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Neonatal encephalopathy (NE) caused by hypoxia-ischemia (HI) affects around 1 per 1000 term newborns and is the leading cause of acquired brain injury and neurodisability. Despite the use of hypothermia (HT) as a standard of care, the incidence of NE and its devastating outcomes remains a major issue. Ongoing research surrounding add-on neuroprotective strategies against NE is important as HT effects are limited, leaving 50% of treated patients with neurological sequelae. Little is known about the interaction between necroptotic blockade and HT in neonatal HI. Using a preclinical Lewis rat model of term human NE induced by HI, we showed a neuroprotective effect of Necrostatin-1 (Nec-1: a compound blocking necroptosis) in combination with HT. The beneficial effect of Nec-1 added to HT against NE injuries was observed at the mechanistic level on both pMLKL and TNF-α, and at the anatomical level on brain volume loss visualized by magnetic resonance imaging (MRI). HT alone showed no effect on activated necroptotic effectors and did not preserve the brain MRI volume. This study opens new avenues of research to understand better the specific cell death mechanisms of brain injuries as well as the potential use of new therapeutics targeting the necroptosis pathway.

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

Group B

Group B Streptococcus (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 106 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1β and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.

Compatible pair participation in kidney paired donation (KPD) may increase the likelihood of finding suitable matches for all registered pairs. Retrospective studies have shown variable enthusiasm for participating in KPD in compatible pairs.The study objective was to gather potential living donor (PLD) and transplant candidate (TC) perspectives on compatible pair participation in KPD.Surveys and qualitative interviews.Three transplant programs in Canada: Centre hospitalier de l'Université de Montréal in Montreal (Québec), Vancouver General Hospital, and St. Paul's Hospital in Vancouver (British Columbia).Both PLDs and TCs undergoing evaluation for donation/transplantation between 2016 and 2018 at 3 transplant programs in Canada.Descriptive statistical analysis was performed for the results of the survey and thematic and content analysis method was used for the content of the qualitative interviews.A total of 116 PLDs and 111 TCs completed surveys and an additional 18 PLDs and 17 TCs underwent semi-directed interviews. Of those surveyed, 61.2% of PLDs and 76.6% of TCs reported a willingness to participate in KPD as a compatible pair. The possibility of a more optimally matched kidney for the TC and policies ensuring prioritization of the TC for repeat transplantation in the event of early graft failure increased willingness to participate in KPD. Major concerns expressed during the interviews included the desire to retain the emotional bond of directed donation, the fear of chain breaks or donor reneging, delays in transplantation, and additional travel associated with participation in KPD.The limitations of this study are that it was conducted in only 3 Canadian transplant programs and that the interviews and surveys were in French and in English. As a consequence, the results may not be reflective of the views of individuals not living in these 2 provinces and from ethnic minority populations.Most of the compatible PLDs and TCs surveyed were willing to participate in KPD. Ensuring timely transplantation and a more optimal match for TCs and offering a policy of reciprocity to ensure timely repeat transplantation for compatible recipients if their allograft fails post KPD transplant may further increase compatible pair participation in KPD.La participation de paires d’individus compatibles au don croisé d’un rein (DCR) peut augmenter la probabilité de trouver des donneurs et receveurs compatibles pour tous les individus enregistrés. Des études rétrospectives ont montré un enthousiasme variable des paires d’individus compatibles à participer au DCR.Cette étude visait à recueillir les points de vue de donneurs vivants potentiels et de candidats à la greffe sur la participation de paires d’individus compatibles au DCR.Sondages et interviews qualitatives.Trois programmes de transplantation canadiens : le centre hospitalier de l’Université de Montréal à Montréal (Québec), de même que le Vancouver General Hospital et le St Paul’s Hospital de Vancouver (Colombie-Britannique).Les donneurs vivants potentiels (DVP) et les candidats à la greffe (CG) ayant fait l’objet d’une évaluation pour un don ou une transplantation dans trois programmes de transplantation canadiens entre 2016 et 2018.Une méthode d’analyse statistique descriptive a servi à analyser les résultats du sondage, tandis que le contenu des interviews qualitatives a été analysé à l’aide de méthodes d’analyse thématique et de contenu.En tout, 116 DVP et 111 CG ont répondu au sondage, alors que 18 DVP et 17 CG supplémentaires ont été rencontrés pour des entrevues semi-dirigées. Parmi les répondants au sondage, 61,2 % des DVP et 76,6 % des CG ont indiqué qu’ils seraient prêts à participer au DCR en tant que membre d’une paire d’individus compatibles. La possibilité pour le CG d’obtenir un rein avec un meilleur match et les politiques assurant la priorisation du CG pour une transplantation répétée en cas d’échec précoce de la greffe ont augmenté la volonté de participer au DCR. Parmi les principales préoccupations exprimées au cours des entrevues figuraient notamment le désir de préserver le lien émotionnel du don dirigé, la peur d’une rupture dans la chaîne, la peur du renoncement du donneur, les possibles retards pour la transplantation et les déplacements supplémentaires associés à une participation au DCR.L’étude est limitée par le fait qu’elle n’a été réalisée que dans trois programmes canadiens de transplantation et que les entrevues et les sondages n’étaient menés qu’en français et en anglais. Les résultats pourraient par conséquent ne pas refléter les opinions des personnes issues des minorités ethniques ou ne résidant pas dans ces deux provinces.La majorité des DVP et des CG compatibles qui ont été interrogés étaient ouverts à participer au don croisé d’un rein. Il est possible d’augmenter la participation de paires d’individus compatibles au don croisé d’un rein. Pour ce faire, on doit assurer une par un meilleur match optimale et une greffe en temps opportun pour les candidats à la transplantation; il faut également offrir une politique de réciprocité assurant une greffe répétée en temps opportun aux receveurs compatibles dont l’allogreffe échoue après un DCR.

