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Abstract Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection affecting children that can lead to myocardial injury and shock. Vascular endothelial dysfunction has been suggested to be a common complicating factor in patients with coronavirus disease 2019 (COVID-19). This study aims to characterize endothelial glycocalyx degradation in children admitted with MIS-C. We collected blood and urine samples and measured proinflammatory cytokines, myocardial injury markers, and endothelial glycocalyx markers in 17 children admitted with MIS-C, ten of which presented with inflammatory shock requiring intensive care admission and hemodynamic support with vasopressors. All MIS-C patients presented signs of glycocalyx deterioration with elevated levels of syndecan-1 in blood and both heparan sulfate and chondroitin sulfate in the urine. The degree of glycocalyx shedding correlated with tumor necrosis factor-α concentration. Five healthy age-matched children served as controls. Patients with MIS-C presented severe alteration of the endothelial glycocalyx that was associated with disease severity. Future studies should clarify if glycocalyx biomarkers could effectively be predictive indicators for the development of complications in adult patients with severe COVID-19 and children with MIS-C. Key messages Children admitted with MIS-C presented signs of endothelial glycocalyx injury with elevated syndecan-1 and heparan sulfate level. Syndecan-1 levels were associated with MIS-C severity and correlated TNF-α concentration. Syndecan-1 and heparan sulfate may represent potential biomarkers for patients with severe COVID-19 or MIS-C.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by the BBSRC (BBI025751/1 and BB/I025263/1). GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. DCa is funded by the MRC (MC_UU_00011/1 and MC_UU_00011/5). GS is financially supported by the MRC [New Investigator Research Grant, MR/S009310/1] and the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, UK MRC MR/S036520/1]. AH is supported by the South-Eastern Norway Regional Health Authority (2020022) and the Research Council of Norway (274611 and 288083). The POSEIDON work was supported by the German Research Foundation [DFG; grant FOR2107; RI908/11-2 and WI3429/3-2], the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent, under the auspices of the e:Med Programme [01ZX1314G; 01ZX1614G] through grants 01EE1406C, 01EE1409C and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” [01EW1810], through ERA-NET NEURON “Impact of Early life MetaBolic and psychosocial strEss on susceptibility to mental Disorders; from converging epigenetic signatures to novel targets for therapeutic intervention” [01EW1904] and by a grant of the Dietmar-Hopp Foundation. The general design of the Generation R Study is made possible by financial support from Erasmus Medical Center, Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw) and the Ministry of Health, Welfare and Sport. The EWAS data were funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). AN and HT are supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). AN is also supported by a Canadian Institutes of Health Research team grant. The work of HT is further supported by a NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200). JFF has received funding from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, ZonMw the Netherlands no. 529051022) and the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle; 633595, DynaHEALTH). The work of CAMC, JF and RM has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 848158 (EarlyCause Project). Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. SA is funded by a Juan de la Cierva—Incorporación Postdoctoral Contract awarded by Ministry of Economy, Industry and Competitiveness (IJCI-2017-34068). The Project Viva work was supported by the US National Institutes of Health grants R01 HD034568, UH3 OD023286 and R01 ES031259. The CHAMACOS project was supported by grants from the Environmental Protection Agency [R82670901 and RD83451301], the National Institute of Environmental Health Science (NIEHS) [P01 ES009605, R01ES021369, R01ES023067, R24ES028529, F31ES027751], the National Institute on Drug Abuse (NIDA) [R01DA035300], the National Institutes of Health (NIH) [UG3OD023356] and the National Institute of Mental Health (NIMH) [T32MH112510]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the EPA, NIEHS, or NIH. We thank all funding sources for the EDEN study (not allocated for the present study but for the cohort): Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris–Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programs (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (in collaboration with the French Association of Diabetic Patients (AFD), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale complementary health insurance (MGEN), French national agency for food security, French speaking association for the study of diabetes and metabolism (ALFEDIAM), grant # 2012/51290-6 Sao Paulo Research Foundation (FAPESP), EU funded MeDALL project. PREDO: The PREDO Study has been funded by the Academy of Finland (JL: 311617 and 269925, KR: 1312670 ja 128789 1287891), EraNet Neuron, EVO (a special state subsidy for health science research), University of Helsinki Research Funds, the Signe and Ane Gyllenberg foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Jane and Aatos Erkko Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation granted to members of the Predo study board. Methylation assays were funded by the Academy of Finland (269925). SJL is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

International audience; Studies in children have reported associations of screen time and background TV on language skills as measured by their parents. However, few large, longitudinal studies have examined language skills assessed by trained psychologists, which is less prone to social desirability. We assessed screen time and exposure to TV during family meals at ages 2, 3 and 5–6 years in 1562 children from the French EDEN cohort. Language skills were evaluated by parents at 2 years (Communicative Development Inventory, CDI) and by trained psychologists at 3 (NEPSY and ELOLA batteries) and 5–6 years (verbal IQ). Cross-sectional and longitudinal associations were assessed by linear regression adjusted for important confounders. Overall, daily screen time was not associated with language scores, except in cross-sectional at age 2 years, where higher CDI scores were observed for intermediate screen time. Exposure to TV during family meals was consistently associated with lower language scores: TV always on (vs never) at age 2 years was associated with lower verbal IQ (− 3.2 [95% IC: − 6.0, − 0.3] points), independent of daily screen time and baseline language score. In conclusion, public health policies should better account for the context of screen watching, not only its amount.

Background and objectives: End stage renal disease (ESRD) patients are exposed to the risk of ionizing radiation during repeated imaging studies. The variability in diagnostic imaging policies and the accompanying radiation doses across various renal units is still unknown. We studied this variability at the centre level and quantified the associated radiation doses at the patient level. Methods: Fourteen Italian nephrology departments enrolled 739 patients on haemodialysis and 486 kidney transplant patients. The details of the radiological procedures performed over one year were recorded. The effective doses and organ doses of radiation were estimated for each patient using standardized methods to convert exposure parameters into effective and organ doses Results: Computed tomography (CT) was the major contributor (> 77%) to ionizing radiation exposure. Among the haemodialysis and kidney transplant patients, 15% and 6% were in the high (≥ 20mSv per year) radiation dose groups, respectively. In haemodialysis patients, the most exposed organs were the liver (16mSv), the kidney (15mSv) and the stomach (14mSv), while the uterus (6.2mSv), the lung (5.7mSv) and the liver (5.5mSv) were the most exposed in kidney transplant patients. The average cumulative effective dose (CED) of ionizing radiation among centres in this study was highly variable both in haemodialysis (from 6.4 to 18.8mSv per patient-year; p = 0.018) and even more so in kidney transplant (from 0.6 to 13.7mSv per patient-year; p = 0.002) patients. Conclusions: Radiation exposure attributable to medical imaging is high in distinct subgroups of haemodialysis and transplant patients. Furthermore, there is high inter-centre variability in radiation exposure, suggesting that nephrology units have substantially different clinical policies for the application of diagnostic imaging studies.

