynamics. Seventeen experienced trail runners underwent an incremental treadmill protocol on two separate occasions, with a 7-day gap between assessments. Gas exchange and muscle oxygenation data were collected, and the oxygen saturation breakpoint (SmO2BP) measured in the intercostal muscles was compared to the RCP, which was identified by the increase in the VE/V.CO2 slope and the point at which the PetCO2 started to decrease. No statistically significant differences were observed between the two methods for any of the variables analyzed. Bland-Altman analysis showed significant agreement between the NIRS and gas analyzer methods for speed (r = 0.96, p < 0.05), HR (r = 0.98, p < 0.05), V.O2 relative to body mass (r = 0.99, p < 0.05), and %SmO2 (r = 0.98, p < 0.05). The interclass correlation coefficient values showed moderate to good reliability (0.60 to 0.86), and test-retest analysis revealed mean differences within the confidence intervals for all variables. These findings suggest that the SmO2BP measured using a portable NIRS device in the intercostal muscles is a reliable and valid tool for estimating the RCP for experienced trail runners and might be useful for coaches and athletes to monitor endurance training.

DICER ribonuclease removes harmful R-loops.

R-loops, which consist of a DNA-RNA hybrid and a displaced DNA strand, are known to threaten genome integrity. To counteract this, different mechanisms suppress R-loop accumulation by either preventing the hybridization of RNA with the DNA template (RNA biogenesis factors), unwinding the hybrid (DNA-RNA helicases), or degrading the RNA moiety of the R-loop (type H ribonucleases [RNases H]). Thus far, RNases H are the only nucleases known to cleave DNA-RNA hybrids. Now, we show that the RNase DICER also resolves R-loops. Biochemical analysis reveals that DICER acts by specifically cleaving the RNA within R-loops. Importantly, a DICER RNase mutant impaired in R-loop processing causes a strong accumulation of R-loops in cells. Our results thus not only reveal a function of DICER as an R-loop resolvase independent of DROSHA but also provide evidence for the role of multi-functional RNA processing factors in the maintenance of genome integrity in higher eukaryotes.

Synbiotic Supplementation Improves Quality of Life and Inmunoneuroendocrine Response in Patients with Fibromyalgia: Influence of Codiagnosis with Chronic Fatigue Syndrome.

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are two medical conditions in which pain, fatigue, immune/inflammatory dysregulation, as well as various mental health disorders predominate in the diagnosis, without evidence of a clear consensus on the treatment of FM and CFS. The main aim of this research was to analyse the possible effects of a synbiotic (Synbiotic, Gasteel Plus® (Heel España S.A.U.), through the study of pro-inflammatory/anti-inflammatory cytokines (IL-8/IL-10) and neuroendocrine biomarkers (cortisol and DHEA), in order to evaluate the interaction between inflammatory and stress responses mediated by the cytokine-HPA (hypothalamic-pituitary-adrenal) axis, as well as mental and physical health using body composition analysis, accelerometry and previously validated questionnaires. The participants were women diagnosed with FM with or without a diagnostic of CFS. Each participant was evaluated at baseline and after the intervention, which lasted one month. Synbiotic intervention decreased levels of perceived stress, anxiety and depression, as well as improved quality of life during daily activities. In addition, the synbiotic generated an activation of HPA axis (physiological cortisol release) that can compensate the increased inflammatory status (elevated IL-8) observed at baseline in FM patients. There were no detrimental changes in body composition or sleep parameters, as well as in the most of the activity/sedentarism-related parameters studied by accelerometry. It is concluded that synbiotic nutritional supplements can improve the dysregulated immunoneuroendocrine interaction involving inflammatory and stress responses in women diagnosed with FM, particularly in those without a previous CFS diagnostic; as well as their perceived of levels stress, anxiety, depression and quality of life.

Incidence of hypertension in young transgender people after a 5-year follow-up: association with gender-affirming hormonal therapy.