Background: Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death. Objectives: Using an established rat model of group B Streptococcus (GBS)-induced chorioamnionitis, we hypothesized that ampicillin treatment increases placental inflammation, as shown in other bacterial infections. Methods: At gestational day 19, 19 Lewis dams were intraperitoneally (i.p.) inoculated by 108 CFU of β-hemolytic serotype Ia GBS (strain #16955 susceptible to ampicillin). Dams were treated i.p. with either 200 mg/kg of ampicillin (n = 9) or 0.9% saline (n = 10) at 48 and 60 h post-GBS inoculation. Cesarean sections were performed 72 h post-GBS inoculation. Results: Ampicillin treatment was associated with an increased number of polymorphonuclear cells (PMN) infiltrating the decidua (mean 1,536 vs. 532 PMN/mm2; p < 0.001) and a higher placental concentration of IL-1β (mean 26.4 vs. 7.9 pg/mg; p < 0.01) compared to saline-treated dams. These effects were observed in dams without GBS bacteremia. Conversely, ampicillin treatment was associated with a decreased placental concentration of proinflammatory cytokines in dams with GBS bacteremia. Conclusions: Ampicillin increases placental inflammation in a rat model of GBS-induced chorioamnionitis without bacteremia. This proinflammatory effect of ampicillin could be due to bacterial lysis. Our findings do not query the intrapartum antibiotic prophylaxis against GBS disease. They pave the way for future preclinical studies combining anti-inflammatory treatments and antibiotic therapy for GBS-induced chorioamnionitis.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis, which is a major risk factor for premature birth and brain injuries. Males are at greater risk than females for developing lifelong neurobehavioural disorders, although the origins of this sex bias remain poorly understood. We previously showed that end-gestational inflammation triggered by GBS led to early neurodevelopmental impairments mainly in the male rat progeny. Identifying key inflammatory players involved in maternofetal immune activation by specific pathogens is critical to develop appropriate novel therapeutic interventions. We aimed to map out the GBS-induced profile of innate immune biomarkers in the maternal-placental-fetal axis, and to compare this immune profile between male and female tissues. We describe here that the GBS-induced immune signalling involved significantly higher levels of interleukin (IL)-1β, cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) and polymorphonuclear cells (PMNs) infiltration in male compared to female maternofetal tissues. Although male – but not female – fetuses presented increased levels of IL-1β, fetuses from both sexes in-utero exposed to GBS had increased levels of TNF-α in their circulation. Levels of IL-1β detected in fetal sera correlated positively with the levels found in maternal circulation. Here, we report for the first time that the maternofetal innate immune signalling induced by GBS presents a sexually dichotomous profile, with more prominent inflammation in males than females. These sex-specific placental and fetal pro-inflammatory responses are in keeping with the higher susceptibility of the male population for preterm birth, brain injuries and neurodevelopmental disorders such as cerebral palsy and autism spectrum disorders.