The new outbreak of coronavirus disease 2019 (COVID-19) has infected and caused the death of millions of people worldwide. Intensive efforts are underway around the world to establish effective treatments. Immunoglobulin from immunized animals or plasma from convalescent patients might constitute a specific treatment to guarantee the neutralization of the virus in the early stages of infection, especially in patients with risk factors and a high probability of progressing to severe disease. Worldwide, a few clinical trials using anti-SARS-CoV-2 immunoglobulins from horses immunized with the entire spike protein or fragments of it in the treatment of patients with COVID-19 are underway. Here, we describe the development of an anti-SARS-CoV-2 equine F(ab')

In order to provide additional information on the behaviour of biochemical parameters related to stress responses to a specific long-term competition, we aimed to compare the stressful effects of a long-lasting competition on physiological variables in men and women. This is a prospective observational analytical study. Twenty-five professional athletes, 15 men and 10 women, travelled 460 km for 4 days in an international edition of the Ecomotion/Pro AR World. After the competition, we detected an increase in α-amylase and cortisol levels and a decrease in salivary immunoglobulin A (lgA) levels. The relative percentage changes in α-amylase, IgA and cortisol levels were significantly higher in women than in men, whereas women had lower relative percentage changes in glucose and lactate levels compared with men. There was a decrease in lymphocyte, eosinophil and monocyte counts, with relative percentage decreases in lymphocytes and monocytes being significantly higher in female athletes than in males. There were increases in the serum activities of total creatine kinase (CK), the creatine kinase myocardial isoform (CKMB), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) at the end of the test, with significantly higher elevations of total CK, CKMB and LDH in men and ALT in women. Long-lasting competition induced stress, muscle damage, anaemia and changes in the immune system. Women had more intense responses of cortisol and leukocytes. Um zusätzliche Informationen zum Verhalten biochemischer Parameter in Verbindung mit stressbedingten Reaktionen auf einen speziellen Langstreckenwettkampf zu gewinnen, verglichen wir die stressbedingten Auswirkungen eines Langstreckenwettkampfs auf physiologische Variablen bei Männern und Frauen. Bei dieser Studie handelt es sich um eine prospektive Beobachtungsanalyse. 25 Profisportler (15 Männer und 10 Frauen) legten in einer internationalen Ausgabe der Ecomotion/Pro AR World in 4 Tagen 460 km zurück. Nach dem Wettkampf fanden sich erhöhte α-Amylase- und Kortisolspiegel sowie eine Abnahme der Immunglobulin-A(IgA)-Spiegel im Speichel. Die relativen prozentualen Veränderungen der α-Amylase-, IgA- und Kortisolspiegel waren bei Frauen signifikant höher als bei Männern. Frauen wiesen geringere relative Veränderungen der Glukose- und Laktatwerte auf als Männer. Es zeigte sich eine Abnahme der Lymphozyten-, Eosinophilen- und Monozytenzahlen, wobei die relative prozentuale Abnahme der Lymphozyten und Monozyten bei weiblichen Athleten signifikant höher ausfiel als bei männlichen. Am Ende des Tests wurden signifikant höhere Serumaktivitäten der Gesamtkreatinkinase (CK), der Kreatinkinase-Myokard-Isoform (CKMB), der Alanin-Aminotransferase (ALT), der Aspartat-Aminotransferase (AST) und der Laktatdehydrogenase (LDH) gemessen. Hierbei wiesen die Männer eine signifikant höhere Zunahme der Gesamt-CK-, CKMB- und LDH-Werte auf, während bei den Frauen der ALT-Wert signifikant stärker erhöht war. Der Langzeitwettkampf führte zu Stress, Muskelschäden, Blutarmut und Veränderungen im Immunsystem. Frauen zeigten intensivere Reaktionen bei den Kortisol- und Leukozytenwerten.

SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

The goal of the study was to investigate some of the factors suspected to be related to children’s handedness: presentation during the last weeks of gestation and at birth (cephalic or breech), side of presentation (right or left), number of weeks of gestation, season of birth, parents’ handedness and sex. We analyzed the relationships between these factors and the child’s handedness at five years. Children (n = 1897) from the EDEN cohort participated in the study, among which 1129 were tested for handedness at five. The father’s handedness, but not the mother’s, was significantly related to the child’s hand preference. The percentage of left-handed children was significantly larger when the father was non-right-handed compared to right-handed, and tended to be larger among children in non-left-cephalic presentation compared to left-cephalic presentation. Girls, but not boys, were significantly less lateralized when they were born before 37 weeks of pregnancy than after. Finally, children born in winter or spring were slightly but significantly less lateralized than children born in summer or autumn. All six children who were not lateralized at 5 presented one or several of these factors. These results are discussed in light of the mixed model of handedness.

Background Intrauterine fetal death (IUFD) is a tragic event and, despite efforts to reduce rates, its incidence remains difficult to reduce. The objective of the present study was to examine the etiological factors that contribute to the main causes and conditions associated with IUFD, over an 11-year period in a region of North-East Italy (Friuli Venezia Giulia) for which reliable data in available. Methods Retrospective analysis of all 278 IUFD cases occurred between 2005 and 2015 in pregnancies with gestational age ≥ 23 weeks. Results The incidence of IUFD was 2.8‰ live births. Of these, 30% were small for gestational age (SGA), with immigrant women being significantly over-represented. The share of SGA reached 35% in cases in which a maternal of fetal pathological condition was present, and dropped to 28% in the absence of associated pathology. In 78 pregnancies (28%) no pathology was recorded that could justify IUFD. Of all IUFDs, 11% occurred during labor, and 72% occurred at a gestational age above 30 weeks. Conclusion The percentage of IUFD cases for which no possible cause can be identified is quite high. Only the adoption of evidence-based diagnostic protocols, with integrated immunologic, genetic and pathologic examinations, can help reduce this diagnostic gap, contributing to the prevention of future IUFDs.

International audience; Objective: 25-hydroxyvitamin D (25OHD) deficiency has been associated with sleep disorders in adults. Only three cross-sectional studies were performed in children and showed an association between 25OHD deficiency and both obstructive sleep apnea syndrome and primary snoring. No longitudinal study has been performed in children from the general population. We analyzed the association between cord-blood vitamin D level at birth and night-sleep duration trajectories for children between 2 and 5-6 years old in a non-clinical cohort.Method: We included 264 children from the French EDEN mother-child birth-cohort with both cord-blood 25OHD level determined by radio-immunoassay at birth, and night-sleep trajectories for children between 2 and 5-6 years old obtained by the group-based trajectory modeling method. Associations between 25OHD and sleep trajectories were assessed by multinomial logistic regression adjusted for maternal and child characteristics.Results: The trajectories short sleep (

SummaryDespite sperm mitochondrial relevance to the fertilization capacity, the processes involved in the production of ATP and functional dynamics of sperm mitochondria are not fully understood. One of these processes is the paradox involved between function and formation of reactive oxygen species performed by the organelle. Therefore, this review aimed to provide data on the role of sperm mitochondria in oxidative homeostasis and functionality as well the tools to assess sperm mitochondrial function.