In order to assess the risk of hypertension development, we performed a retrospective analysis of the clinical records of consecutive transgender patients who began gender-affirming hormonal therapy in our Outpatient Gender Identity Clinic with <30 years of age and had a follow-up >5 years. 149 transgender women treated with estradiol and 153 transgender men treated with testosterone were included; 129 of the transgender women received also androgen blockers (54 spironolactone, 49 cyproterone acetate and 26 LHRH agonists). The annual incidence of hypertension in young transgender men (1.18%) seemed comparable to that of the general population. In young transgender women, it seemed higher (2.14%); we found that the choice of androgen blocker had a remarkable effect, with a highly significant increase in patients treated with cyproterone acetate (4.90%) vs. the rest (0.80%); the adjusted hazard-ratio was 0.227 (p = 0.001). Correlation, logistic regression and mediation analyses were performed for the associations of the available clinical variables with the increase in systolic blood pressure and the onset of hypertension, but besides the use of cyproterone acetate, only the ponderal gain was found significant (Spearman's r: 0.361, p < 0.001); with a 36.7% mediation effect (31.2-42.3%). Cyproterone acetate has additional known risks, such as meningioma; although we cannot conclusively prove that it has a role in the development of hypertension, we conclude that the use of cyproterone acetate for this indication should be reconsidered.

The Consumption of a Synbiotic Does Not Affect the Immune, Inflammatory, and Sympathovagal Parameters in Athletes and Sedentary Individuals: A Triple-Blinded, Randomized, Place-bo-Controlled Pilot Study.

This investigation aimed to identify the effect of a synbiotic in athletes and sedentary people, and their potential varying responses regarding the immune system, autonomic regulation and body composition. Twenty-seven participants were involved in the protocol: 14 sedentary and 13 semi-professional soccer players. Both groups were randomly divided into an experimental and control group. A synbiotic (Gasteel Plus®, Heel España S.A.U.) comprising a blend of probiotic strains, including Bifidobacterium lactis CBP-001010, Lactobacillus rhamnosus CNCM I-4036, and Bifidobacterium longum ES1, was administered to the experimental group, and a placebo was given to the control group for 30 days. Heart rate variability, body composition, and immune/inflammatory cytokines were determined. Statistically significant differences were observed between sedentary individuals and athletes in heart rate variability but not between the experimental and control groups. A difference between the athletic and sedentary group is observed with the influence of training on the effects of the synbiotic on the levels of fat mass and body-fold sum. No significant differences were shown in cytokines after the protocol study. No changes occur with the synbiotic treatment between the athlete and sedentary groups, while no negative effect was produced. Further research will be necessary to see chronic effects in the analyzed biomarkers.

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine.

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein's dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

BRCA2 promotes DNA-RNA hybrid resolution by DDX5 helicase at DNA breaks to facilitate their repair‡.

The BRCA2 tumor suppressor is a DNA double-strand break (DSB) repair factor essential for maintaining genome integrity. BRCA2-deficient cells spontaneously accumulate DNA-RNA hybrids, a known source of genome instability. However, the specific role of BRCA2 on these structures remains poorly understood. Here we identified the DEAD-box RNA helicase DDX5 as a BRCA2-interacting protein. DDX5 associates with DNA-RNA hybrids that form in the vicinity of DSBs, and this association is enhanced by BRCA2. Notably, BRCA2 stimulates the DNA-RNA hybrid-unwinding activity of DDX5 helicase. An impaired BRCA2-DDX5 interaction, as observed in cells expressing the breast cancer variant BRCA2-T207A, reduces the association of DDX5 with DNA-RNA hybrids, decreases the number of RPA foci, and alters the kinetics of appearance of RAD51 foci upon irradiation. Our findings are consistent with DNA-RNA hybrids constituting an impediment for the repair of DSBs by homologous recombination and reveal BRCA2 and DDX5 as active players in their removal.

UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide.

Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R-loop removal. We show that UAP56 depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. We demonstrate an RNA-DNA helicase activity in UAP56 and show that its overexpression suppresses R loops and genome instability induced by depleting five different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA-DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful cotranscriptional RNA structures that otherwise would block transcription and replication.

