The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Associated factors with mycotoxin exposure in Spanish population.

Human exposure to mycotoxins is a global concern since filamentous fungi can contaminate food and feed from crops to ready-to-eat meals. Human urine biomonitoring is a widely used technique to evaluate mycotoxins exposure, as an alternative to food correlation studies. The aim of this study is to describe human exposure to mycotoxins and to investigate the associated sociodemographic, lifestyle and dietary variables. Participants were 540 women from the Valencia (Spain) cohort of the Spanish Childhood and Environment Project (INMA). A validated multi-mycotoxin method using HPLC-Q-TOF-MS was applied to determine the concentration of ten selected mycotoxins: Enniatin A, Enniatin B, Enniatin A1, Enniatin B1, Beauvericine, Aflatoxin B1, Aflatoxin B2, Aflatoxin G1, Aflatoxin G2 and Ochratoxin A. A simultaneous untargeted screening of mycotoxins and their metabolites has been performed. Mycotoxins associations were assessed by bivariate and multivariate regression models using participants' sociodemographic, lifestyle and dietary data collected through questionnaires. Mycotoxins were detected in 81% of urine samples. The method quantified mycotoxins concentrations in up to 151 samples. Most quantified mycotoxins were: Enniatin B [% of detection (concentration range)] = 26% (1.0-39.7 ng/mg) and Enniatin B1 = 7% (0.5-14.4 ng/mg). Besides the ten-targeted mycotoxins, other mycotoxins and metabolites were studied, and higher incidence was observed for Deepoxy-deoxynivalenol (45%), Ochratoxin B (18%) and Ochratoxin α (17%). Higher mycotoxins concentrations were associated with rural areas as well as with participants belonged to lower social class, beer, light sodas and fruit juice consumers. On the contrary, higher processed meat intake was related to lower mycotoxins' levels. Studies are required to better evaluate the exposure to mycotoxins from food and their environmental relationships.

The impact of prenatal mercury on neurobehavioral functioning longitudinally assessed from a young age to pre-adolescence in a Spanish birth cohort.

The objective is to investigate the relation between cord blood mercury concentrations and child neurobehavioural functioning assessed longitudinally during childhood until pre-adolescence. METHODS: The study involves mothers and their offspring engaged in the Spanish INMA birth cohort (n = 1147). Total mercury (THg) was determined in cord blood. Behavioural problems were assessed several times during childhood using the ADHD-DSM-IV at age 4, SDQ at ages 7 and 11, CPRS-R:S and the CBCL at ages 7, 9 and 11. Covariates were obtained through questionnaires during the whole period. Multivariate generalised negative binomial (MGNB) models or mixed-effects MGNB (for those tests with information at one or more time points, respectively) were used to investigate the relation between cord blood THg and the children's punctuations. Models were adjusted for prenatal fish intake. Effect modification by sex, prenatal and postnatal fish intake, prenatal fruit and vegetable intake, and maternal polychlorinated biphenyl concentrations (PCBs) was assessed by interaction terms. RESULTS: The geometric mean ± standard deviation of cord blood THg was 8.22 ± 2.19 µg/L. Despite adjusting for fish consumption, our results did not show any statistically significant relationship between prenatal Hg and the children's performance on behavioural tests conducted between the ages of 4 and 11. Upon assessing the impact of various factors, we observed no statistically significant interaction. CONCLUSION: Despite elevated prenatal THg exposure, no association was found with children's behavioural functioning assessed from early childhood to pre-adolescence. The nutrients in fish could offset the potential neurotoxic impact of Hg. Further birth cohort studies with longitudinal data are warranted.

Notable surgical trials in gynecologic oncology: a 10-year overview.

In the last decade, we have witnessed important advances in novel therapeutics in the management of gynecologic cancers. These studies have built on the findings from preexisting data and have provided incremental contributions leading to changes that have not only impacted the accuracy of cancer detection and its metastatic components but also led to improvements in oncologic outcomes and quality of life. Key landmark trials have changed the standard of care in cervix, uterine, and ovarian cancer. A number of these have been controversial and have generated significant debate among gynecologic oncologists. The main objective of this review was to provide an overview on each of these trials as a reference for immediate and consolidated access to the study aims, methodology, results, and conclusion.

Children who sleep more may have longer telomeres: evidence from a longitudinal population study in Spain.