Reactive oxygen species (ROS) carried or induced by particulate matter (PM) are suspected to induce oxidative stress in vivo, leading to adverse health impacts, such as respiratory or cardiovascular diseases. The oxidative potential (OP) of PM, displaying the ability of PM to oxidize the lung environment, is gaining a strong interest to examine health risks associated to PM exposure. In this study, OP was measured by two different acellular assays (dithiothreitol, DTT and ascorbic acid, AA) on PM10 filter samples from 15 yearly time series of filters collected at 14 different locations in France between 2013 and 2018, including urban, traffic and Alpine valley site typologies. A detailed chemical speciation was also performed on the same samples allowing the source-apportionment of PM using positive matrix factorization (PMF) for each series, for a total number of more than 1700 samples. This study provides then a large-scale synthesis on the source-apportionment of OP using coupled PMF and multiple linear regression (MLR) models. The primary road traffic, biomass burning, dust, MSA-rich, and primary biogenic sources had distinct positive redox-activity towards the OPDTT assay, whereas biomass burning and road traffic sources only display significant activity for the OPAA assay. The daily median source contribution to the total OPDTT highlighted the dominant influence of the primary road traffic source. Both the biomass burning and the road traffic sources contributed evenly to the observed OPAA. Therefore, it appears clearly that residential wood burning and road traffic are the two main target sources to prioritized in order to decrease significantly the OP in Western Europe and, would the OP being a good proxy of human health impact, to lower the health risks from PM exposure.

International audience; Objective: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA).Design: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network).Patients: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network.Main outcome measure: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA.Results: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation.Conclusion: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

Group B Streptococcus (GBS) is a leading cause of placental infection, termed chorioamnionitis. Chorioamnionitis is associated with an increased risk of neurobehavioral impairments, such as autism spectrum disorders, which are more prominent in males than in female offspring. In a pre-clinical model of chorioamnionitis, a greater inflammatory response was observed in placenta associated with male rather than female fetuses, correlating with the severity of subsequent neurobehavioral impairments. The reason for this sex difference is not understood. Our hypothesis is that androgens upregulate the placental innate immune response in male fetuses. Lewis dams were injected daily from gestational day (G) 18 to 21 with corn oil (vehicle) or an androgen receptor antagonist (flutamide). On G 19, dams were injected with saline (control) or GBS. Maternal, fetal sera and placentas were collected for protein assays and in situ analyses. Our results showed that while flutamide alone had no effect, a decrease in placental concentration of pro-inflammatory cytokines and infiltration of polymorphonuclear cells was observed in flutamide/infected compared to vehicle/infected groups. These results show that androgens upregulate the placental innate immune response and thus may contribute to the skewed sex ratio towards males observed in several developmental impairments resulting from perinatal infection/inflammation.

// Hazel Anne Rogers 1 , Rebecca Chapman 1 , Holly Kings 1 , Julie Allard 1 , Jodie Barron-Hastings 1 , Kristian W. Pajtler 2, 3, 4 , Martin Sill 2, 3 , Stefan Pfister 2, 3, 4 and Richard Guy Grundy 1 1 Children’s Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK 2 Hopp Children’s Cancer Centre at the NCT (KiTZ), Heidelberg, Germany 3 German Cancer Research Centre (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany 4 Department of Haematology and Oncology, University Hospital, Heidelberg, Germany Correspondence to: Richard Guy Grundy, email: richard.grundy@nottingham.ac.uk Keywords: ependymoma; brain tumor; epigenetics; pediatric Received: May 16, 2018 Accepted: November 01, 2018 Published: November 23, 2018 ABSTRACT Background: Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target. Results: Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations Conclusions: Agents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown in vitro . However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using in vitro cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing. Materials and Methods: The effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling.

Group B Streptococcus (GBS) is one the most common bacterium responsible of maternal infections during pregnancy. Offspring in utero-exposed to GBS-induced placental inflammation displayed sex-specific forebrain injuries. Sex differences have been reported in several neuropsychiatric disorders. Hence, we hypothesized that female rats in utero-exposed to GBS may present sex-specific neurobehavioral impairments. Lewis rats were injected intraperitoneally every 12 h from gestational day (G) 19 to G22 with either saline (controls) or inactivated serotype Ia GBS (109 CFU). Before puberty, no difference in terms of spontaneous motor activity, exploratory or anxiety-related behaviors was noticed between experimental conditions. During puberty, GBS-exposed females – but not males – performed worse than same-sex controls in a forced motor task. During adulthood, GBS-exposed females – but not males – displayed increased spontaneous locomotor activity and decreased inhibition. In conclusion, our findings show for the first time that adult females – but not males – in utero-exposed to GBS-induced inflammation presented a hyperactive and disinhibited phenotype emerging after puberty.

Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death.Using an established rat model of group B Streptococcus (GBS)-induced chorioamnionitis, we hypothesized that ampicillin treatment increases placental inflammation, as shown in other bacterial infections.At gestational day 19, 19 Lewis dams were intraperitoneally (i.p.) inoculated by 108 CFU of β-hemolytic serotype Ia GBS (strain #16955 susceptible to ampicillin). Dams were treated i.p. with either 200 mg/kg of ampicillin (n = 9) or 0.9% saline (n = 10) at 48 and 60 h post-GBS inoculation. Cesarean sections were performed 72 h post-GBS inoculation.Ampicillin treatment was associated with an increased number of polymorphonuclear cells (PMN) infiltrating the decidua (mean 1,536 vs. 532 PMN/mm2; p0.001) and a higher placental concentration of IL-1β (mean 26.4 vs. 7.9 pg/mg; p0.01) compared to saline-treated dams. These effects were observed in dams without GBS bacteremia. Conversely, ampicillin treatment was associated with a decreased placental concentration of proinflammatory cytokines in dams with GBS bacteremia.Ampicillin increases placental inflammation in a rat model of GBS-induced chorioamnionitis without bacteremia. This proinflammatory effect of ampicillin could be due to bacterial lysis. Our findings do not query the intrapartum antibiotic prophylaxis against GBS disease. They pave the way for future preclinical studies combining anti-inflammatory treatments and antibiotic therapy for GBS-induced chorioamnionitis.

Background Group B streptococcus (GBS) is the main bacteria that infects pregnant women and can cause abortion and chorioamnionitis. The impact of GBS effects on human trophoblast cells remains largely elusive, and actions toward anti-inflammatory strategies in pregnancy are needed. A potent anti-inflammatory molecule, uvaol is a triterpene from olive oil and its functions in trophoblasts are unknown. We aimed to analyze biomechanical and functional effects of inactivated GBS in trophoblast cells, with the addition of uvaol to test potential benefits. Methods HTR-8/SVneo cells were treated with uvaol and incubated with inactivated GBS. Cell viability and death were analyzed. Cellular elasticity and topography were accessed by atomic force microscopy. Nitrite production was evaluated by Griess reaction. Nuclear translocation of NFkB p65 was detected by immunofluorescence and Th1/Th2 cytokines by bead-based multiplex assay. Results GBS at 10 8 CFU increased cell death, which was partially prevented by uvaol. Cell stiffness, cytoskeleton organization and morphology were changed by GBS, and uvaol partially restored these alterations. Nuclear translocation of NFkB p65 began 15 min after GBS incubation and uvaol inhibited this process. GBS decreased IL-4 secretion and increased IL-1β, IFN-γ and IL-2, whereas uvaol reverted this. Conclusions The increased inflammation and cell death caused by GBS correlated with biomechanical and cytoskeleton changes found in trophoblast cells, while uvaol was effective its protective role. General significance Uvaol is a natural anti-inflammatory product efficient against GBS-induced inflammation and it has potential to be acquired through diet in order to prevent GBS deleterious effects in pregnancy.

International audience; Infection or inflammation during pregnancy is known to lead to maternal immune activation triggering a fetal inflammatory response syndrome associated with deleterious effects, such as brain injury and neurodevelopmental disabilities. Group B Streptococcus (GBS) - one of the most common bacterium colonizing pregnant women - can be responsible for chorioamnionitis. Given that interleukin (IL)-1β has a major role in anti-GBS host defense, we hypothesized that IL-1β-driven innate immune response is implicated in GBS-induced chorioamnionitis. Using a rat model of GBS-induced chorioamnionitis, this study showed that inflammatory response to this pathogen was associated with maternal and placental IL-1β hyper expression. Following placental chemokine (C-X-C motif) ligand 1 (CXCL1) production, polymorphonuclear leukocytes (PMN) placental infiltration started at 24 h post-GBS exposure, and MMP-10 was released within these placentas. At 72 h, PMN infiltration extended to membranes and to membranes' arteries. This was associated with IL-1β release within the fetus blood at 72 h. Such a GBS-associated inflammatory cascade might be deleterious for fetal organs. These results pave the way toward targeted placento-protective anti-inflammatory strategies against GBS-induced chorioamnionitis.

