Of Humans and Gerbils— Independent Diversification of Neuroligin-4 Into X- and Y-Specific Genes in Primates and Rodents

The neural cell adhesion protein neuroligin-4 has puzzled neuroscientists and geneticist alike for almost two decades. Its clinical association with autism spectrum disorders (ASD) is well established, however, its diversification into sex chromosome-specific copies, NLGN4X and NLGN4Y, remains uncharted territory. Just recently, the presence of substantial neuroligin-4 sequence differences between humans and laboratory mice, in which Nlgn4 is a pseudoautosomal gene, could be explained as a consequence of dramatic changes affecting the pseudoautosomal region on both sex chromosomes in a subset of rodents, the clade eumuroida. In this study, we describe the presence of sex chromosome-specific copies of neuroligin-4 genes in the Mongolian gerbil (Meriones unguiculatus) marking the first encounter of its kind in rodents. Gerbils are members of the family Muridae and are closely related to mice and rats. Our results have been incorporated into an extended evolutionary analysis covering primates, rodents, lagomorphs, treeshrews and culogos comprising together the mammalian superorder euarchontoglires. We gathered evidence that substantial changes in neuroligin-4 genes have also occurred outside eumuroida in other rodent species as well as in lagomorphs. These changes feature, e.g., a general reduction of its gene size, an increase in its average GC-content as well as in the third position (GC3) of synonymous codons, and the accumulation of repetitive sequences in line with previous observations. We further show conclusively that the diversification of neuroligin-4 in sex chromosome-specific copies has happened multiple times independently during mammal evolution proving that Y-chromosomal NLGN4Y genes do not originate from a single common NLGN4Y ancestor

Role of the Hepatic Parenchyma in Liver Transplant Tolerance: A Paradigm Revisited

Unlike other solid organs, liver transplants are spontaneously accepted in a wide range of animal models. In the clinic, transplanted livers also display privileged immunological properties allowing weaning of immunosuppression therapy in up to 20% of selected patients. To explain this phenomenon, many studies have focused on the role of donor-derived ‘passenger’ leukocytes that are thought to induce antigen-specific tolerance by migrating from the graft into recipient secondary lymphoid tissues. Although convincing evidence exists that these cells are able to elicit antiallograft T cell hyporesponsiveness, several studies argue against an exclusive role for this cell population and even question whether it is critical in conferring donor MHC-specific tolerance. Instead, these studies suggest that the hepatic parenchyma plays a more critical role in this phenomenon. In this review we will reinterpret the results of old and more recent literature in light of recent advances in the field of liver immunology to explain the contribution of both passenger leukocytes and liver tissue in the liver tolerance effect

Managing juvenile idiopathic arthritis within the context of their life:What we learnt from children and youth living with juvenile idiopathic arthritis and their parents

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and causes short- and long-term disability. Optimal management requires pharmacologic and non-pharmacologic interventions. Few studies have explored the youth and family experience of the management of JIA. This study's objective was to explore the management experience of youth with JIA and their parents. Methods: This qualitative study used semi-structured interviews with youth 12–18 years of age with JIA receiving biological medication and parents of children with JIA on biological medication. Participants were recruited in clinics using convenience sampling. A thematic analysis approach was employed for data analysis. Results: Nine youth and 14 parents participated. Four themes were identified that encompassed an overarching theme of participants managing JIA within the context of their life: aspects of life affected by JIA and its management, lived experience with JIA management, medication decision-making, and involvement in decision-making. Juvenile idiopathic arthritis management is situated within the context of their life but is normally (outside acute events) not central. Conclusion: Two dimensions were added to those in the literature: parents' overall approaches to health and the sense of urgency surrounding decision-making. Our findings reinforce the importance of person- and family-centred care in paediatric rheumatology. That is, identifying what matters most to youth and their parents given their current life circumstances to provide a foundation for discussions of how they want to manage their JIA.</p

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Commentary – ordering lab tests for suspected rheumatic disease

One of the least-appreciated advances in pediatric rheumatology over the past 25 years has been the delineation of the many ways in which children with rheumatic disease differ from adults with the same illnesses. Furthermore, we are now learning that paradigms that are useful in evaluating adults with musculoskeletal complaints have limited utility in children. Nowhere is that more true than in the use of commonly used laboratory tests, particularly antinuclear antibody (ANA) and rheumatoid factor (RF) assays. This short review will provide the practitioner with the evidence base that supports a more limited use of ANA and RF testing in children

Withdrawing biologics in non-systemic JIA:what matters to pediatric rheumatologists?

Abstract Objective Approximately one third of children with JIA receive biologic therapy, but evidence on biologic therapy withdrawal is lacking. This study aims to increase our understanding of whether and when pediatric rheumatologists postpone a decision to withdraw biologic therapy in children with clinically inactive non-systemic JIA. Methods A survey containing questions about background characteristics, treatment patterns, minimum treatment time with biologic therapy, and 16 different patient vignettes, was distributed among 83 pediatric rheumatologists in Canada and the Netherlands. For each vignette, respondents were asked whether they would withdraw biologic therapy at their minimum treatment time, and if not, how long they would continue biologic therapy. Statistical analysis included descriptive statistics, logistic and interval regression analysis. Results Thirty-three pediatric rheumatologists completed the survey (40% response rate). Pediatric rheumatologists are most likely to postpone the decision to withdraw biologic therapy when the child and/or parents express a preference for continuation (OR 6.3; p < 0.001), in case of a flare in the current treatment period (OR 3.9; p = 0.001), and in case of uveitis in the current treatment period (OR 3.9; p < 0.001). On average, biologic therapy withdrawal is initiated 6.7 months later when the child or parent prefer to continue treatment. Conclusion Patient’s and parents' preferences were the strongest driver of a decision to postpone biologic therapy withdrawal in children with clinically inactive non-systemic JIA and prolongs treatment duration. These findings highlight the potential benefit of a tool to support pediatric rheumatologists, patients and parents in decision making, and can help inform its design

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities

International consensus recommendations for management of new onset refractory status epilepticus including febrile infection-related epilepsy syndrome: Statements and supporting evidence

Objective: This study was undertaken to develop consensus-based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile infection-related epilepsy syndrome (FIRES) based on best evidence and experience. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. Significance: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research