Most β-d-xylosides with hydrophobic aglycones are nontoxic primers for glycosaminoglycan assembly in animal cells. However, when Ebselen was conjugated to d-xylose, d-glucose, d-galactose, and d-lactose (8A-D), only Ebselen β-d-xyloside (8A) showed significant cytotoxicity in human cancer cells. The following facts indicated that the aglycone Ebselen and β-d-xyloside primed glycosaminoglycans co-contributed to the observed cytotoxicity: 1. Ebselen induced S phase cell cycle arrest, whereas 8A induced G2/M cell cycle arrest; 2. 8A augmented early and late phase cancer cell apoptosis significantly compared to that of Ebselen and 8B-D; 3. Both 8A and phenyl-β-d-xyloside primed glycosaminoglycans with similar disaccharide compositions in CHO-pgsA745 cells; 4. Glycosaminoglycans could be detected inside of cells only when treated with 8A, indicating Ebselen contributed to the unique property of intracellular localization of the primed glycosaminoglycans. Thus, 8A represents a lead compound for the development of novel antitumor strategy by targeting glycosaminoglycans.

A nutraceutical is defined as a standardized pharmaceutical-grade nutrient. Among hundreds of nutraceuticals, polysaccharide or glycan-based products such as those containing chondroitin sulfate glycosaminoglycan isolated from animal cartilage have been on the top nutraceutical selling list for many years. It is expected that the nutraceutical market will reach $250 billion dollars worldwide by 2018. Glycans are most abundant biopolymers on earth those are synthesized by bacteria, fungi, plants, insects, and animals. Glycans that are synthesized by animals or from all marine sources can be modified with covalently linked sulfates or containing acidic monosaccharides whereas glycans that are synthesized by terrestrial plants or fungi usually do not contain sulfates. Glycans such as starch are common sources of energy for animals, therefore they are on the nutrient-side of nutraceuticals. Undigestible polysaccharides from plants could serve as dietary fiber for humans that change the contents of the gastrointestinal tract and affect how other nutrients and chemicals are absorbed, thus dietary fibers could be called nutraceuticals. Other intra- and extracellular glycans from different sources serve as biological active components that regulate a myriad of physiological functions. The reported biological functions for such glycans are not limited to immune system regulatory, anti-coagulating, anti-tumor, anti-viral, anti-oxidant, anti-aging, and lipid-lowing activities, which make them pharmaceutical-side nutraceuticals. This review will present the full spectrum of glycan-based nutraceuticals and summarize current knowledge (published data from 1960s to current) of the structure, biological function, and mechanisms of glycans from both terrestrial and marine sources.

Testicular heat stress affects sperm quality and fertility. However, the chronology of these effects is not yet fully understood. This study aimed to establish the early sequential effects of heat stress in bull sperm quality. Semen and blood samples of Nellore breed bulls were collected and distributed into control and testicular heat stress (scrotal bags/96 h) groups. Semen samples were evaluated for sperm motility, abnormalities, plasma membrane integrity, acrosomal membrane integrity, mitochondrial membrane potential, sperm lipid peroxidation, seminal plasma lipid peroxidation, and DNA fragmentation. Blood plasma was also evaluated for lipid peroxidation. An increase in sperm abnormalities was observed 7 days following heat stress. After 14 days, sperm lipid peroxidation increased and mitochondrial membrane function, sperm motility, and plasma membrane integrity decreased. Heat stress effects were still observed after 21 days following heat stress. An increase in sperm DNA fragmentation was observed as a late effect after 28 days. Thus, the initial effects of heat stress (i.e., increasing sperm abnormalities and lipid peroxidation) suggest the presence of oxidative stress in the semen that alters mitochondrial function, sperm motility, plasma membrane integrity, and belatedly, DNA fragmentation. Although sperm abnormalities persisted and increased over time, sperm lipid peroxidation, in turn, increased only until 21 days after heat stress. In this regard, these findings provide a greater understanding of the chronological effects of experimentally induced heat stress on bovine sperm, providing valuable insights about spermatogenesis during the first 28 days following heat stress.

To study the long-term outcomes following childhood ischemic and hemorrhagic stroke.This was a retrospective study, looking at children consecutively admitted to a rehabilitation department following childhood stroke. We collected demographic, medical, and severity data, motor deficit, cognitive assessment, and long-term academic outcome.One hundred and twenty-eight children were included, following arterial ischemic (AIS; n = 46) or hemorrhagic (HS; n = 82) stroke. At discharge, motor deficit was still present in 70% of children (versus 89% immediately after stroke). HS predicted significantly better motor and functional outcomes than AIS. After a median follow-up of 43 months, 40% received special education. The receipt of special education was predicted by persistent motor deficit, but when full-scale IQ was taken into account, IQ was the only significant predictor of special education.Childhood stroke leads to severe and long lasting motor, functional, cognitive, and academic impairments, in a population of children admitted in a rehabilitation department.

OBJECTIVE PET radiopharmaceuticals are often injected in patients before all quality controls are performed and before sterility results are available. We propose a process validation to produce very safe and pure [N]NH3 for human use. METHODS [N]NH3 was produced in the cyclotron target. Online purification was performed by anionic exchange resin. All the production steps were subjected to a sterility test. Some additional controls were added to those required by the monograph. RESULTS The radiochemical yield of the syntheses was 26.3 and 61.5% corrected for decay, with a radiochemical purity of 100%. In addition to quality controls requested by the European Pharmacopeia monograph, we carefully analyzed the product for the presence of possible contaminants. Some elements, mainly metals, were found in very low amounts at concentrations in the range of ppb. The radionuclidic purity was verified. The achievement of the parameters of osmolality, by addition of saline solution to the preparation, made the analysis of chemical purity difficult and worsened the measurement of radiochemical purity by high performance liquid chromatography. Only pH control is necessary before administration to patients and therefore a safe production process was set up to prevent microbiological contamination. All phases were carefully standardized, starting from in-target production of [N]NH3, to final splitting in the syringes. Sterility tests showed no bacterial growth, indicating the safety of the production process. CONCLUSION All our syntheses followed the monograph indications and were optimal to obtain PET imaging of a patient's myocardium.

Biomarkers of inflammation, muscle damage, and oxidative stress after high-intensity exercise have been described previously; however, further understanding of their role in the postexercise recovery period is necessary. Because these markers have been implicated in cell signaling, they may be specifically related to the training adaptations induced by high-intensity exercise. Thus, a clear model showing their responses to exercise may be useful in characterizing the relative recovery status of an athlete. The purpose of this study was twofold: (a) to investigate the time course of markers of muscle damage and inflammation in the blood from 3 to 72 hours after combined training exercises and (b) to investigate indicators of oxidative stress and damage associated with increased reactive oxygen species production during high-intensity exercise in elite athletes. Nineteen male athletes performed a combination of high-intensity aerobic and anaerobic training exercises. Samples were acquired immediately before and at 3, 6, 12, 24, 48, and 72 hours after exercise. The appearance and clearance of creatine kinase and lactate dehydrogenase in the blood occurred faster than previous studies have reported. The neutrophil/lymphocyte ratio summarizes the mobilization of 2 leukocyte subpopulations in a single marker and may be used to predict the end of the postexercise recovery period. Further analysis of the immune response using serum cytokines indicated that high-intensity exercise performed by highly trained athletes only generated inflammation that was localized to the skeletal muscle. Biomarkers are not a replacement for performance tests, but when used in conjunction, they may offer a better indication of metabolic recovery status. Therefore, the use of biomarkers can improve a coach's ability to assess the recovery period after an exercise session and to establish the intensity of subsequent training sessions.