Group B Streptococcus (GBS) is a commensal bacterium present in the lower genital tract of 15-30% of healthy pregnant women. GBS is the leading cause of chorioamnionitis and cerebral injuries in newborns, occurring most often in the absence of maternofetal pathogen translocation. Despite GBS being the most frequent bacterium colonizing pregnant women, no preclinical studies have investigated the impact of end-gestational maternal GBS exposure on the offspring's brain development and its behavioral correlates. Our hypothesis is that GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring. Our goal was to study the impact of maternal GBS infection on the placental and neurodevelopmental features in the offspring using a new preclinical rat model. GBS-exposed placentas exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring. GBS-exposed male offspring had reduced thickness of periventricular white matter. In addition, they exhibited autistic-like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity. Overall, these data show for the first time that gestational exposure to GBS plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD). These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology. Autism Res 2017, 10: 233-245. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Chorioamnionitis and intrauterine growth retardation (IUGR) are risk factors for cerebral palsy (CP). Common bacteria isolated in chorioamnionitis include group B Streptococcus (GBS) serotypes Ia and III. Little is known about the impact of placental inflammation induced by different bacteria, including different GBS strains. We aimed to test the impact of chorioamnionitis induced by two common GBS serotypes (GBSIa and GBSIII) on growth and neuromotor outcomes in the progeny. Dams were exposed at the end of gestation to either saline, inactivated GBSIa or GBSIII. Inactivated GBS bacteria invaded placentas and triggered a chorioamnionitis featured by massive polymorphonuclear cell infiltrations. Offspring exposed to GBSIII – but not to GBSIa – developed IUGR, persisting beyond adolescent age. Male rats in utero exposed to GBSIII traveled a lower distance in the Open Field test, which was correlating with their level of IUGR. GBSIII-exposed rats presented decreased startle responses to acoustic stimuli beyond adolescent age. GBS-exposed rats displayed a dysmyelinated white matter in the corpus callosum adjacent to thinner primary motor cortices. A decreased density of microglial cells was detected in the mature corpus callosum of GBSIII-exposed males – but not females – which was correlating positively with the primary motor cortex thickness. Altogether, our results demonstrate a causal link between pathogen-induced acute chorioamnionitis and (1) IUGR, (2) serotype- and sex-specific neuromotor impairments and (3) abnormal development of primary motor cortices, dysmyelinated white matter and decreased density of microglial cells.

L'autorite du juge est souvent menacee par la subjectivite des decisions rendues, auquel on oppose un imperatif d'impartialite. Du point de vue philosophique, l'impartialite, liee a la position tierce du juge, est percue comme sa capacite a mettre entre parenthese sa subjectivite, ses opinions et convictions personnelles, ses sentiments et ses affects, qui pourraient influencer de maniere arbitraire sa decision. Cette impartialite est concue par la tradition rationaliste comme une distance avec le corps et ses fragilites : il s'agit de juger en pur esprit (Platon) ou en etre inanime (Montesquieu). Deux traditions contestent cette conception de l'impartialite : selon les empiristes, aucun jugement n'est possible en surplomb, sans affect ni emotion (Hume) ; selon les sceptiques, la pretendue impartialite du juge est un rideau de fumee qui cache le pouvoir des juges et surtout, l'arbitraire de leurs decisions (Montaigne). Les penseurs contemporains comme Hannah Arendt tentent de concilier l'imperatif de rationalite et le recours aux sentiments et a l'imagination pour bien juger, et aboutissent ainsi a une notion d'impartialite qui n'est pas ontologique, mais concue comme un retour critique sur soi.

Introduction Environ 30% des nouveau-nes sont exposes a une antibioprophylaxie intrapartum. La derniere meta-analyse Cochrane evaluant l’impact de l’antibiotherapie intrapartum dans la menace d’accouchement premature sans rupture des membranes a mis en evidence une augmentation significative de la mortalite neonatale associee a ce traitement (RR : 1,57 ; IC95% : 1,03–2,40). Notre hypothese est que l’antibiotherapie maternelle par ampicilline, dans un contexte de chorioamniotite a streptocoque de groupe B (SGB), declenche un pic inflammatoire maternofœtal aboutissant a des lesions placentaires et cerebrales neonatales. Materiel et methodes Au jour de gestation 19, 19 rates de souche Lewis ont recu une inoculation par voie intraperitoneale (IP) de SGB (souche s-hemolytique de serotype Ia, 108 UFC/100 μL). Deux injections IP de 200 mg/kg d’ampicilline versus saline ont ete realisees a 48 et 60 heures post-inoculation. Les rates ont ete cesarisees a 72 heures apres l’inoculation de SGB pour collecter les placentas, les cerveaux fœtaux, des echantillons sanguins fœtaux et maternels. Resultats Une chorioamniotite aigue, caracterisee par une infiltration de polynucleaires neutrophiles, a ete detectee dans tous les placentas etudies. Une tendance vers une diminution du nombre de fœtus vivants par portee a ete observee dans le groupe expose au SGB plus ampicilline, comparativement au groupe expose au SGB plus saline (p = 0,1). A 72 heures post-inoculation, 37,5% et 66,7% des rates traitees, respectivement a l’ampicilline et a la saline, presentaient une bacteriemie a SGB (non significatif). Chez les rates sans bacteriemie a SGB a 72 heures, la concentration placentaire moyenne d’interleukine-1s etait trois fois superieure chez celles ayant ete traitees par ampicilline versus saline (p Conclusion Ces resultats ouvrent la voie a de nouvelles etudes precliniques evaluant l’effet d’un traitement anti-inflammatoire, tel l’anakinra, associe a l’ampicilline dans ce contexte de chorioamniotite a SGB. Aides financieres Agence regionale de sante Auvergne-Rhone-Alpes, Hoppenheim/Montreal Children Hospital Foundation.