BACKGROUND: Inadequate sleep duration has been suggested as a chronic stressor associated with changes in telomere length (TL). This study aimed to explore the association between sleep duration and TL using the INMA birth cohort study data. METHODS: A total of 1014 children were included in this study (cross-sectional: 686; longitudinal: 872). Sleep duration (h/day) was reported by caregivers at 4 years and classified into tertiles (7-10 h/day; >10-11 h/day; >11-14 h/day). Leucocyte TL at 4 and 7-9 years were measured using quantitative PCR methods. Multiple robust linear regression models, through log-level regression models, were used to report the % of difference among tertiles of sleep duration. RESULTS: In comparison to children who slept between >10 and 11 h/day, those in the highest category (more than 11 h/day) had 8.5% (95% CI: 3.56-13.6) longer telomeres at 4 years. Longitudinal analysis showed no significant association between sleep duration at 4 years and TL at 7-9 years. CONCLUSION: Children who slept more hours per day had longer TL at 4 years independently of a wide range of confounder factors. Environmental conditions, such as sleep duration, might have a major impact on TL during the first years of life. IMPACT: Telomere length was longer in children with longer sleep duration (>11 h/day) independently of a wide range of confounder factors at age 4 and remained consistent by sex. Sleep routines are encouraged to promote positive child development, like the number of hours of sleep duration. Considering the complex biology of telomere length, future studies still need to elucidate which biological pathways might explain the association between sleep duration and telomere length.

Genetic Susceptibility to Neurotoxicity Related to Prenatal Inorganic Arsenic Exposure in Young Spanish Children.

We explored the influence of child and maternal single nucleotide polymorphisms (SNPs) in genes related to neurological function and arsenic metabolism (i.e., ABCA1, ABCB1, PON1, CYP3A, BDNF, GSTP1, MT2A, and APOE as well as AS3MT) on the association between prenatal arsenic (As) exposure and methylation efficiency and neuropsychological development in 4-5-year-old children. Participants were 549 mother-child pairs from the INMA (Environment and Childhood) Spanish Project. We measured inorganic arsenic (iAs) and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine samples collected during pregnancy. Neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Several SNPs were determined in maternal and child DNA; AS3MT and APOE haplotypes were inferred. The median ∑As (sum of iAs, DMA, and MMA) was 7.08 µg/g creatinine. Statistically significant interactions for children's APOE haplotype were observed. Specifically, ε4-carrier children had consistently lower MSCA scores in several scales with increasing ∑As and MMA concentrations. These results provide evidence regarding the neurotoxic effects of early life exposure to As, observing that the APOE ε4 allele could make children more vulnerable to this exposure.

Exposure to mercury among Spanish adolescents: Eleven years of follow-up.

The toxic effects of mercury exposure on human health are a public health concern. The most important source of this exposure is the consumption of fish and marine mammals. This study aims to describe hair mercury concentrations and their evolution from birth until eleven years of age in adolescents from the INMA (Environment and Childhood) birth cohort study, and to assess the association of hair mercury concentrations at eleven years of age with sociodemographic and dietary factors. The sample comprised 338 adolescents from the sub-cohort of Valencia (in eastern Spain). Total mercury (THg) was measured in hair samples collected at 4, 9 and 11 years old and in cord blood at birth. The equivalent of hair for cord-blood THg concentrations was calculated. Fish consumption and other characteristics at 11 years old were collected through questionnaires. Multivariate linear regression models were conducted to explore the association between THg concentrations, fish consumption and covariates. The geometric mean of hair THg concentrations at 11 years of age was 0.86 µg/g (95%CI: 0.78-0.94) and 45.2% of the participants presented concentrations above the equivalent RfD proposed by the US EPA (1 µg/g). Consumption of fish such as swordfish, canned tuna and other large oily fish was associated with higher levels of hair mercury at 11 years of age. Swordfish had the highest effect with an increase of 125% in hair mercury (95%CI: 61.2-214.9%) given a 100 g/week increase in its consumption, and, taking into account the frequency of consumption, canned tuna was the main contributor to Hg exposure among our population. The hair THg concentrations at 11 years of age represented a reduction of around 69% with respect to that estimated at childbirth. Even though THg exposure shows a sustained decreasing trend, it can still be considered elevated. INMA birth cohort studies provide a longitudinal assessment of mercury exposure in a vulnerable population, its associated factors and temporal trends, and this information could be used to adjust recommendations about this issue.