Children with developmental coordination disorder also manifest difficulties in non-motor domains (attentional, emotional, behavioral and socialization skills). Longitudinal studies can help disentangle the complex relationships between the development of motor skills and other cognitive domains. This study aims to examine the contribution of early cognitive factors to changes in motor skills during the preschool period. Children (N = 1144) from the EDEN mother-child cohort were assessed for motor skills with the Copy Design task (NEPSY battery) and the parent-rated Ages and Stages Questionnaire (fine and gross motor skills scores) at ages 3 and 5-6 years. At 3 years, language skills were evaluated using tests from the NEPSY and ELOLA batteries. Emotional problems, conduct problems, inattention and hyperactivity symptoms, peer relationships and pro-social behavior were assessed with the Strengths and Difficulties Questionnaire (SDQ) also at 3 years. Linear and logistic regression models were performed to examine whether positive and negative changes in motor skills between 3 and 5-6 years are associated with specific cognitive skills at 3 years, while adjusting for a broad range of pre- and postnatal environmental factors. In the linear regression model, the SDQ Inattention symptoms score at 3 years was associated with negative changes in motor skills (standardized β = - 0.09, SD = 0.03, p value = 0.007) and language skills at 3 years were associated with positive changes in motor skills (standardized β = 0.05, SD = 0.02, p value = 0.041) during the preschool period. In logistic regression models, the SDQ Inattention symptoms score at 3 years was associated with a higher likelihood of a declining trajectory of motor skills (OR [95% CI] = 1.37 [1.02-1.84]). A higher language skills score at 3 years was associated with an increased likelihood of a resilient trajectory (1.67 [1.17-2.39]). This study provides a better understanding of the natural history of developmental coordination delays by identifying cognitive factors that predict changes in motor skills between the ages of 3 and 5-6 years.

International audience; Objective. Sleep duration may vary inter-individually and intra-individually over time. We aimed at both identifying night-sleep duration (NSD) trajectories among preschoolers and studying associated factors. Methods. NSD were collected within the French birth-cohort study EDEN at ages 2, 3 and 5-6 years through parental questionnaires, and were used to model NSD trajectories among 1205 children. Familial socioeconomic factors, maternal sociodemographic, health and lifestyle characteristics as well as child health, lifestyle, and sleep characteristics at birth and/or at age 2 years were investigated in association with NSD using multinomial logistic regressions. Results. Five distinct NSD trajectories were identified: short (SS

Background: The abdominal muscles are extremely important because they are directly involved in the functions of support, containment of viscera, and help in the process of expiration, defecation, urination, vomiting, and also at the time of childbirth. Many exercises and equipment are used to strengthen the abdominal muscles, and the workouts are proposed for a variety of purposes, such as preventing and rehabilitating low back pain, improving sports performance, achieving aesthetic standards, among others. Exercises that potentiate the electromyographic activity promote a greater recruitment of muscle fibers and are more effective to improve or maintain of the force. The electromyographic activity analysis allows us to reflect on the quality of the exercises proposed, consequently, to choose and order the exercises properly in a training session. Methods: Our systematic review protocol will developed following the reporting items for the systematic review. To identify relevant studies, we sought articles on the following bases: MEDLINE, PubMed, Europubmed, SciELO, Physiotherapy Evidences Data Base (PEDro), Cochrane, and Google Scholar. The methodological quality of the studies included in the review will evaluated using a checklist and quality assessment. For intervention studies, risk of bias will estimated using the Cochrane Collaboration tool. Results: The results of this study will show the electromyographic activation of the abdomen in the different types of exercises. Conclusion: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. Systematic review registration: PROSPERO CRD42018086172.

The overall objective of the EDEN study was to examine the relations and potential interactions between maternal exposures and health status during pregnancy, fetal development, health status of the infant at birth and the child's health and development.

The aim of the study was to identify which groups of women contribute to interinstitutional variation of caesarean delivery (CD) rates and which are the reasons for this variation. In this regard, 15,726 deliveries from 11 regional centers were evaluated using the 10-group classification system. Standardized indications for CD in each group were used. Spearman’s correlation coefficient was used to calculate (1) relationship between institutional CD rates and relative sizes/CD rates in each of the ten groups/centers; (2) correlation between institutional CD rates and indications for CD in each of the ten groups/centers. Overall CD rates correlated with both CD rates in spontaneous and induced labouring nulliparous women with a single cephalic pregnancy at term (P=0.005). Variation of CD rates was also dependent on relative size and CD rates in multiparous women with previous CD, single cephalic pregnancy at term (P<0.001). As for the indications, “cardiotocographic anomalies” and “failure to progress” in the group of nulliparous women in spontaneous labour and “one previous CD” in multiparous women previous CD correlated significantly with institutional CD rates (P=0.021,P=0.005, andP<0.001, resp.). These results supported the conclusion that only selected indications in specific obstetric groups accounted for interinstitutional variation of CD rates.

Cannabis is the most commonly used illicit drug in psychosis patients and has been identified as a risk factor for relapse and subsequent hospital readmission, having substantial economic implications. To clarify the contribution of cannabis consumption to hospital readmission, a consecutive inpatient cohort of 161 early psychosis patients was included into the study. Data on cannabis use at admission and number of hospital readmissions and length of stay (LOS, number of inpatient days) in a 6-year follow-up was extracted from clinical notes. 62.4% of the patients had lifetime cannabis use. Their admission lasted on average 54.3 ± 75 days and over the following 6 years patients had 2.2 ± 2.8 hospital readmissions, for a total of 197.4 ± 331.5 days. Cannabis use significantly predicted the number of hospital readmissions and LOS in the following 6 years, the latter remaining significant after adjusting for use of other substance. Cannabis-using patients of male gender and Black ethnicity had a longer LOS at follow-up compared to female patients and other ethnic groups, respectively. Having a history of cannabis use when admitted to an early intervention inpatient unit for psychosis is associated with a higher number of subsequent hospital readmissions and a longer LOS, especially in male and Black patients.