Accidental doping. Prevention strategies / Dopaje accidental. Estrategias de prevención

There is growing consumption of nutritional supplements aimed at improving performance because the number of athletes, mainly amateurs, is growing very significantly. This great demand supposes a market of huge proportions, supposing an economic activity that in Spain reached 920 million Euros in the year 2018.This consumption occurs at all levels of sport, from 13% in global numbers, to 100% in some groups of professional sportsmen and women. However, the use of these substances in very few circumstances is done under the advice of a professional, and the athlete takes them on their own. This fact, with the possibility that the product to be taken may contain prohibited substances that do not appear on the labeling, means that an adverse analytical finding can occur in a doping control through so-called accidental doping, which is the use of adulterated or contaminated nutritional supplements containing substances prohibited in sport that have not been declared on the labeling. Between 11.6% and 25.8% of nutritional supplements contaminated with anabolic androgenic steroids have been found to exist. This paper describes the various causes of accidental doping, the substances most frequently used, paying particular attention to the ways of preventing this type of doping based on information and education, product certification and information, the form of prescription, criteria for use and safety of the origin of the products, and precautions followed in case of consumption

Hay un consumo creciente de suplementos nutricionales destinados a mejorar el rendimiento porque el número de deportistas, fundamentalmente aficionados, está creciendo de forma muy importante. Esta gran demanda supone un mercado de proporciones gigantescas, suponiendo un actividad económica que en España alcanzó los 920 millones de euros en el año 2018.Este consume se produce en todos los niveles deportivos, desde el 13 % en cifras globales, hasta el 100 % en algunos grupos de deportistas profesionales. Sin embargo, el uso de estas sustancias en muy pocas circunstancias se realiza bajo al asesoramiento de un profesional y el deportista los toma por su cuenta. Este hecho, junto a la posibilidad de que el producto que se vaya a tomar pueda contener sustancias prohibidas que no figuran en el etiquetado supone que se pueda producir un hallazgo analítico adverso en un control de dopaje a través del denominado dopaje accidental que consiste el que se produce por consumir suplementos nutricionales adulterados o contaminados que contienen sustancias prohibidas en el deporte que no se han declarado en el etiquetado. Se ha comprobado que existe entre el 11,6 y el 25,8% de suplementos nutricionales contaminados con esteroides androgénicos anabolizantes. En este trabajo se describen las diversas causas de dopaje accidental, las sustancias más frecuentemente utilizadas prestando una especial atención a las formas de prevención de este tipo de dopaje que se basan en la información y educación, en la certificación e información de los productos, en la forma de prescripción, en los criterios de uso y seguridad del origen de los productos y en las precauciones que se deben tomar en caso de consumirlos

Evaluation of lung parenchyma, blood vessels, and peripheral blood lymphocytes as a potential source of acute phase reactants in patients with COPD.

Background: Previous studies have shown that the arterial wall is a potential source of inflammatory markers in COPD. Here, we sought to compare the expression of acute phase reactants (APRs) in COPD patients and controls both at the local (pulmonary arteries and lung parenchyma) and systemic (peripheral blood leukocytes and plasma) compartments. Methods: Consecutive patients undergoing elective surgery for suspected primary lung cancer were eligible for the study. Patients were categorized either as COPD or control group based on the spirometry results. Pulmonary arteries and lung parenchyma sections, peripheral blood leukocytes, and plasma samples were obtained from all participants. Gene expression levels of C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2, and SAA4) were evaluated in tissue samples and peripheral blood leukocytes by reverse transciption-PCR. Plasma CRP and SAA protein levels were measured by enzyme-linked immunosorbent assays. Proteins were evaluated in paraffin-embedded lung tissues by immunohistochemistry. Results: A total of 40 patients with COPD and 62 controls were enrolled. We did not find significant differences in the gene expression between COPD and control group. Both CRP and SAA were overexpressed in the lung parenchyma compared with pulmonary arteries and peripheral blood leukocytes. The expression of SAA was significantly higher in the lung parenchyma than in the pulmonary artery (2-fold higher for SAA1 and SAA4, P=0.015 and P<0.001, respectively; 8-fold higher for SAA2, P<0.001) and peripheral blood leukocytes (16-fold higher for SAA1, 439-fold higher for SAA2, and 5-fold higher for SAA4; P<0.001). No correlation between plasma levels of inflammatory markers and their expression in the lung and peripheral blood leukocytes was observed. Conclusions: The expression of SAA in lung parenchyma is higher than in pulmonary artery and peripheral blood leukocytes. Notably, no associations were noted between lung expression of APRs and their circulating plasma levels, making the leakage of inflammatory proteins from the lung to the bloodstream unlikely. Based on these results, other potential sources of systemic inflammation in COPD (eg, the liver) need further scrutiny.

