Anomalies immunitaires chez les enfants exposés au VIH mais non infectés

La thérapie antirétrovirale prévient la transmission mère-enfant du VIH dans plus de 98% des cas lorsqu’administrée pendant la grossesse, le travail et au nouveau-né. L’accessibilité à la thérapie antirétrovirale dans près de 70% des 1,5 millions cas de grossesses VIH+ dans le monde mène à la naissance de plus d’un million d’enfants exposés non infectés chaque année. Le nombre d’enfants exposés non infectés est à la hausse ainsi que les préoccupations concernant leur santé. En effet, plusieurs groupes ont signalé une augmentation de la morbidité et de la mortalité chez les enfants exposés non infectés. L’analyse des données rétrospectives de 705 enfants exposés non infectés de la cohorte mère-enfant du CMIS a révélé qu’à 2 mois d’âge, les enfants nés de mères ayant une charge virale supérieure à 1,000 copies d’ARN / ml avaient une fréquence de lymphocytes B significativement plus élevés par rapport aux enfants exposés non infectés nés de mères ayant une charge virale indétectable. L’objectif de cette étude est de caractériser ces anomalies. Les lymphocytes, provenant du sang de cordon ombilical et de sang veineux obtenu à 6 et 12 mois d’âge, ont été phénotypés par cytométrie en flux à l’aide des marqueurs CD3 / CD10 / CD14 / CD16 / CD19 / CD20 / CD21 / CD27 / IgM pour les lymphocytes B et CD4 / CD8 / CD3 / CCR7 / CD45RA pour les lymphocytes T. De plus, afin d’étudier les capacités fonctionnelles des lymphocytes B CD19+, la réponse antigène-spécifique au vaccin antitétanique a été mesurée par marquage avec des tétramères fluorescents de fragment C du toxoïde tétanique. Nos travaux ont mis en évidence des différences statistiquement significatives entre les enfants exposés non-infectés (ENI) nés de mères avec une charge virale détectable comparativement à ceux nés de mères avec une charge virale indétectable. À la naissance, les enfants ENI nés de mères avec une charge virale détectable avaient significativement moins de lymphocytes B totaux, plus de lymphocytes B mémoires classiques, activés, plasmablastes et lymphocytes T CD8+ mémoires centrales. À 6 mois, ils avaient significativement plus de lymphocytes B naïfs et significativement moins de lymphocytes T CD8+ effecteurs mémoires. À 12 mois d’âge, ils avaient significativement plus de lymphocytes B et T CD8+ totaux; significativement moins de lymphocytes T CD4+ totaux et leurs lymphocytes T affichaient un profil significativement plus activé (plus de cellules mémoires). L’analyse de la réponse antigène-spécifique a révélé une fréquence plus élevé de lymphocytes B mémoires IgM+ suggérant que les enfants nés de mères avec une virémie détectable ont plus de mal à établir une mémoire immunitaire efficace face au vaccin antitétanique. Nos données suggèrent qu’il y a exposition durant le premier trimestre de grossesse à la virémie maternelle et que cette exposition impacte le système immunitaire en développement du fœtus. Les mécanismes sous-jacents causant ces anomalies doivent encore être élucidés et l’épuisement du compartiment T à la naissance et à 6 mois reste à être investigué. Dans un pays industrialisé où l’accès aux soins est facilité, ces anomalies ont des conséquences modérées mais dans des pays à faible et moyen revenu, les conséquences peuvent être beaucoup plus tragiques voir fatales.Antiretroviral therapy prevents mother to child transmission of HIV in 98% of cases when administered during pregnancy, labor and to the newborn. The availability of antiretroviral therapy for nearly 70% of the 1.5 million HIV+ pregnancies in the world leads to the birth of more than one million HIV-exposed uninfected children yearly. The number of HIV-exposed uninfected children is on the rise along with concerns about their health. Indeed, several groups reported an increase in morbidity and mortality in HIV-exposed uninfected children. Preliminary analysis of retrospective data of 705 HIV-exposed uninfected children from the Centre maternel et infantile sur le SIDA (CMIS) Mother-Child Cohort (CHU Sainte-Justine) revealed that at 2 months of age, children born to mothers with viral load greater than 1,000 RNA copies / ml had a significantly higher frequency of B cells compared to HIV-exposed uninfected children born to mothers with an undetectable viral load. The objective of this study is to characterize these anomalies. Lymphocytes from the umbilical cord blood and venous blood obtained at 6 and 12 months of age, were phenotyped by flow cytometry using markers CD3 / CD10 / CD14 / CD16 / CD19 / CD20 / CD21 / CD27 / IgM for B cells and CD4 / CD8 / CD3 / CCR7 / CD45RA for T cells. Moreover, to study the functional capabilities of CD19+ B-cell, antigen-specific response to the tetanus vaccine was measured by flow cytometry with fluorescent tetramers of tetanus toxoid C fragment. Our work has demonstrated statistically significant differences between ENI born to mothers with detectable viral load compared with those born to mothers with an undetectable viral load. At birth, they had significantly fewer total B cells, more classical memory B cells, activated memory B cells, plasmablasts and central memory CD8+ T cells. At 6 months of age, they had significantly more naive B cells and significantly fewer effector memory CD8+ T cells. At 12 months of age, they had significantly more total B cell and CD8+ T cells, fewer total CD4+ T cells and those T cells showed an activated profile (more memory cells). The analysis of antigen-specific response revealed a higher frequency of IgM+ memory B cells suggesting that children born to mothers with detectable viremia have a harder time establishing an effective immune memory against the tetanus vaccine. Our data suggest that there is exposure during the first trimester of pregnancy to maternal viremia and that this exposure affects the developing immune system of the foetus. The underlying mechanisms causing these abnormalities have yet to be elucidated and exhaustion of the T compartment at birth and six months remains to be investigated. In industrialized countries where access to care is facilitated, these anomalies have moderate consequences, but in low- and middle-income countries, the consequences can be much more tragic