Load-Time and Load-Speed Relationship in the Resisted Sled Sprint Exercise: What Independent Variable Most Accurately Determines the Relative Load?

ABSTRACT: Jiménez-Lozano, M, Yáñez-García, JM, Mora-Custodio, R, Valle-Salguero, A, Díez-Fernández, DM, Franco-Márquez, F, González-Badillo, JJ, and Rodríguez-Rosell, D. Load-time and load-speed relationship in the resisted sled sprint exercise: what independent variable most accurately determines the relative load? J Strength Cond Res 37(11): 2167-2177, 2023-The aims of this study were to analyze the load-speed and load-time relationships in the resisted sled sprint exercise using different variables as relative load and to estimate the decrement of speed sprint and the increase of sprint time across different loads. Thirty young healthy men performed a progressive loading test in the countermovement jump (CMJ) exercise to determinate the load that elicited a 2 m·s-1 peak velocity (PV2-load) and in the full squat exercise to obtain the 1 repetition maximum (1RM) value and the load that elicited a 1 m·s-1 mean velocity (V1-load). In addition, subjects performed a progressive loading test in the resisted sled sprint exercise, whereas time and instantaneous speed at 10 (T10 and V10) and 20 m (T20 and V20) were measured. The independent variables used were body mass (BM), 1RM and V1-load in the squat exercise, the PV2-Load in the loaded CMJ exercise, 1RM + BM, V1-Load + BM, and PV2-Load + BM. To analyze whether relationships were dependent on individual performance obtained in unloaded sprint, the total sample was divided into 3 subgroups: high performance (T20 < 3.00 s), medium performance (T20:3.00-3.12 s), and low performance (T20 > 3.12 seconds) groups. The independent variables showing the highest relationships with time and speed in 10 and 20 m were %BM, %BM + V1-load, and %BM + PV2-load. Statistically significant differences between performance groups in %DSS (decrease of sprint speed) and %IST (increase sprint time) in 20 m were found when %BM was used as relative load, whereas there were no significant differences between groups for %BM + PV2-load or %BM + V1-load. In conclusion, the use of %BM + PV2-load and %BM + V1-load should be considered as variables for monitoring the relative load in the resisted sled sprint exercise.

WITHDRAWN: Adipocyte Deletion of ADAM17 Leads to Insulin Resistance in Association with Age and HFD in Mice.

Withdrawal: Valeria Lopez Salazar, Rhoda Anane Karikari, Lun Li, Rabih El-Merahbi, Maria Troullinaki, Moya Wu, Tobias Wiedemann, Alina Walth, Manuel Gil Lozano, Maria Rohm, Stephan Herzig, Anastasia Georgiadi. Adipocyte Deletion of ADAM17 Leads to Insulin Resistance in Association with Age and HFD in Mice (2021). The FASEB Journal. 35:s1. doi: 10.1096/fasebj.2021.35.S1.00447. The above abstract, published online on May 14, 2021 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, FASEB, and Wiley Periodicals Inc. The withdrawal is due to a request made by the authors prior to publication. The Publisher apologizes that this abstract was published in error.

Pre and postnatal exposure to mercury and sexual development in 9-year-old children in Spain: The role of brain-derived neurotrophic factor.

Early exposure to mercury has been related to endocrine disruption. Steroid hormones play a crucial role in neural cell migration, differentiation, etc., as well as protecting against several neurotoxic compounds. We investigate the relation between mercury exposure and children's sexual development, and we evaluate the possible influence of different brain-derived neurotrophic factor (BDNF) polymorphisms on this association. Our study sample comprised 412 9-year-old children participating in the INMA cohort (2004-2015). Mercury concentrations were measured at birth (cord blood) and at 4 and 9 years of age (hair). Sexual development was assessed by levels of sex steroid hormones (estradiol and testosterone) in saliva and the Tanner stages of sex development at 9 years (categorized as 1: prepuberty and >1: pubertal onset). Covariates and confounders were collected through questionnaires during pregnancy and childhood. Polymorphisms in the BDNF gene were genotyped in cord blood DNA. Multivariate linear regression analyses were performed between mercury levels and children's sexual development by sex. Effect modification by genetic polymorphisms and fish intake was assessed. We found marginally significant inverse associations between postnatal exposure to mercury (at 9 years) and testosterone levels (ß[95%CI] = -0.16[-0.33,0.001], and -0.20[-0.42,0.03], for boys and girls, respectively). Additionally, we found that prenatal mercury was negatively associated with Tanner stage >1 in boys. Finally, we found significant genetic interactions for some single nucleotide polymorphisms in the BDNF gene. In conclusion, pre and postnatal exposure to mercury seems to affect children's sexual development and BDNF may play a role in this association, but further research would be needed.