International audience; BACKGROUND & AIMS: Programming of infant development and later health may depend on early-milk polyunsaturated fatty acids (PUFA) contents, that are very variable between women for reasons not well elucidated. Indeed, a high n-6/n-3 PUFA in milk was associated with higher adiposity, arterial pressure and lower psychomotor scores in childhood. We aimed to explore the respective contribution of several maternal and perinatal factors to the variability of linoleic (LA), α-linolenic (ALA), arachidonic (AA), and docosahexaenoic (DHA) acid levels in early milk. METHODS: Fatty acids of 934 colostrum samples from the EDEN mother-child cohort were analyzed by gas chromatography. The dietary intakes during the last trimester of pregnancy were estimated using a quantitative food frequency questionnaire. Relationship between milk PUFA and dietary fatty acids, and other maternal or pregnancy variables were analyzed by multiple linear regression.RESULTS: The means (±SD) of colostrum LA, ALA, AA and DHA levels were, respectively, 9.85 ± 1.85, 0.65 ± 0.22, 0.86 ± 0.16, and 0.64 ± 0.19% of total fatty acids. Obese mothers colostrum contained the highest level of LA and AA and the lowest level of ALA and DHA. Colostrum LA, AA and DHA levels were higher in primiparous women. Mother's age was positively associated with colostrum AA and DHA. Dietary n-6 PUFA were associated with higher LA and lower DHA levels in colostrum, while dietary n-3 PUFA were related to higher LA and lower AA levels. Contrary to what was observed for DHA, AA level in colostrum was not related to its dietary intake. High dietary AA/DHA and total n-6/n-3 ratios were critical for the content of DHA in colostrum lipids.CONCLUSIONS: Our study brings new insights in the understanding of the main maternal factors involved in PUFA levels variability in early milk. These data are important to consider for dietary counseling for women prior to and during pregnancy.

Objective The aim was to study, with a developmental approach, the longitudinal association between night-waking from age 2 to 5–6 years and behavior at age 5–6 years. Methods Within the French birth cohort study Etude sur les Determinants pre et post natals du developpement et de la sante de l'ENfant (EDEN), repeated measures of children's night-waking were collected at age 2, 3 and 5–6 through parental questionnaires and were used to model night-waking trajectories. Behavior was assessed with the “Strengths and Difficulties Questionnaire,” which provides five subscales measuring a child's conduct problems, emotional symptoms, peer relation problems, antisocial behavior, and hyperactivity/attention problems. The behavioral subscales were dichotomized at the tenth percentile. Multivariable logistic regressions, adjusted for parents' socio-economic factors, parental characteristics, and children's characteristics and sleep habits allowed us to study, in 1143 children, the association between night-waking trajectories from 2 to 5–6 years and behavior at age 5–6 years. Results The “2 to 5–6 rare night-waking” trajectory represented 78% of the included population (n = 896), and the “2 to 5–6 common night-waking” 22% (n = 247%). Children belonging to the “2 to 5–6 common night-waking trajectory” had, at age 5–6, increased risk of presenting emotional symptoms (odds ratio [OR] = 2.17, 95% CI = 1.27–3.70, p = 0.004), conduct problems (OR = 1.63, 95% CI = 1.00–2.65, p = 0.050), and hyperactivity/attention problems (OR = 1.61, 95% CI = 1.00–2.57, p = 0.049). After adjusting for baseline behavior at age two years, only the association with emotional symptoms remained significant (OR = 2.02, 95% CI = 1.15–3.55, p = 0.015). Results did not differ according to sex. Conclusion Results suggest that the persistence of night-waking difficulties in early years is positively associated with emotional symptoms, hyperactivity/inattention, and conduct problems.

Background Executive function (EF) impairment is a major predictor of overall outcome after traumatic brain injury (TBI). TBI severity is a factor of poor outcome, but most studies include a majority of children with mild and moderate TBI. The aims of this study were to estimate EF impairment after severe childhood TBI and to explore factors predicting EF outcome. The secondary aim was to compare recovery trajectories by age-at-injury groups. Methods This was a prospective longitudinal study of children with severe TBI who were tested for EFs by performance-based tests and questionnaires at 3, 12 and 24 months. Results Children with TBI (n = 65) showed significant impairment in working memory, inhibition, attention and global EF, with little or no recovery at 24 months. For flexibility and performance-based EF score, children were impaired at 3 months only and showed normal scores by 12 months. No impairment was found in planning. At 3 and 24 months, Glasgow Coma Scale score and parental education predicted global EF. Coma length was not a significant predictor of outcome. Age at injury predicted progress in EF, but the relationship was not linear; children 10–12 years old at injury showed better outcome than older and younger children. Conclusions EFs are impaired after severe TBI in childhood. The relationship between age at injury and outcome is not linear. Relying on only performance-based EF tests can underestimate EF impairment.

This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

INTRODUCTION:The frequency of methicillin-resistant Staphylococcus aureus (MRSA) has increased in the community. This study evaluated the prevalence of MRSA and community-acquired (CA)-MRSA in 120 healthy elderly.METHODS:The MRSA were evaluated for the presence of the IS256, mecA, agr, icaA, icaD, fnbB , and pvl genes with PCR. Results: Frequency of S. aureus and MRSA colonization was 17.8% and 19%, respectively. CA-MRSA isolate showed SCC mec IV, fnbB+ , and icaD+ .CONCLUSIONS:CA-MRSA was detected, with genotype determined as SCC mec type IV/IS256/ fnbB+ / icaA / icaD+ / bbp-/agr2 / bap / pvl, characterizing this population as a possible reservoir of this organism in the community.

International audience; on behalf of the EDEN Mother-Child Cohort Study Group (Etude des Déterminants pré-et postnatals précoces du développement et de la santé de l'Enfant)* Objective To examine the relationship of polyunsaturated fatty acid (PUFA) in breast milk with children's IQ. Study design In the French Etude des Déterminants pré-et postnatals précoces du développement et de la santé de l'Enfant (EDEN) mother-child cohort, colostrum samples were collected at the maternity unit. Colostrum omega-6 and omega-3 PUFA were analyzed by gas chromatography. At age 5-6 years, the IQs of 1080 children were assessed using the Wechsler Preschool and Primary Scale of Intelligence-III. The relationships of breastfeeding duration and PUFA levels with children's IQs were examined by linear regression. Results Full scale IQ of ever breastfed children was 4.5 (95% CI: 2.7, 6.2) higher than never breastfed children in the unadjusted model, but this was not statistically significant in the adjusted model (1.3 points higher [-0.4, 3.0]). Any breastfeeding duration was associated with full scale (0.20 [0.00, 0.41] points/month) and verbal [0.31 [0.09, 0.52]) IQ. Colostrum linoleic acid (LA) levels were negatively associated with Verbal IQ (-0.6 [-1.1, 0.0] points per 1% level increase). Children exposed to colostrum high in LA and low in docosahexaenoic acid (DHA) had lower IQs than those exposed to colostrum high in DHA (3.0 [0.5, 5.5] points) and those exposed to colostrum low in LA and DHA (4.4 [1.6, 7.3] points). Finally, the association between breastfeeding duration and child IQ was stronger when LA levels were high. Conclusions Duration of breastfeeding and colostrum PUFA levels were associated with children's IQs in the EDEN cohort. These data support breastfeeding and add evidence for the role of early PUFA exposure on childhood cognition. (J Pediatr 2017;■■:■■-■■).