La négation en français au moyen des termes aucun, personne et rien : le point de vue des ouvrages de référence parus entre le XVIe et le XIXe siècle

Ce mémoire porte sur l'évolution de la négation en français entre le XVIe et le XIXe siècle. Plus spécifiquement, il traite de l'utilisation, telle que consignée par les grammaires et dictionnaires de l'époque, des mots aucun, personne, et rien. Il s'agit d'analyser les descriptions, explications et exemples que l'on y trouve à propos du fonctionnement de la négation en français et des expressions dans lesquelles entraient les mots aucun, personne et rien. Entre autres, nous avons voulu vérifier, à travers le discours des grammairiens et lexicographes, si ces expressions ont pu accepter à une certaine époque la présence des marqueurs de négation pas et point, sans mener à une interprétation de double négation. Pour cette étude, un corpus de 67 grammaires et dictionnaires a été constitué. Des extraits relatifs aux mots aucun, personne, rien, pas et point et des extraits relatifs à la négation en général ont ensuite été recueillis dans ces ouvrages de référence. Ces extraits ont ensuite été organisés selon les thèmes qui y étaient abordés en vue de les analyser. Les mots aucun, personne et rien ont d'abord véhiculé une valeur affirmative pour ensuite véhiculer une valeur négative. Cependant, nous verrons que ces mots n'ont pas tous évolué au même rythme. Le corpus constitué permet de suivre l'évolution des constructions syntaxiques dans lesquelles ces mots sont employés, des phrases positives jusqu'aux phrases négatives, en passant par des cas d'emplois interrogatifs et dubitatifs.\ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : XVIe siècle au XIXe siècle, aucun, concordance négative, dictionnaires, grammaires, histoire du français, négation, personne, polarité négative, rien

Do Queensland cattle possess rumen bacteria capable of degrading Leucaena toxins?