Acute effects of heat on health variables during continuous exercise and their comparison with normal and cold conditions: A systematic review / Efectos agudos del calor sobre variables de salud durante el ejercicio continuo en comparación con condiciones normales y frías: una revisión sistemática

Background: There has been an increasing number of running practitioners in the last years. Although running activity involves several benefits for practitioners, it might also induce health problems when practicing under heat conditions. Purpose: The main aim of this systematic review was to evaluate how high temperatures affect runner's health during continuous exercise. Search strategy: The search for articles for this study was carried out in two different databases, Web of Science and Pubmed.Study selection: The inclusion criteria were a) Studies that investigated the effects of endurance exercise, at least at 27º, on health variables, determining exercise intensity, indicating total time for exercise and presenting pre- and post-test results or compare with normal or cold conditions. Results: 1336 articles were identified after the searching process. 333 runners were evaluated in fifteen articles that were included in the qualitative synthesis. High increases in heart rate, body and skin temperature, some urine and blood markers, blood pH, ventilation, rate of perceived exertion and sweat rate were identified during continuous activity under heat conditions, and also when comparing with normal or cold conditions. Lower values were found in body mass, eosinophil than those observed before the running activity. Lower values for oxygen consumption and plasma lactate may occur in hot conditions when comparing with normal conditions. Conclusions: Studies analyzed conclude that an uncontrolled long-term activity in hot conditions may induce health problems related to high body and skin temperatures. Cooling strategies should be assessed after continuous exercise under hot conditions. In addition exercise in hot conditions produces greater increases in immune functions, heart rate, breathing stress, metabolic responses and rate of perceived exertion, also compared with normal and cold conditions

Introducción: El número de corredores ha incrementado en los últimos años. Aunque la actividad de correr implica varios beneficios para los practicantes, también puede provocar problemas de salud cuando se practica en condiciones de calor. Propósito: El objetivo de esta revisión fue evaluar cómo las altas temperaturas afectan la salud del corredor. Estrategia de búsqueda: La búsqueda de artículos para este estudio se llevó a cabo en Web of Science y Pubmed. Selección de estudios: Los criterios de inclusión fueron estudios que investigaron los efectos del ejercicio de resistencia, al menos a 27º, sobre variables de salud, determinando la intensidad y duración del ejercicio y se presentaron resultados previos y posteriores a la prueba o compararon con condiciones normales o frías. Resultados: 1336 artículos fueron identificados después del proceso de búsqueda. 333 corredores fueron evaluados en quince artículos que fueron incluidos en la síntesis cualitativa. Durante la actividad en condiciones de calor, se identificaron incrementos elevados en la frecuencia cardíaca, la temperatura corporal y de la piel, algunos marcadores de orina y sangre, el pH sanguíneo, la ventilación, el esfuerzo percibido y la sudoración. Se encontraron valores más bajos de masa corporal y eosinófilos que los observados antes de la actividad de carrera. Valores más bajos de consumo de oxígeno y lactato aparecen en condiciones de calor cuando se comparan con las condiciones normales. Conclusiones: Los estudios analizados concluyen que una actividad no controlada a largo plazo en condiciones de calor puede inducir problemas de salud relacionados con altas temperaturas corporales y de la piel. Además, el ejercicio en condiciones de calor produce mayores incrementos en las funciones inmunitarias, la frecuencia cardíaca, el estrés respiratorio, las respuestas metabólicas y el esfuerzo percibido, también en comparación con las condiciones normales y frías

The THO Complex as a Paradigm for the Prevention of Cotranscriptional R-Loops.