Background It is vitally important to seek input from key stakeholders to increase the quality and relevance of health-related research and accelerate its adoption into practice. Patients and caregivers have rarely been involved in setting research priorities in the transplantation and donation field. The objectives of this explorative study are: (i) to discuss research priorities within the Canadian National Transplant Research Program during a priority-setting exercise with patients, caregivers, organ donors and researchers and (ii) to compare the identified priorities with research published in 2 prestigious transplantation journals. Methods A pilot workshop attended by 10 patients and caregivers and 5 researchers was held in Montréal (Quebec, Canada) in August 2014 to identify research priorities. Priorities were identified using a thematic analysis of the workshop transcription conducted by multiple coders. These priorities were compared with the topics of research articles published in 2 major transplantation journals between 2012 and 2014. Results The themes of the 10 research priorities identified by study participants were related to different research domains: social, cultural, and environmental health factors (4); biomedical or clinical (4); and research about health systems and services (2). 26.7% of the research articles published were related to the identified priorities. Thirteen percent looked at ways to improve graft survival and 8.5% looked at the development of tolerance, 2 priorities identified by participants. Fewer than 5% examined the other 8 research priorities identified as important by workshop participants. Conclusions This is the first study reporting patients' and researchers' priorities in the field of transplantation and donation in Canada. There is a discrepancy between topics that key stakeholders find important and research published in 2 major transplantation journals. The research priorities identified during our initial workshop will be validated through a national survey and workshop.

Background Cardiovascular disease (CVD) is a major cause of mortality among kidney transplant recipients (KTRs). These patients have a high prevalence of risk factors, such as hypertension, diabetes, and dyslipidemia. Despite regular medical care, few of them reach the recommended therapeutic targets. The objective of this study is to describe KTRs' perspectives on CVD and related risk factors, as well as their priorities for posttransplant care. Methods Twenty-six KTRs participated in a semistructured interview about their personal experience and offered their perspectives on CVD risk factors posttransplant. The interview was digitally recorded and the transcripts were analyzed using a thematic and content methodology. Results CVD and related risk factors appear to be underestimated and trivialized. Only 2 of 26 patients identified CVD prevention and treatment as a priority. The most important posttransplant priorities identified by patients were related to immunosuppressive drugs (13 of 26), posttransplant follow-up (10) and graft survival (9). However, 21 of 26 patients stated they wanted to be better informed about posttransplant CVD risk factors. Conclusions CVD and related risk factors are not a priority for KTRs, and the importance of CVD is underestimated and trivialized. KTRs did recommend that tailored information be provided by various professionals and at several points in the transplantation process. This knowledge will help us develop a new approach to increase awareness of posttransplant CVD and related risk factors.

La gestion éducative des manifestations associées au trouble de déficit de l’attention avec hyperactivité (TDA/H) est un défi pour les parents et l’enseignant de l’enfant qui en est atteint. Ainsi, une concertation MEQ-MSSS (2003) valorise l’implication parentale à l’école pour favoriser la réussite scolaire de ces élèves. Les études actuelles nous informent surtout des bénéfices de l’implication scolaire parentale dans la population générale. La présente étude décrit la collaboration famille-école entourant les enfants du primaire ayant un TDA/H, puis analyse ses effets sur le rendement scolaire, en écartant l’effet des variables suivantes le revenu familial, la scolarité des parents, le potentiel intellectuel de l’enfant ainsi que son sous-type diagnostique (hyperactif-impulsif, inattentif ou mixte). Les résultats montrent que la collaboration est associée au rendement scolaire, et ce encore plus fortement pour les enfants ayant un profil hyperactif-impulsif., Managing children’s behaviours associated with attention-deficit/hyperactivity disorder (ADHD) is challenging for parents and teachers. The MEQ-MSSS plan of action (2003) support parental involvement at school in order to promote school success in children with ADHD. However, the current literature provides information on the advantages of parental involvement for the general population. This study describes some aspects of home-school partnership (HSP) for elementary school-age children with ADHD in addition to its effect on school achievement while controlling the family’s income, parental education as well as the child’s IQ and ADHD subtype (hyperactive/impulsive, inattentive, mixed). Results show that HSP is associated with school achievement, particularly for predominantly hyperactive/impulsive children.