Prenatal arsenic exposure, arsenic methylation efficiency, and neuropsychological development among preschool children in a Spanish birth cohort.

BACKGROUND: Prenatal arsenic (As) exposure could negatively affect child neuropsychological development, but the current evidence is inconclusive. OBJECTIVES: To explore the relationship between prenatal urinary total As (TAs) concentrations, the As species and the methylation efficiency, and child neuropsychological development in a Spanish birth cohort. We also studied the effect modification produced by sex and several nutrients and elements. MATERIALS AND METHODS: Study subjects were 807 mother-child pairs participating in the INMA (Childhood and Environment) Project. Urinary TAs and its metabolites, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), inorganic As (iAs) and arsenobetaine were measured in the first trimester of pregnancy. Methylation efficiency was determined through the percentages of the metabolites and using principal component analysis. Children's neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Multivariable linear regression models were built to assess the association between TAs, the As species and the maternal methylation efficiency, and the neuropsychological scores. We explored effect modification by sex, iron status, maternal nutrients status (serum manganese and selenium, and urinary zinc), and maternal vitamins intake (folate, and vitamins B12 and B6). RESULTS: The geometric mean (95%CI) of ∑As (sum of DMA, MMA and iAs) was 7.78 (7.41, 8.17) µg/g creatinine. MMA concentrations were inversely associated with the scores for the general, verbal, quantitative, memory, executive function and working memory scales (i.e. ß [CI95%] = -1.37 [-2.33, -0.41] for the general scale). An inverse association between %MMA and the memory scores was found. Children whose mothers had lower manganese, zinc and ferritin concentrations obtained lower scores on several MSCA scales with decreasing As methylation efficiency. DISCUSSION: An inverse association was observed between MMA concentrations and children's neuropsychological development. Maternal levels of manganese, zinc and ferritin affected the association between As methylation efficiency and MSCA scores.

DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (ß = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (ß = 0.004, p-value = 4.97 × 10-5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (ß = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (ß = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling.

AIMS/HYPOTHESIS: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. METHODS: Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2AdipoqCre) and performed a large panel of metabolic tests. RESULTS: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. CONCLUSIONS/INTERPRETATION: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. DATA AVAILABILITY: Array data have been submitted to the GEO database at NCBI (GSE148699).

Urinary arsenic species and methylation efficiency during pregnancy: Concentrations and associated factors in Spanish pregnant women.

BACKGROUND: Arsenic (As) is considered to be toxic for humans, the main routes of exposure being through drinking water and the diet. Once ingested, inorganic arsenic can be methylated sequentially to monomethyl and dimethyl arsenicals. Several factors can affect both As exposure and methylation efficiency. OBJECTIVES: To describe the urinary concentrations of the different As species and evaluate the methylation efficiency during pregnancy, as well as their associated factors in a birth cohort of pregnant Spanish women. METHODS: Participants in this cross-sectional study were 1017 pregnant women from two areas of Spain who had taken part in the INMA (Environment and Childhood) project (2003-2008). Total As (organic and inorganic compounds) and its main metabolites (monomethylarsonic acid, [MMA], dimethylarsinic acid, [DMA], inorganic As [iAs]) and arsenobetaine [AB]) were measured in urine samples collected during the first trimester. Sociodemographic and dietary information was collected through questionnaires. Multivariate linear regression models were used to explore the association between As species concentrations and covariates. Arsenic methylation efficiency was determined through the percentages of the metabolites and using As methylation phenotypes, obtained from principal component analysis. RESULTS: Median urine concentrations were 33.0, 21.6, 6.5, 0.35 and 0.33 µg/g creatinine for total As, AB, DMA, MMA and iAs, respectively. Daily consumption of rice and seafood during the first trimester of pregnancy were positively associated with the concentration of As species (i.e., ß [CI95%] = 0.36 [0.09, 0.64] for rice and iAs, and 1.06 [0.68, 1.44] for seafood and AB). TAs, AB and iAs concentrations, and DMA and MMA concentrations were associated with legume and vegetable consumption, respectively. The medians of the percentage of As metabolites were 89.7 for %DMA, 5.1 for %MMA and 4.7 for %iAs. Non-smoker women and those with higher body mass index presented a higher methylation efficiency (denoted by a higher %DMA and lower %MMA). DISCUSSION: Certain dietary, lifestyle, and environmental factors were observed to have an influence on both As species concentrations and methylation efficiency in our population. Further birth cohort studies in low exposure areas are necessary to improve knowledge about arsenic exposure, especially to inorganic forms, and its potential health impact during childhood.