Leucaena leucocephala is a leguminous fodder tree used by northern Australian producers to provide protein and boost the weight gains of extensively grazing cattle. There is a range of commercial Leucaena cultivars available which all contain a toxic non-protein amino acid, mimosine. Many rumen bacteria can degrade mimosine to 3,4-dihydroxypyridine (3,4-DHP), which is also toxic to cattle. To enable cattle to safely gain the full benefits of Leucaena, a bacterium, Synergistes jonesii, was isolated that could degrade the toxic metabolites 3,4 DHP and 2,3-hydroxypyridine (2,3-DHP) (Allison et al. 1992). A fermenter-grown mixed bacterial inoculum, containing S. jonesii, has been produced by DAF for over 20 years as an oral drench for cattle to prevent Leucaena toxicity and maximise weight gains (Klieve et al. 2002)

Development of a mixed microbial drench for detoxification of three Leucaena cultivars

The adoption of Leucaena leucocephala in Queensland, as a high protein, leguminous fodder shrub, has been hindered by insect infestation, with psyllids thriving on Leucaena planted in high humidity regions. A psyllid-resistant cultivar of Leucaena has therefore been developed (Redlands). Nonetheless, all Leucaena cultivars contain the non-protein amino acid, mimosine, which in the rumen of cattle can be degraded by many different bacteria to the toxic metabolite 3hydroxy-4-(1H)-pyridone (3,4-DHP). For over 20 years, a mixed microbial drench containing Synergistes jonesii has been produced by DAF to degrade mimosine, 3, 4-DHP and its degradation product 2,3-dihydroxypyridine (2,3-DHP), to reduce any toxic side-effects of feeding Leucaena to cattle (Klieve et al. 2002). This drench is produced in an in-vitro fermentation system supplied with leaf material from the Leucaena cultivar, Cunningham. Previous research found replacing the Cunningham leaf with either psyllid-resistant Redlands or psyllid-tolerant Wondergraze leaf, negatively impacted the mixed bacterial populations’ ability to degrade 3,4-DHP (Ouwerkerk et al. 2019). This study aimed to test how supplying leaf material from a combination of three cultivars, Cunningham, Redlands and Wondergraze of Leucaena (TriMix) to the fermentation system, would affect S. jonesii populations, the ability of the mixed microbial populations to degrade mimosine, 3,4-DHP and 2,3 DHP and if these microbial populations would grow and retain activity, in fermentations supplied leaf from each single Leucaena cultivar

Changes in mixed microbial inoculums to prevent the toxic side-effects in cattle grazing new varieties of Leucaena.

Leucaena leucocephala is a legume fodder crop that grows in tropical and subtropical environments. Leucaena provides a high quality feed for cattle boosting liveweight gain both per animal and per hectare, improving profitability for steer turnover by 121% compared with the base scenario of grazing buffel grass (Bowen and Chudleigh, 2018). A number of commercial leucaena cultivars, Cunningham, Peru, Taramba, El Salvadore, and Wondergraze, are used in Queensland. Leucaena contains a toxic amino acid, mimosine, which many rumen bacteria can degrade to a toxic metabolite 3-hydroxy-4-(1H)-pyridone (DHP). Productivity from leucaena-pasture can be reduced by DHP-induced depressions in intake. A DHP degrading bacterium, Synergistes jonesii was isolated from a mixed bacterial population isolated from a goat from Hawaii (Allison et al., 1992). For over twenty years DAF has provided a mixed bacterial rumen inoculum, containing S. jonesii, for cattle grazing Leucaenapastures, produced in an in vitro fermentation system with Cunningham cultivar as the feed source. All of the commercial cultivars are susceptible to attack by psyllid insects, limiting their use in higher rainfall areas - to address this limitation, a commercial psyllid-resistant cultivar, Redlands, was released in 2019. To assess if the leucaena inoculum is impacted by Redland’s anti-psyllid, chemical characteristics a series of 30 day in vitro anaerobic fermentations were undertaken feeding either Redlands, Cunningham or Wondergraze cultivars. The fermentations were conducted following the method of Klieve et al. (2002). Fermentations were started with either cryopreserved leuceana inoculum from a single day of a production fermentation; or day 30 of a Wondergraze or Redlands fermentation. Daily samples were taken and assays set up on days 10, 15, 20, 25 and 30 to monitor the fermentation’s ability to break down mimosine, 3,4 DHP and 2,3 DHP. Genomic DNA extracted from daily samples was used in a S. jonesii quantitative PCR and for barcoded amplicon sequencing of the 16S rRNA gene V3 –V4 region using the Illumina MiSeq platform

