L’œil et ses malaises : une histoire à retracer : effet délétère de l’inflammation médiée par interleukine-1 sur le développement nerveux et vasculaire de l’œil

L’inflammation est une composante importante de la naissance prématurée (NP) et a été indépendamment liée à plusieurs morbidités périnatales, dont la cécité. Cependant, l’effet de l’inflammation gestationnelle médiée par l’interleukine (IL)-1 sur le développement oculaire n’a pas encore été défini. Nous avons étudié l’impact de l’inflammation sur le développement de la rétine, des vaisseaux rétiniens et de la choroïde grâce à un modèle murin de NP induite par IL-1, en plus de tester une nouvelle approche thérapeutique ciblant le récepteur IL-1R. Des souris enceintes ont reçu une injection d’IL-1 in utero afin d’induire la NP. Certaines souris ont reçu des injections sous-cutanées d’antagonistes d’IL-1R : 101.10 (non compétitif) ou Kineret (compétitif). Les yeux de la progéniture ont été prélevés pour mesurer l’expression génique pro-inflammatoire, augmentée pour Casp1, Il1b, Il8 et Il12. Suite à l'induction prénatale d'une inflammation, des cellules inflammatoires infiltrent chroniquement la rétine et la choroïde. Après la naissance, ces souriceaux ont subi un ralentissement de croissance des vaisseaux rétiniens et un amincissement de la choroïde, et subséquemment de la rétine. Cela a causé des déficits fonctionnels à l’électrorétinographie, où l’amplitude de l’onde b est réduite. L’administration anténatale de 101.10 a protégé la progéniture des effets délétères de l’IL-1, contrairement à Kineret. L’inflammation utérine génère donc une réponse inflammatoire dans l’œil du fœtus, qui nuit au développement normal des vaisseaux, induisant une dégradation de la rétine et de sa fonction. Nous suggérons l’administration anténatale de 101.10 pour protéger le fœtus de l’inflammation et de ses conséquences sur la vision.Inflammation has an important role in preterm birth (PTB) and has been independently linked to many perinatal morbidities, including blindness. However, the specific role of gestational inflammation mediated by the interleukin (IL)-1 on vascular development in the eye hasn’t yet been defined. Using a murine model of IL-1 induced PTB, we studied that role in the developing retina and choroid, while testing a novel therapeutic approach targeting the IL-1 receptor, IL-1R. Pregnant mice were injected with IL-1 in utero to induce PTB. Subcutaneous injections of IL-1R antagonists were received by some of them: 101.10 (non-competitive) or Kineret (competitive). Progeny’s eyes were collected to measure inflammatory gene expression, which was elevated for Casp1, Il1b, Il8 and Il12. After the prenatal induction of inflammation, inflammatory cells infiltrate the retina and choroid before birth and stay present throughout development. After birth, pups exposed to IL-1 during gestation suffer from retinal vessel growth delay, choroidal and subsequent retinal thinning. This causes functional deficits on electroretinography, seen as a diminished b-wave amplitude. Antenatal administration of 101.10 was efficient in preventing those damages, whereas Kineret had a variable effect. Thus, uterine inflammation generates an inflammatory response in the eyes of the fetus, impairing vascular and retinal development and function. We suggest antenatal administration of 101.10 to protect the fetal eyes from deleterious inflammation and potential consequences on vision

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Although the severity of neonatal outcomes is inversely correlated with gestational age, all PTBs can lead to potentially life-threatening neonatal outcomes and major lifelong health complications. Because advances in neonatal care have substantially decreased neonatal mortality, the incidence of PTB and its complications is unabatedly rising. PTB currently affects more than 10% of births worldwide, with similar numbers in developed countries. Correspondingly, improving neonatal outcome is a key objective of the World Health Organization. The recently approved (in Europe) tocolytics drug, Atosiban, used to prolong preterm gestation, has not been shown to improve neonatal outcome, nor have other tocolytic agents used in clinic. Thus, PTB remains an unmet medical need. Recent evidence shows that most, if not all, PTBs are associated with (overt or occult) inflammatory processes in gestational tissues, independent of infection. Pro- inflammatory cytokines are produced from maternal and fetal cells in response to sterile or infectious stressors. These seem to orchestrate a multi-tissue response including myometrial contractility, cervical ripening, and weakening/rupture of fetal membranes, leading to the onset of preterm labor. This integrated system might have been conserved through mammalian evolution due to increased maternal and/or fetal survival when gestation is terminated in specific settings, such as infection. Hence, inflammation may be a common pathway to the numerous aetiologies of PTB. Most importantly, recent evidence suggests that inflammation is transmitted to the fetus, thereby inducing organ injuries that may underlie the development of major neonatal diseases. Targeting inflammation prenatally instead of myometrial contraction could be a more successful and safe approach for the management of PTB, as suggested by recent animal studies.  Résumé La naissance prématurée est la principale cause de mortalité et de morbidité néonatale. Bien que la sévérité des issus néonataux soit inversement corrélée avec l’âge gestationnel à la naissance, toutes les naissances prématurées peuvent mener à des issus néonataux potentiellement mortels et à des complications avec répercussions s’échelonnant sur toute la vie. Étant donné que la mortalité néonatale a considérablement diminuée avec les récentes avancées en néonatalogie, l’incidence de la naissance prématurée et de ses complications sont en hausse. La naissance prématurée affecte présentement plus de 10% des naissances à travers le monde, avec des taux similaires dans les pays développés. Conséquemment, d’améliorer l’issu néonatal est un objectif clé de l’Organisation Mondiale de la Santé. Le tocolytique Atosiban récemment approuvé (en Europe) pour prolonger les gestations pré- maturées n’a pas démontré d’efficacité pour améliorer les issus néonataux, tout comme les autres tocolytiques utilisés en clinique, et la naissance prématurée demeure un besoin médical non-atteint. Des données récentes démontrent que la plupart, sinon toutes les naissances prématurées sont associées avec des processus inflammatoires (francs ou silencieux) dans les tissus gestationnels, indépendamment de l’infection. Les cytokines pro-inflammatoires sont produites dans les cellules maternelles et fœtales en réponse à des stresseurs stériles ou infectieux, et semblent orchestrer une réponse multi-tissulaire incluant la contractilité myométriale, la préparation cervicale, et l’affaiblissement/rupture des membranes fœtales, menant au commencement du travail préterme. Ce système intégré pourrait avoir été conservé durant l’évolution mammifère à cause d’une survie accrue de la mère et/ou du fœtus lorsque la gestation est terminée dans un contexte spécifique, comme l’infection. Donc, l’inflammation pourrait constituer une voie commune finale pour les nombreuses causes de la naissance prématurée. De façon importante, des données récentes sug- gèrent que cette inflammation est transmise au fœtus et en retour induit des dommages aux organes qui pourraient sous-tendre le développement de maladies néonatales majeures. De cibler l’inflammation en prénatal plutôt que les contractions myométriales pourrait constituer une approche sécuritaire et plus efficace, comme suggéré par de récentes études animales. 