Different proteins associate with the nascent RNA and the RNA polymerase (RNAP) to catalyze the transcription cycle and RNA export. If these processes are not properly controlled, the nascent RNA can thread back and hybridize to the DNA template forming R-loops capable of stalling replication, leading to DNA breaks. Given the transcriptional promiscuity of the genome, which leads to large amounts of RNAs from mRNAs to different types of ncRNAs, these can become a major threat to genome integrity if they form R-loops. Consequently, cells have evolved nuclear factors to prevent this phenomenon that includes THO, a conserved eukaryotic complex acting in transcription elongation and RNA processing and export that upon inactivation causes genome instability linked to R-loop accumulation. We revise and discuss here the biological relevance of THO and a number of RNA helicases, including the THO partner UAP56/DDX39B, as a paradigm of the cellular mechanisms of cotranscriptional R-loop prevention.

Mixed Th2 and non-Th2 inflammatory pattern in the asthma-COPD overlap: a network approach.

Introduction: The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. Objectives: We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. Methods: This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO. ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. Results: In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p=0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p<0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Conclusion: Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions.

Insulin resistance and the metabolic syndrome are related to the severity of steatosis in the pediatric population with obesity

Background: To determine the factors associated with an increased risk for severe steatosis (SS) and establish the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) as a screening tool. Methods: A cross-sectional study was performed in obese children to assess the relationship between the metabolic syndrome (MetS) and glucose metabolism alterations (GMA) and the risk for severe steatosis. Results: A total of 94 children (51 males) aged from six to 14 years were included. Thirteen children (14.8%) had severe steatosis (SS). The anthropometric variables associated with SS included body mass index (BMI) (SS 34.1 vs non-SS 29.7, p = 0.005), waist circumference (cm) (100 vs 92.5, p = 0.015) and hip circumference (cm) (108 vs 100, p = 0.018). The blood parameters included alanine aminotransferase (ALT) (UI/dl) (27 vs 21, p = 0.002), gamma-glutamil transpeptidase (GGT) (UI/dl) (16 vs 15, p = 0.017), fasting glycemia (mg/dl) (96 vs 88, p = 0.006), fasting insulin (UI/dl) (25 vs 15.3, p < 0.001) and HOMA-IR score (7.1 vs 3.7, p < 0.001). Eighteen children with MetS were found to be at an increased risk for severe steatosis (odds ratio [OR] 11.36, p <0.001). After receiver operating characteristic (ROC) curve analysis, the best area under the curve (AUC) was obtained for HOMA-R of 0.862. The HOMA-R 4.9 cut-off value had a 100% sensitivity (CI 95%: 96.2-100) and 67.9% specificity (CI 95%: 57.1-78.7) for severe steatosis. Conclusions: The presence of MetS and glucose metabolism alterations are risk factors for severe steatosis. The 4.9 cut-off value for HOMA-IR may be a risk factor for severe steatosis in obese children (AU)

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Human THO-Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability.

R-loops, formed by co-transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R-loop accumulation centers on the conserved THO/TREX complex, an RNA-binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R-loops, we searched for new THO-interacting factors. We found that human THO interacts with the Sin3A histone deacetylase complex to suppress co-transcriptional R-loops, DNA damage, and replication impairment. Functional analyses show that histone hypo-acetylation prevents accumulation of harmful R-loops and RNA-mediated genomic instability. Diminished histone deacetylase activity in THO- and Sin3A-depleted cell lines correlates with increased R-loop formation, genomic instability, and replication fork stalling. Our study thus uncovers physical and functional crosstalk between RNA-binding factors and chromatin modifiers with a major role in preventing R-loop formation and RNA-mediated genome instability.

Insulin resistance and the metabolic syndrome are related to the severity of steatosis in the pediatric population with obesity.