Enriching for rumen bacteria to degrade the Pimelea plant toxin simplexin, in an anaerobic in vitro fermenter

Three species of Australian native plants, Pimelea trichostachya, P. simplex and P. elongata, are endemic to the arid rangelands of Queensland, New South Wales and South Australia and are responsible for Pimelea poisoning, also known as St George or Marree disease. Pimelea poisoning occurs in cattle ingesting Pimelea plants, with the orthoester simplexin identified as the responsible toxin. There is no effective treatment and economic losses have been estimated at over $50 million during significant Pimelea poisoning events. In a previous feeding trial, animals were fed increasing amounts of Pimelea, and after initially showing signs of poisoning, the animals appeared to adapt to ingesting Pimelea, possibly through rumen microbial degradation of the toxin (Fletcher et al., 2014). Kangaroos, forestomach fermenters, often graze pastures containing Pimelea with no apparent ill effects. To investigate the degradation effect further, a series of 30 day in vitro, anaerobic fermentations were undertaken

ChemMatrix, a poly(ethylene glycol)-based support for the solid-phase synthesis of complex peptides

CM (ChemMatrix) resin is a new, totally poly(ethylene glycol) (PEG)-based resin, made exclusively from primary ether bonds and, therefore, highly chemically stable. It exhibits good loading and is user-friendly because of its free-flowing form upon drying. It performs excellently for the preparation of hydrophobic, highly structured, and poly-Arg peptides, as compared to polystyrene (PS) resins. In the most striking example, stepwise solid-phase assembly of the highly complex -amyloid (1-42) peptide resulted in a crude material of 91% purity. In contrast, literature procedures using PS or PEG-PS-based resins for this peptide required convergent approaches, additional time-consuming steps, or both. In addition to the difficulties of its synthesis, characterization of the -amyloid (1-42) peptide as a monomer is also a challenge, and methods for characterization by HPLC and MALDI-TOF have also been developed. © 2006 American Chemical Society

Kids' Outcomes And Long-term Abilities (KOALA): protocol for a prospective, longitudinal cohort study of mild traumatic brain injury in children 6 months to 6 years of age

Introduction: Mild traumatic brain injury (mTBI) is highly prevalent, especially in children under 6 years. However, little research focuses on the consequences of mTBI early in development. The objective of the Kids' Outcomes And Long-term Abilities (KOALA) study is to document the impact of early mTBI on children's motor, cognitive, social and behavioural functioning, as well as on quality of life, stress, sleep and brain integrity. Methods and analyses KOALA is a prospective, multicentre, longitudinal cohort study of children aged 6 months to 6 years at the time of injury/recruitment. Children who sustain mTBI (n=150) or an orthopaedic injury (n=75) will be recruited from three paediatric emergency departments (PEDs), and compared with typically developing children (community controls, n=75). A comprehensive battery of prognostic and outcome measures will be collected in the PED, at 10 days, 1, 3 and 12 months postinjury. Biological measures, including measures of brain structure and function (magnetic resonance imaging, MRI), stress (hair cortisol), sleep (actigraphy) and genetics (saliva), will complement direct testing of function using developmental and neuropsychological measures and parent questionnaires. Group comparisons and predictive models will test the a priori hypotheses that, compared with children from the community or with orthopaedic injuries, children with mTBI will (1) display more postconcussive symptoms and exhibit poorer motor, cognitive, social and behavioural functioning;(2) show evidence of altered brain structure and function, poorer sleep and higher levels of stress hormones. A combination of child, injury, socioenvironmental and psychobiological factors are expected to predict behaviour and quality of life at 1, 3 and 12 months postinjury. Ethics and dissemination The KOALA study is approved by the Sainte-Justine University Hospital, McGill University Health Centre and University of Calgary Conjoint Health Research Ethics Boards. Parents of participants will provide written consent. Dissemination will occur through peer-reviewed journals and an integrated knowledge translation plan