Play, Learn, and Teach Outdoors—Network (PLaTO-Net): terminology, taxonomy, and ontology

Background: A recent dialogue in the feld of play, learn, and teach outdoors (referred to as “PLaTO” hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the feld evolves and diversifes in its approaches, contents, and contexts over time and in diferent countries, cultures, and settings. Within this paper, we report the systematic and iterative processes under‑taken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). Methods: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and defnitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then fnalized based on the feedback received from 50 international PLaTO member participants who responded to≥3 rounds of the consultation survey and dialogue. Finally, eforts to share and disseminate project outcomes were made through diferent online platforms. Results: This paper presents the fnal defnitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontol‑ogy model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The fnal terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). Conclusions: This project contributes to advancing PLaTO-based research and facilitating intersectoral and inter‑disciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO’s synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO

Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. METHODS:: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. RESULTS/CONCLUSIONS:: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease

Performance report for a 10-year-old MD/PhD Program: A survey of trainees at the University of Ottawa

Purpose: Integrated MD/PhD programs are relatively new in Canada and represent a platform to train the next generation of clinician-scientists. However, MD/PhD programs vary substantially by structure, funding and mentorship opportunities, and there exists a paucity of data on the overall students’ successes and challenges. The purpose of this study is to assess objective and subjective metrics of the MD/PhD Program at the University of Ottawa. Methods: Students in all years of the program were invited to complete a 58- question survey, and the resulting data were analyzed by descriptive statistics. Results: Our survey had an 88.5% (23/26) participation rate. The program has been gaining interest and the number of applications increased by 178% between 2013 and 2018. Tuition support was considered an essential element in accepting the admission offer, as 47.8% of students would have declined admission without full tuition coverage. The MD/PhD students were heavily engaged in scholarly activities, with an average of 8.3 presentations/ publications per respondent. Respondents indicated low satisfaction with formal career planning advice (28.6% satisfied/very satisfied) and program transition guidance (22.2%). When delivered informally by peers, both career planning advice and program transition guidance were experienced as more satisfying (65.2% and 63.6%, respectively). Only 34.8% of survey respondents identified as female, highlighting the challenge of achieving diversity in clinician-scientist training programs. Conclusion: Our report contributes to the body of knowledge on concrete obstacles experienced by students within MD/PhD programs and key areas that can be improved upon—locally, provincially and nationally—to further advance student success

Retinopathy of prematurity: Inflammation, choroidal degeneration, and novel promising therapeutic strategies

Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis

Background Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.Methods Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.Results NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.Conclusions In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination

Differences in age-related retinal and cortical atrophy rates in multiple sclerosis

The timing of neurodegeneration in MS remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression

Antenatal suppression of il-1 protects against inflammation-induced fetal injury and improves neonatal and developmental outcomes in mice

Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β induced Tnfa, Il6, Ccl2, Pghs2, and Mpges1 expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF2α, resulting in PTB and marked neonatal mortality. Surviving neonates had increased Il1b, Il6, Il8, Il10, Pghs2, Tnfa, and Crp expression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.Mathieu Nadeau-Vallée, Peck-Yin Chin, Lydia Belarbi, Marie-Ève Brien, Sheetal Pundir, Martin H. Berryer, Alexandra Beaudry-Richard, Ankush Madaan, David J. Sharkey, Alexis Lupien-Meilleur, Xin Hou, Christiane Quiniou, Alexandre Beaulac, Ines Boufaied, Amarilys Boudreault, Adriana Carbonaro, Ngoc-Duc Doan, Jean-Sebastien Joyal, William D. Lubell, David M. Olson, Sarah A. Robertson, Sylvie Girard and Sylvain Chemto