A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling.

The glucocorticoid receptor (GR) represents the crucial molecular mediator of key endocrine, glucocorticoid hormone-dependent regulatory circuits, including control of glucose, protein, and lipid homeostasis. Consequently, aberrant glucocorticoid signaling is linked to severe metabolic disorders, including insulin resistance, obesity, and hyperglycemia, all of which also appear upon chronic glucocorticoid therapy for the treatment of inflammatory conditions. Of note, long-term glucocorticoid exposure under these therapeutic conditions typically induces glucocorticoid resistance, requiring higher doses and consequently triggering more severe metabolic phenotypes. However, the molecular basis of acquired glucocorticoid resistance remains unknown. In a screen of differential microRNA expression during glucocorticoid-dependent adipogenic differentiation of human multipotent adipose stem cells, we identified microRNA 29a (miR-29a) as one of the most down-regulated transcripts. Overexpression of miR-29a impaired adipogenesis. We found that miR-29a represses GR in human adipogenesis by directly targeting its mRNA, and downstream analyses revealed that GR mediates most of miR-29a's anti-adipogenic effects. Conversely, miR-29a expression depends on GR activation, creating a novel miR-29-driven feedback loop. miR-29a and GR expression were inversely correlated both in murine adipose tissue and in adipose tissue samples obtained from human patients. In the latter, miR-29a levels were additionally strongly negatively correlated with body mass index and adipocyte size. Importantly, inhibition of miR-29 in mice partially rescued the down-regulation of GR during dexamethasone treatment. We discovered that, in addition to modulating GR function under physiologic conditions, pharmacologic glucocorticoid application in inflammatory disease also induced miR-29a expression, correlating with reduced GR levels. This effect was abolished in mice with impaired GR function. In summary, we uncovered a novel GR-miR-29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA-related mechanism that might contribute to GR dysregulation and resistance in peripheral tissues.-Glantschnig, C., Koenen, M., Gil-Lozano, M., Karbiener, M., Pickrahn, I., Williams-Dautovich, J., Patel, R., Cummins, C. L., Giroud, M., Hartleben, G., Vogl, E., Blüher, M., Tuckermann, J., Uhlenhaut, H., Herzig, S., Scheideler, M. A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling.

Prenatal Se concentrations and anthropometry at birth in the INMA study (Spain).

We assessed whether prenatal selenium (Se) exposure is associated with anthropometry at birth, placental weight and gestational age. Study subjects were 1249 mother-child pairs from the Valencia and Gipuzkoa cohorts of the Spanish Childhood and Environment Project (INMA, 2003-2008). Se was determined in serum samples taken at the first trimester of pregnancy. Socio-demographic and dietary characteristics were also collected by questionnaires. Mean (SD) serum Se concentration was 79.57 (9.64) µg/L. Se showed weak associations with both head circumference and gestational age. The association between serum Se concentration and birth weight and length was negative, and direct for placental weight and probability of preterm birth, although the coefficients did not reach statistical significance. Individuals with total mercury (THg) levels >15 µg/L reversed the serum Se concentration effect on head circumference. Significant interactions were found between sex and both gestational age and prematurity. Spontaneous birth gestational ages were estimated to be lower for males and their probability of prematurity was higher. In conclusion, prenatal Se exposure may be associated with lower head circumference and lower gestational ages at spontaneous birth. Interactions with THg exposure and gender should be considered when assessing these relationships.

Effect of cost on early removal of contraceptive implants: a prospective cohort study.