Both the myocardial perfusion pattern and myocardial blood flow (MBF) are used to assess patients with suspected coronary artery disease (CAD). The aim of this study was to compare the perfusion pattern (using the summed difference score [SDS]) to MBF in a consecutive group of patients undergoing PET/CT with 13 N-ammonia (47 consecutive patients, aged 65 ± 12 years (42 men) with known or suspected CAD, underwent vasodilator stress/rest PET/CT withThere were no significant differences between patients with no ischemia (SDS ≤ 1) and those with ischemia (SDS 1) in CFR (2.84 ± 0.73 vs 2.63 ± 0.89, P = NS) and DMBF (1.34 ± 0.45 vs 1.24 ± 0.53 mL·minute

Studies have demonstrated the importance of mitochondria to sperm functionality, as the main source of ATP for cellular homoeostasis and motility. However, the role of mitochondria on sperm metabolism is still controversial. Studies indicate that, for some species, glycolysis may be the main mechanism for sperm energy production. For ram sperm, such pathway is not clear. Thus, we evaluated ram sperm in response to mitochondrial uncoupling and glycolysis inhibition aiming to assess the importance of each pathway for sperm functionality. Statistical analysis was performed by the SAS System for Windows, using the General Linear Model Procedure. Data were tested for residue normality and variance homogeneity. A p

This study assessed the association between timing and course of maternal depression from pregnancy onwards and children's cognitive development at ages 5 to 6. Potential interaction effects with child sex and family socioeconomic status were explored.One thousand thirty-nine mother-child pairs from the French EDEN mother-child birth cohort were followed from 24 to 28 weeks of pregnancy onwards. Based on Center for Epidemiological Studies Depression (CES-D) and Edinburgh Postnatal Depression Scale (EPDS) scores assessed at six timepoints, longitudinal maternal depressive symptom trajectories were calculated with a group-based semiparametric method. Children's cognitive function was assessed at ages 5 to 6 by trained interviewers with the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III), resulting in three composite scores: Verbal IQ (VIQ), Performance IQ (PIQ), and Full-Scale IQ (FSIQ).Five trajectories of maternal symptoms of depression could be distinguished: no symptoms, persistent intermediate-level depressive symptoms, persistent high depressive symptoms, high symptoms in pregnancy only, and high symptoms in the child's preschool period only. Multiple linear regression analyses showed that, compared to children of mothers who were never depressed, children of mothers with persistent high levels of depressive symptoms had reduced VIQ, PIQ, and FSIQ scores. This association was moderated by the child's sex, boys appearing especially vulnerable in case of persistent maternal depression.Chronicity of maternal depression predicts children's cognitive development at school entry age, particularly in boys. As maternal mental health is an early modifiable influence on child development, addressing the treatment needs of depressed mothers may help reduce the associated burden on the next generation.

We compared the effects of 12 weeks of 3 different exercise types on type 2 diabetic (T2DM) male and female human subjects, randomly divided into 4 groups: aerobic training (AT; n = 11), strength training (ST; n = 10), combined training (CBT; n = 10), and no training (NT; n = 12). Metabolic control, anthropometric parameters, lipid and hematologi- cal profiles, kidney and liver function markers, hormones, antioxidant enzymes, and oxidative stress markers were assessed prior to and after the training programs. At baseline, fasting blood glucose and hemoglobin A1c in the ST group were higher than in the NT group; after the training, we no longer observed differences in these groups, suggesting an improvement on these parameters. In the AT group, catalase and superoxide dismutase activity, nitrite concentration, levels of sulfhydryl groups, and peak rate of oxygen consumption were elevated after the training (p < 0.05). No changes were observed in anti- oxidant enzymes or oxidative stress markers in the ST group. The levels of sulfhydryl groups diminished in the NT group (p < 0.01) and increased in the CBT group (p < 0.05). These data demonstrate that the AT program for the T2DM subjects provided important upregulation in antioxidant enzymes and increased nitric oxide bioavailability, which may help minimize oxidative stress and the development of the chronic complications of diabetes. We propose that the beneficial effects ob- served in the metabolic parameters of the ST group occurred in response to the poor baseline metabolic health n this group, and not necessarily in response to the training itself.

In young children, visual attention, analysis or memory is only rarely evaluated. Moreover, tools to test for such higher-order visual capacities in children are limited. In an attempt to develop and refine such tools, we selected nine tests to assess visuo-attentional abilities before formal reading education (grade 1). The battery consisted of gaze fixation, visual field, visual extinction, binocular visual pursuit, visual memory, "A" cancellation, Teddy bears cancellation, embedded figures, and matching tasks. This battery was used in the general population (n=110) to calculate cut-off scores identifying the lower 5% of the general population to obtain a screening measure for neurovisual disabilities in children. To evaluate our battery's sensitivity and specificity to neurovisual disorders over ophthalmological diseases, a neurovisual group (n=9) and an ophthalmologic group (n=13) also completed the tests. Overall, all but three tests of the battery could be used to discriminate between neurovisual and ophthalmologic children. The ophthalmologic children failed the visual field extent examination and the cancellation tasks, consistent with deleterious effects of ophthalmologic disease on visual perception as well as higher-order vision. Using the cut-off scores, the battery identified only 2 out of 13 ophthalmologic patients, but 5 out of 9 neurovisual patients. In the general population, these cut-off scores identified seven children. These children were previously undiagnosed with any disability (i.e., no diagnosis of ophthalmological, neurological, or psychiatric disease) and thus did not receive any rehabilitation. This preliminary study highlights the necessity for a neurovisual disorder screening tool for young children.

International audience; The present study aimed to show that bidirectional reading and language exposure influence the position of egocentric reference (ER), the perceived direction of the body's sagittal axis proposed to act as an anchor for movements in extracorporeal space. Directional factors (e.g., visual scanning bias and reading habits) have been proposed to influence visuospatial performance, such as in line bisection and figure drawing. In past studies, bidirectional readers have been less consistent in demonstrating a bias compared to unidirectional readers. Using a straight-ahead pointing task to assess egocentric reference, we compared 14 unidirectional left-to-right readers (Uni-LR) to three bidirectional reading groups that differed in the reading direction of their native language and/or the level of their second language literacy: 16 low-English literate, native right-to-left, bidirectional readers (Lo-Bi-RL), 13 high-English literate, native right-to-left, bidirectional readers (Hi-Bi-RL), and 15 native left-to-right, bidirectional readers (Bi-LR). Participants were asked to point straight-ahead while blindfolded using either a left-to-right or a right-to-left scanning direction to approach the subjective sagittal midline. Uni-LRs showed left-side spatial bias when scanning left-to-right and right-side bias during right-to-left scanning, Bi-LRs and Lo-Bi-RLs (i.e., intermediate level or less in their second language) demonstrated the opposite pattern, and Hi-Bi-RLs showed left-side spatial bias regardless of scanning direction. Results are discussed in terms of accuracy and spatial bias regarding the interaction between reading direction and spatial cognition based on the level of bidirectional literacy and language exposure.

Although 22q terminal deletions are well documented, very few patients with mosaicism have been reported. We describe two new cases with mosaic 22q13.2-qter deletion, detected by karyotype analysis, showing the neurological phenotype of 22q13.3 deletion syndrome. Case 1 represents an exceptional case of mosaicism for maternal 22q13.2-qter deletion (45% of cells) and 22q13.2-qter paternal segmental isodisomy (55% of cells). This complex situation was suspected because cytogenetic, FISH and array-CGH analyses showed the presence of an 8.8 Mb mosaic 22q13.2-qter deletion, whereas microsatellite marker analysis was consistent with maternal deletion without any evidence of mosaic deletion. Molecular analysis led to the definition of very close, but not coincident, deletion and uniparental disomy (UPD) break points. Furthermore, we demonstrated that the segmental UPD arose by gene conversion in the same region. In Case 2, mosaicism for a paternal 8.9 Mb 22q13.2-qter deletion (73% of cells) was detected. In both patients, the level of mosaicism was also verified in saliva samples. We propose possible causative mechanisms for both rearrangements. Although the size of the deletions was quite similar, the phenotype was more severe in Case 2 than in Case 1. As maternal UPD 22 has not been generally associated with any defects and as the size of the deletion is very similar in the two cases, phenotype severity is likely to depend entirely on the degree of mosaicism in each individual.