EnglishBoundary layer dynamics plays an important role on the dispersion of atmospheric pollutants, especially in mountainous areas. However, it is complicated to monitor its evolution with inexpensive measurements. Temperature sensor transects were set up along three slopes in the Arve Valley in the framework of the Decombio program. This program aimed at evaluating the impacts of the reduction of emissions from biomass heating on atmospheric particulate concentrations in a site featuring with frequent pollution episodes. This measurement setup makes it possible to acquire continuous information on the atmospheric stability via temperature difference between sensors at different altitudes. We show that, at daily scale, variations in PM10 concentrations are closely related to the variation of thermal gradient, particularly in the areas of Passy and Chamonix. francaisLa dynamique de la couche limite joue un role tres important sur la dispersion des polluants atmospheriques, particulierement en zone de montagne. Il est cependant difficile de suivre son evolution avec des moyens de mesures peu onereux. Des transects de capteurs de temperature ont ete mis en place sur les pentes le long de trois versants dans la vallee de l'Arve dans le cadre du programme Decombio. Dans un contexte de site frequemment soumis a des episodes de pollution atmospherique en hiver, ce programme avait pour objectif d'evaluer les impacts d'une action de reduction des emissions dues au chauffage au bois sur les concentrations atmospheriques de particules. Le dispositif de mesures a permis d'acquerir une information en continu sur l'etat de stabilite atmospherique via la difference de temperature entre capteurs positionnes a des altitudes differentes. Il est montre qu'a l'echelle journaliere, la variation des concentrations atmospheriques de PM10 est etroitement liee a la variation du gradient thermique, notamment au niveau des zones de Passy et Chamonix.

In June 2016, following the decision of the Supreme Court of Canada to decriminalise assistance in dying, the Canadian government enacted Bill C-14, legalising medical assistance in dying (MAID). In 2014, the province of Quebec had passed end-of-life care legislation making MAID available as of December 2015. The availability of MAID has many implications, including the possibility of combining this practice with organ donation through the controlled donation after cardiac death (cDCD) protocol. cDCD most often occurs in cases where the patient has a severe neurological injury but does not meet all the criteria for brain death. The donation is subsequent to the decision to withdraw life-sustaining treatment (LST). Cases where patients are conscious prior to the withdrawal of LST are unusual, and have raised doubts as to the acceptability of removing organs from individuals who are not neurologically impaired and who have voluntarily chosen to die. These cases can be compared with likely scenarios in which patients will request both MAID and organ donation. In both instances, patients will be conscious and competent. Organ donation in such contexts raises ethical issues regarding respect for autonomy, societal pressure, conscientious objections and the dead-donor rule. In this article, we look at relevant policies in other countries and examine the ethical issues associated with cDCD in conscious patients who choose to die.

Les conditions anticycloniques hivernales (ciel clair, nuits froides) conduisent a la formation de couches stables persistantes qui favorisent les episodes de pollution, particulierement en terrain montagneux. La vallee de l’Arve est tres sensible a ce phenomene, en particulier pres de la ville de Passy (Haute-Savoie), situee a 20 kilometres en aval de Chamonix-Mont-Blanc, ou la qualite de l’air est l’une des moins bonnes de France. Au-dela du suivi de la qualite de l’air, tel que realise par Atmo Auvergne-Rhone-Alpes ou par le projet DECOMBIO pilote par l’Institut des Geosciences et de l’Environnement (IGE), il est primordial d’ameliorer la connaissance de la dynamique atmospherique a l’echelle de la vallee en conditions stables pour mieux comprendre comment, couplee au cycle et a la geographie des emissions, elle pilote la dispersion des polluants. C’est la motivation du projet Passy, initie en 2014. Ce projet s’appuie sur les observations de la campagne Passy-2015, presentees dans cet article avec quelques premiers resultats. L’objectif general de cette campagne est de documenter la dynamique atmospherique au sein de la vallee de l’Arve lors des episodes de pollution hivernale. Les travaux menes dans le cadre du projet et de l’analyse des donnees de la campagne s’inscrivent au sein d’une collaboration sur plusieurs annees entre les differents partenaires. Ils contribueront a affiner la prevision du temps et de la qualite de l’air dans ce type de vallee, et plus generalement en conditions stables. Il s’agit en particulier d’ameliorer la capacite a prevoir des phenomenes critiques, comme les temperatures minimales, le verglas, le brouillard, les evenements de pollution ou encore les zones de pollution intense.