OBJECTIVES: To evaluate the effect of the cost of subdermal etonogestrel implant (SEI) on the continuation rate one year after insertion, and to assess the reasons given by users to remove the implant before the expiration date. METHODS: Prospective cohort study conducted among 265 women who chose the SEI as a contraceptive method in a sexual and reproductive health center in the eastern region of Spain, between October/2012 and October/2017. The sample was divided into two cohorts depending on the cost of the implant for the user (free-of-charge or requiring partial payment). Kaplan-Meier survival curves were used to compare the cumulative removal rates of free implants with partially paid implants within the first year of insertion. Cox proportional hazards models were used to control for confounders. RESULTS: After adjusting for confounders, no significant associations were found between the cost of the implant and its removal within a year of insertion. No significant associations were found in the reasons given for implant removal and for the duration of implant use. CONCLUSIONS: Cost was not associated with SEI continuation rates within the first year of use. No other significant variables were found to explain implant removal within one year of use.

Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation.

Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons. We found that Gas1 is expressed in GABAergic and glutamatergic neurons in the Purkinje-molecular layer of the cerebellum, hippocampus, thalamus, and fastigial nucleus, as well as in dopaminergic neurons of the substantia nigra. In all cases, Gas1 was found in the cell bodies, but not in the neuropil. The Purkinje and the molecular layers show the highest levels of Gas1, whereas the granule cell layer has low levels. Moreover, we detected the expression and release of Gas1 from primary cultures of Purkinje cells and from hippocampal neurons as well as from neuronal cell lines, but not from cerebellar granular cells. In addition, using SH-SY5Y cells differentiated with retinoic acid as a neuronal model, we found that extracellular Gas1 promotes neurite outgrowth, increases the levels of tyrosine hydroxylase, and stimulates the inhibition of GSK3ß. These findings demonstrate that Gas1 is expressed and released by neurons and promotes differentiation, suggesting an important role for Gas1 in cellular signaling in the CNS.

Functional Capacity and Self-Esteem of People With Cerebral Palsy.

OBJECTIVE: We assessed whether functional capacity predicts self-esteem in people with cerebral palsy (CP). METHOD: We conducted a cross-sectional observational study of 108 people with CP, ages 16-65 yr, who were residents of Spain. Self-esteem was captured using the Rosenberg Self-Esteem Scale (RSES), and functional capacity using the Barthel Index (BI). Sociodemographic characteristics were recorded. The relationship between the RSES score and the BI score was analyzed using linear regression. RESULTS: RSES scores increased significantly as BI scores increased (regression coefficient = 0.047, 95% confidence interval [0.017, 0.078], p = .003). People with a higher level of education, active employment, and independent living arrangements tended to have better functional capacity and higher self-esteem. CONCLUSION: Greater functional capacity predicted higher self-esteem; this effect is probably partly mediated by education, employment, and living arrangements.

Intravenous Thrombolysis in Unknown-Onset Stroke: Results From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry.

BACKGROUND AND PURPOSE: Stroke patients with unknown onset (UKO) are excluded from thrombolytic therapy. We aim to study the safety and efficacy of intravenous alteplase in ischemic stroke patients with UKO of symptoms compared with those treated within 4.5 hours in a large cohort. METHODS: Data were analyzed from 47 237 patients with acute ischemic stroke receiving intravenous tissue-type plasminogen activator in hospitals participating in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry between 2010 and 2014. Two groups were defined: (1) patients with UKO (n=502) and (2) patients treated within 4.5 hours of stroke onset (n=44 875). Outcome measures were symptomatic intracerebral hemorrhage per Safe Implementation of Treatment in Stroke on the 22 to 36 hours post-treatment neuroimaging and mortality and functional outcome assessed by the modified Rankin Scale at 3 months. RESULTS: Patients in UKO group were significantly older, had more severe stroke at baseline, and longer door-to-needle times than patients in the ≤4.5 hours group. Logistic regression showed similar risk of symptomatic intracerebral hemorrhage (adjusted odds ratio, 1.09; 95% confidence interval, 0.44-2.67) and no significant differences in functional independency (modified Rankin Scale score of 0-2; adjusted odds ratio, 0.79; 95% confidence interval, 0.56-1.10), but higher mortality (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.41) in the UKO group compared with the ≤4.5 hours group. Patients treated within 4.5 hours showed reduced disability over the entire range of modified Rankin Scale compared with the UKO group (common adjusted odds ratio, 1.29; 95% confidence interval, 1.01-1.65). CONCLUSIONS: Our data suggest no excess risk of symptomatic intracerebral hemorrhage but increased mortality and reduced favorable outcome in patients with UKO stroke compared with patients treated within the approved time window.