Anticoagulant heparan sulfate proteoglycans bind and activate antithrombin by virtue of a specific 3-O-sulfated pentasaccharide. They not only occur in the vascular wall but also in extravascular tissues, such as the ovary, where their functions remain unknown. The rupture of the ovarian follicle at ovulation is one of the most striking examples of tissue remodeling in adult mammals. It involves tightly controlled inflammation, proteolysis, and fibrin deposition. We hypothesized that ovarian heparan sulfates may modulate these processes through interactions with effector proteins. Our previous work has shown that anticoagulant heparan sulfates are synthesized by rodent ovarian granulosa cells, and we now have set out to characterize heparan sulfates from human follicular fluid. Here we report the first anticoagulant heparan sulfate purified from a natural human extravascular source. Heparan sulfate chains were fractionated according to their affinity for antithrombin, and their structure was analyzed by 1H NMR and MS/MS. We find that human follicular fluid is a rich source of anticoagulant heparan sulfate, comprising 50.4% of total heparan sulfate. These antithrombin-binding chains contain more than 6% 3-O-sulfated glucosamine residues, convey an anticoagulant activity of 2.5 IU/ml to human follicular fluid, and have an anti-Factor Xa specific activity of 167 IU/mg. The heparan sulfate chains that do not bind antithrombin surprisingly exhibit an extremely high content in 3-O-sulfated glucosamine residues, which suggest that they may exhibit biological activities through interactions with other proteins.

Low-molecular-weight heparin (LMWH) has been suggested to reduce the risk of cancer progression in both preclinical and clinical studies but the underlying mechanisms remain poorly explored. The aim of the study was to investigate the anti-metastatic role of enoxaparin, a clinically-used LMWH, in a murine model of colon cancer and to explore its underlying mechanisms.Using a reproducible mouse model of colon carcinomas, we assessed the capacity of enoxaparin, a LMWH, to affect tumor metastasis of colon carcinoma cell lines in mice.The hepatic growth of colon carcinoma metastases was strongly inhibited by enoxaparin compared to (Ctrl) group (p=0.001). This effect was associated to an inhibition of heparanase mRNA expression and protein production both in vivo and in vitro. In addition, enoxaparin inhibited the liver and serum production of interferon gamma (Ifnγ)-inducible chemokine receptor ligands. Overexpression of heparanase prompted proliferation, migration and growth of colon carcinoma in vitro and in vivo to a point that was not affected by enoxaparin in vivo anymore.Enoxaparin decreased liver metastases in a mouse model of colon carcinoma. These results suggest that enoxaparin may benefit patients with cancer and deserves further laboratory and clinical investigations.

Evidence from animal studies suggests maternal caffeine intake during pregnancy has detrimental effects on subsequent brain development in offspring. However, human data in this area are limited. The aim of this study was to assess whether caffeine intake by women during pregnancy is associated with impaired cognitive development in offspring at age 5.5 years.Multivariate modeling was conducted using data of 1083 mother-child pairs from a population-based birth cohort in France followed from pregnancy to age 5.5 years of the children. Measures included an estimate of maternal caffeine intake during pregnancy, children's IQ at age 5.5, and individual and family characteristics.Prenatal caffeine exposure was common in the sample (91%) with 12% displaying an intake ≥200 mg/day (high). Multivariable modeling showed a significant negative relationship between caffeine intake and children's IQ at 5.5 years (-.94 [95% confidence interval = -1.70, -.17] full IQ unit per 100 mg daily caffeine intake). In particular, children of mothers consuming ≥200 mg/day were more likely to have borderline or lower IQ compared with children of mothers consuming100 mg/day (13.5% vs. 7.3%; odds ratio = 2.30, 95% confidence interval = 1.13, 4.69).We found an association between caffeine intake during pregnancy and impaired cognitive development in offspring, a result in line with animal data. More epidemiologic and biologically grounded research is needed to determine whether this association is causal. This finding suggests that conservative guidelines regarding the maximum caffeine intake recommended in pregnancy (i.e., 200 mg/day) should be maintained.

Purpose : We have carried out experiments to determine if human cervical mucus can act as an in vitro selective barrier against spermatozoa morphologically normal that carry genetic structural abnormalities. Methods : Sperm chromatin abnormalities have been evaluated by Chromomycin A3 and “endogenous” nick translation. Results : The data obtained have shown that spermatozoa possessing higher levels of DNA protamination are more proficient in crossing the cervical mucus barrier. Moreover, the levels of positivity to endogenous nick translation treatment was practically zero in such spermatozoa. Conclusions : We suggest that sperm penetration of cervical mucus could be used to select sperm preparations free of fragmented DNA or chromatin structural abnormalities for assisted reproduction.

Aims and background The results of several randomized trials and meta-analyses have been reported on adjuvant treatment for early breast cancer and treatment guidelines have been defined accordingly, but detailed data are lacking on the appropriateness of treatment prescription in clinical practice. Methods We performed a prospective, observational, multicenter study to monitor the prescription, delivery and effectiveness of radiotherapy following conservative surgery for early breast cancer; 1610 patients treated with postoperative radiation to the breast in 1997 were entered by 12 centers in Lombardy, Italy. Here we report the results of a secondary analysis focused on the prescription of medical adjuvant treatment (1547 eligible patients). Results Chemotherapy only was prescribed to 526 patients (33%), hormonal therapy only to 539 (33%), and both treatments to 85 patients (5%); 460 women (29%) received no medical adjuvant treatment. We compared the collected data with guidelines defined in 1995 by the St Gallen Consensus Conference. Undertreatment was most frequent in node-negative patients at intermediate/high risk, no treatment (instead of tamoxifen or chemotherapy) being prescribed in 21–45% of cases. Node-negative patients at low risk, on the other hand, were overtreated with tamoxifen in 31% of cases. In node-positive, premenopausal women compliance with guidelines was far better, with a 91–96% rate of chemotherapy prescription. In node-positive, postmenopausal, estrogen receptor-positive patients chemotherapy was unduly prescribed in as many as 56% of cases. Comparison of clinical practice with the next version of the guidelines (1998) showed a somewhat better compliance. Conclusions Despite the availability of official and authoritative guidelines, adjuvant treatment prescription for early breast cancer in Lombardy in 1997 was suboptimal, especially in well-defined subgroups of patients.