BACKGROUND: To determine the factors associated with an increased risk for severe steatosis (SS) and establish the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) as a screening tool. METHODS: A cross-sectional study was performed in obese children to assess the relationship between the metabolic syndrome (MetS) and glucose metabolism alterations (GMA) and the risk for severe steatosis. RESULTS: A total of 94 children (51 males) aged from six to 14 years were included. Thirteen children (14.8%) had severe steatosis (SS). The anthropometric variables associated with SS included body mass index (BMI) (SS 34.1 vs non-SS 29.7, p = 0.005), waist circumference (cm) (100 vs 92.5, p = 0.015) and hip circumference (cm) (108 vs 100, p = 0.018). The blood parameters included alanine aminotransferase (ALT) (UI/dl) (27 vs 21, p = 0.002), gamma-glutamil transpeptidase (GGT) (UI/dl) (16 vs 15, p = 0.017), fasting glycemia (mg/dl) (96 vs 88, p = 0.006), fasting insulin (UI/dl) (25 vs 15.3, p < 0.001) and HOMA-IR score (7.1 vs 3.7, p < 0.001). Eighteen children with MetS were found to be at an increased risk for severe steatosis (odds ratio [OR] 11.36, p < 0.001). After receiver operating characteristic (ROC) curve analysis, the best area under the curve (AUC) was obtained for HOMA-R of 0.862. The HOMA-R 4.9 cut-off value had a 100% sensitivity (CI 95%: 96.2-100) and 67.9% specificity (CI 95%: 57.1-78.7) for severe steatosis. CONCLUSIONS: The presence of MetS and glucose metabolism alterations are risk factors for severe steatosis. The 4.9 cut-off value for HOMA-IR may be a risk factor for severe steatosis in obese children.

Roles of human POLD1 and POLD3 in genome stability.

DNA replication is essential for cellular proliferation. If improperly controlled it can constitute a major source of genome instability, frequently associated with cancer and aging. POLD1 is the catalytic subunit and POLD3 is an accessory subunit of the replicative Pol δ polymerase, which also functions in DNA repair, as well as the translesion synthesis polymerase Pol ζ, whose catalytic subunit is REV3L. In cells depleted of POLD1 or POLD3 we found a differential but general increase in genome instability as manifested by DNA breaks, S-phase progression impairment and chromosome abnormalities. Importantly, we showed that both proteins are needed to maintain the proper amount of active replication origins and that POLD3-depletion causes anaphase bridges accumulation. In addition, POLD3-associated DNA damage showed to be dependent on RNA-DNA hybrids pointing toward an additional and specific role of this subunit in genome stability. Interestingly, a similar increase in RNA-DNA hybrids-dependent genome instability was observed in REV3L-depleted cells. Our findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA-DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol ζ interaction.

Mortality from cystic fibrosis in Europe: 1994-2010.

OBJECTIVE: To date, available mortality trends due to cystic fibrosis (CF) have been limited to the analysis of certain countries in different parts of the world showing that mortality trends have been constantly decreasing. However, no studies have examined Europe as a whole. The present study aims to analyze CF mortality trends by gender within the European Union (EU) and to quantify potential years of life lost (PYLL). DESIGN: Deaths from the 27 EU countries were obtained from the statistical office of the EU from the years 1994-2010. Crude and age-standardized mortality rates (ASR) were estimated for women and men using the standard European population, expressed in deaths per 1,000,000 persons. The PYLL from ages 0 up to 30 years were estimated. Trends were studied by a joinpoint regression analysis. RESULTS: During the study period, 5,130 deaths (2,443 in males and 2,687 in females) were identified. Females had a slightly higher mortality rate than males, with a downward trend observed for both genders. In males, the ASR changed from 1.34 in 1994 to 1.03 in 2010. In females, the ASR changed from 1.42 in 1994 to 0.92 in 2010. The mean age at death and PYLL increased for both genders. The joinpoint analysis did not identify any significant joinpoint for either gender for ASR or PYLL. CONCLUSIONS: Our data suggest a continued downward trend of CF mortality throughout the EU, with differences by country and gender.