Group B Streptococcus (GBS) is a commensal bacterium present in the lower genital tract of 15-30% of healthy pregnant women. GBS is the leading cause of chorioamnionitis and cerebral injuries in newborns, occurring most often in the absence of maternofetal pathogen translocation. Despite GBS being the most frequent bacterium colonizing pregnant women, no preclinical studies have investigated the impact of end-gestational maternal GBS exposure on the offspring's brain development and its behavioral correlates. Our hypothesis is that GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring. Our goal was to study the impact of maternal GBS infection on the placental and neurodevelopmental features in the offspring using a new preclinical rat model. GBS-exposed placentas exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring. GBS-exposed male offspring had reduced thickness of periventricular white matter. In addition, they exhibited autistic-like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity. Overall, these data show for the first time that gestational exposure to GBS plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD). These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology. Autism Res 2017, 10: 233-245. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

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The crystal structure of p24, the single-stranded DNA (ssDNA) binding subunit of the plant defense transcription factor PBF-2, has been determined to 2.3 A resolution. p24 is representative of a novel family of ubiquitous plant-specific proteins that we refer to as the Whirly family because of their quaternary structure. PBF-2 is composed of four p24 molecules that interact through a helix-loop-helix motif. This interaction produces a central pore, with beta-strands radiating outwards, resulting in a whirligig appearance to the quaternary structure. The noncrystallographic C(4) symmetry arrangement of p24 subunits is novel for ssDNA binding proteins and may explain the binding specificity of PBF-2. This structural arrangement also supports the role of PBF-2 in binding melted promoter regions to modulate gene expression.

Background: Docosahexaenoic acid (DHA) kinetics appear to change with intake, which is an effect that we studied in an older population by using uniformly carbon-13–labeled DHA ( 13 C-DHA). Objective: We evaluated the influence of a fish-oil supplement over 5 mo on the kinetics of 13 C-DHA in older persons. Design: Thirty-four healthy, cognitively normal participants (12 men, 22 women) aged between 52 and 90 y were recruited. Two identical kinetic studies were performed, each with the use of a single oral dose of 40 mg 13 C-DHA. The first kinetic study was performed before participants started taking a 5-mo supplementation that provided 1.4 g DHA/d plus 1.8 g eicosapentaenoic acid (EPA)/d (baseline); the second study was performed during the final month of supplementation (supplement). In both kinetic studies, blood and breath samples were collected #8 h and weekly over 4 wk to analyze 13 C enrichment. Results: The time 3 supplement interaction for 13 C-DHA in the plasma was not significant, but there were separate time and supplement effects (P , 0.0001). The area under the curve for plasma 13 C-DHA was 60% lower while subjects were taking the supplement than at baseline (P , 0.0001). The uniformly carbon-13– labeled EPA concentration was 2.6 times higher 1 d posttracer while patients were taking the supplement than at baseline. The mean (6SEM) plasma 13 C-DHA half-life was 4.5 6 0.4 d at baseline compared with 3.0 6 0.2 d while taking the supplement (P , 0.0001). Compared with baseline, the mean whole-body half-life was 61% lower while subjects were taking the supplement. The loss of 13 C-DHA through b-oxidation to carbon dioxide labeled with carbon-13 increased from 0.085% of dose/h at baseline to 0.208% of dose/h while subjects were taking the supplement. Conclusions: In older persons, a supplement of 3.2 g EPA + DHA/d increased b-oxidation of 13 C-DHA and shortened the plasma 13 C-DHA half-life. Therefore, when circulating concentrations of EPA and DHA are increased, more DHA is available for b-oxidation. This trial was registered at clinicaltrials.gov as NCT01577004. Am J Clin Nutr doi: 10.3945/ajcn.113.074708.

Using secondary analysis of existing data from the Montreal Longitudinal Preschool Study (MLPS, Canada), we examine the basic influence of early behavioral change upon later peer affiliation at the end of elementary school. We also verify the reliable nature of the teacher-ratings, as a more cost-effective alternative to socio-metric measures. Key child variables and their sources include kindergarten teacher-ratings of social skills and classroom behaviors. Results revealed prospective associations between teacher-ratings of children’s general ability to get along with peers and later peer affiliations. Results also revealed prospective associations between early natural occurring change in child cognitive and socio-emotional behaviors during the kindergarten year and later affiliations with popular, deviant, and rejected peers. These issues are above and beyond the influence of family characteristics and baseline cognitive and behavioral characteristics. Our findings have promising implications for contrived change resulting from interventions directed at behavioral change.