Intake of dietary flavonoids and incidence of ischemic heart disease in the Danish diet, cancer, and health cohort

Background/Objectives: Few studies have investigated the association between dietary flavonoid intake, including all major subclasses, and the long-term risk of ischemic heart disease (IHD). We examined whether dietary flavonoid intake associated with IHD incidence, assessing the possible modifying role of sex and smoking, in participants from the Danish Diet, Cancer, and Health study. Subjects/Methods: In a cohort study design, 54,496 adults (46.8 % male), aged 50 – 64 years, without a history of IHD, were followed for up to 23 years. Habitual dietary flavonoid intake was estimated from food frequency questionnaires using Phenol-Explorer. Incident cases of IHD were identified within Danish nationwide health registries. Restricted cubic splines in Cox proportional hazards models were used to examine associations between flavonoid intake and IHD risk. Results: During follow-up, 5560 IHD events were recorded. No overall association was seen between total flavonoid intake, nor any subclass, and IHD, following adjustment for demographics, lifestyle, and dietary confounders. Stratified by sex and smoking status, higher intakes of specific subclasses associated with lower IHD risk among ever-smokers [Q5 vs. Q1 flavonols HR (95 % CI): 0.90 (0.82, 0.99); flavanol oligo+polymers: 0.88 (0.80, 0.97)], but not among never-smokers, nor either sex specifically. Conclusions: While we did not find clear evidence that higher habitual dietary flavonoid intake was associated with lower IHD risk, these results do not exclude the possibility that certain subclasses may have a protective role in prevention of IHD among population sub-groups; this was evident among smokers, who are at a higher risk of atherosclerosis

Young mixed planted forests store more carbon than monocultures—a meta-analysis

Although decades of research suggest that higher species richness improves ecosystem functioning and stability, planted forests are predominantly monocultures. To determine whether diversification of plantations would enhance aboveground carbon storage, we systematically reviewed over 11,360 publications, and acquired data from a global network of tree diversity experiments. We compiled a maximum dataset of 79 monoculture to mixed comparisons from 21 sites with all variables needed for a meta-analysis. We assessed aboveground carbon stocks in mixed-species planted forests vs. (a) the average of monocultures, (b) the best monoculture, and (c) commercial species monocultures, and examined potential mechanisms driving differences in carbon stocks between mixtures and monocultures. On average, we found that aboveground carbon stocks in mixed planted forests were 70% higher than the average monoculture, 77% higher than commercial monocultures, and 25% higher than the best performing monocultures, although the latter was not statistically significant. Overyielding was highest in four-species mixtures (richness range 2–6 species), but otherwise none of the potential mechanisms we examined (nitrogen-fixer present vs. absent; native vs. non-native/mixed origin; tree diversity experiment vs. forestry plantation) consistently explained variation in the diversity effects. Our results, predominantly from young stands, thus suggest that diversification could be a very promising solution for increasing the carbon sequestration of planted forests and represent a call to action for more data to increase confidence in these results and elucidate methods to overcome any operational challenges and costs associated with diversification