Understanding infertility and sterility requires knowledge of the molecular mechanisms underlying sexual reproduction. We have found that male mice deficient for the gene encoding the protease inhibitor protease nexin-1 (PN-1) show a marked impairment in fertility from the onset of sexual maturity. Absence of PN-1 results in altered semen protein composition, which leads to inadequate semen coagulation and deficient vaginal plug formation upon copulation. Progressive morphological changes of the seminal vesicles also are observed. Consistent with these findings, abnormal PN-1 expression was found in the semen of men displaying seminal dysfunction. The data demonstrate that the level of extracellular proteolytic activity is a critical element in controlling male fertility.

A care network has been created in the Paris area according to two criteria – the continuity and the specificity of the care, with a single place to manage pediatric neurosurgical emergencies. This network makes possible research about brain-injured children. Until recently, the ”Kennard principle”, that is, the assumption that recovery after similar lesions is greater in children than in adults has been supposed to be always true. In fact, if the lesions are diffuse, recovery is not greater in children compared with adults, or in younger children compared with older ones: the prognosis depends on the remaining ability to learn new practices. Normal IQ does not mean absence of sequelae. The cognitive deficits are very similar to those found in adults at the acute phase. For instance, visuo-spatial neglect appears as rather frequent when systematically looked for. The final assessment of outcome after childhood traumatic brain-injury should be done only after several years.

The aim of the present study was to determine the extent to which aesthetic preference, previously attributed to cerebral dominance, may be determined by reading habits. One hundred and sixty two normal subjects were presented pairs of images, one being the mirror-image of the other, and were asked for their aesthetic preference. Half of the subjects were left-to-right readers (French subjects) and the other half were right-to-left readers (Israeli subjects). We found a significant effect of reading habits on aesthetic preference, with left-to-right readers showing a preference for stimuli with a rightward directionality while right-to-left readers preferred stimuli with a leftward directionality. These findings raise the question of an interaction between cultural factors and cerebral dominance.

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations.Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood.Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage.Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB.Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

In order to examine further the role of cultural and environmental factors in human manual preference, two surveys were undertaken in students from Ivory Coast and Sudan. In the first study (Abidjan, Ivory Coast) 382 secondary students, ages 12 to 22, answered a 20-item manual preference questionnaire. The observed frequency of left-hand preference was 7.9%, with very low left-hand use among the 18–22 age group (1%) and high among the 12–15 age group (14%). In the second study (Khartoum, Sudan) 759 undergraduates, ages 18 to 33, answered a 25-item questionnaire. The observed frequency of left manual preference was 5%. Subjects were also asked to indicate any pressure to change hand for writing, eating, or other manual activities and, in the second study, any upper limb injury which temporarily rendered the subject unable to use his (her) preferred hand. Report of an upper limb injury in the past was related to mixed (or inconsistent) hand preference. In both studies, the target activity against left-hand use was eating. These results show that cultural and environmental factors could change “natural” hand preference in three ways: (i) by changing the hand used for only one activity (e.g., eating), with no change for other familiar unimanual activities; (ii) by reducing the degree of hand preference; (iii) by changing the overall preferred hand, generally reducing the prevalence of left-handedness. The design of handedness studies should allow these possibilities to be distinguished.

International audience; Long-chain polyunsaturated fatty acids (LC-PUFAs) of the n6 (ω6) and n3 series are essential for the development of a child's brain. Fetal LC-PUFA exposure as well as infant exposure via breast milk depend on the maternal intake of these LC-PUFAs and of their respective dietary precursors (PUFAs). We aimed to investigate the associations between maternal LC-PUFA and PUFA [(LC)PUFA] dietary intake during pregnancy and child neurodevelopment at ages 2 and 3 y. In 1335 mother-child pairs from the EDEN cohort, we evaluated associations between daily maternal (LC)PUFA intake during the last 3 months of pregnancy with the child's language at age 2 y and with different assessments of development at age 3 y. Associations were investigated separately in breastfed and never-breastfed children. We examined interactions between the ratios of n6 and n3 (LC)PUFA intakes (n6:n3 fatty acid ratio) and duration of breastfeeding. Breastfeeding mothers had a lower n6:n3 fatty acid ratio (8.4 vs. 8.8; P = 0.02). Among never-breastfed children (n = 338), we found negative associations between maternal dietary n6:n3 fatty acid ratios and neurodevelopment, as reflected by the child's language at age 2 y (β ± SE = -2.1 ± 0.7; P = 0.001) and development assessed with the Ages and Stages Questionnaire at age 3 y (-1.5 ± 0.8; P = 0.05). Among mothers with a high n6:n3 fatty acid ratio only, breastfeeding duration was positively associated with language at age 2 y (P-interaction < 0.05). This suggests that the ratio between maternal dietary n6 and n3 (LC)PUFA intake possibly influences the child's brain development during fetal life but not during or by breastfeeding. However, breastfeeding might compensate for prenatal imbalance in maternal dietary n6:n3 fatty acid ratio.

International audience; OBJECTIVE: To investigate the dose-response relationship between breastfeeding duration and cognitive development in French preschool children. STUDY DESIGN: In the French EDEN Mother-Child Cohort Study, we evaluated language ability with the Communicative Development Inventory (CDI) in 1387 2-year-old children and overall development with the Ages and Stages Questionnaire (ASQ) in 1199 3-year-old children. Assessments were compared between breastfed and non-breastfed children and also according to breastfeeding duration in multivariable linear models, controlling for a wide range of potential confounders. We tested departure from linearity. RESULTS: After adjustments, ever-breastfed children scored 3.7 ± 1.8 (P = .038) points higher than never-breastfed children on the CDI and 6.2 ± 1.9 (P = .001) points higher on the ASQ. Among breastfed children, exclusive and any-breastfeeding durations were positively associated with both CDI and ASQ scores. The fine motor domain of ASQ was associated with any-breastfeeding duration, and the problem solving domain with exclusive-breastfeeding duration. We did not observe significant departures from linearity. No interactions were found between the child's sex, parental education or socioeconomic status, and breastfeeding duration. CONCLUSION: Longer breastfeeding duration was associated with better cognitive and motor development in 2- and 3-year-old children and a dose-response relationship was suggested.

The post-coital test involves direct microscopic examination of sperm number and motility in cervical mucus. The results depend on the quality of the mucus and the distribution of spermatozoa within the sample. To progress from such qualitative data to quantitative measurements of the spermatozoa present in post-coital mucus, we have developed methods to measure sperm concentrations in enzymatically liquefied post-coital cervical mucus. The mucus score and sperm motility were measured prior to mucus liquefaction, and, together with sperm concentration, they allowed the calculation of the total number of motile spermatozoa present. A combination of bromelin and glycosidases proved to be more efficient in achieving reliable mucus liquefaction than treatment with bromelin alone, and was used to liquefy a series of 36 post-coital test samples. Total sperm numbers ranged between 19 x 10(3) and 16.8 x 10(6). Of the samples, 75% contained < 3 x 10(6) spermatozoa, and 39% contained < 1 x 10(6) spermatozoa. Sperm motility was very high in these samples, except for a distinct subset of samples (19%) in which the total sperm motility was markedly decreased ( < 20%). The measurement of sperm concentration in liquefied cervical mucus will help to determine normal values for the post-coital test, and to estimate the number of motile spermatozoa reaching the upper female genital tract.