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Background X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity which occurs secondary to mutations in the XIAP/BIRC4 gene. Disease onset usually manifests within the first few years of life, and is associated with a spectrum of clinical features, secondary to immune dysregulation. Males typically present with refractory chronic colitis, hemophagocytic lymphohistiocytosis, and severe and/or recurrent infections. Laboratory analysis may reveal hypogammaglobulinemia and cytopenias. At present, the only curative treatment is allogenic hematopoietic stem cell transplantation. Case presentation A 24-year-old gentleman, immigrant from the Democratic Republic of Congo, was referred to outpatient immunology for evaluation of an inborn error of immunity given a past medical history significant for refractory fistulizing Crohn’s disease, arthritis, liver abscesses, prior disseminated tuberculosis, anemia, and recurrent infections. He had been asymptomatic throughout his childhood and adolescence, with no infections or symptoms of inflammatory disease until the age of 19, when he was diagnosed with Crohn’s disease. He was soon after admitted to hospital and was diagnosed with hemophagocytic lymphohistiocytosis. Primary immunodeficiency gene panel testing revealed a nonsense variant XIAP c833C > G p.(Ser278*), which generates a premature stop codon at exon 2 (of total 7 exons). On flow cytometry analysis, XIAP protein expression was significantly reduced, confirming the diagnosis of XIAP deficiency. Conclusion This is one of the only documented reports of a patient with XIAP deficiency, presenting with symptom-onset in adulthood. This case highlights the need to maintain a high index of suspicion for XIAP deficiency in patients with the appropriate clinical presentation, despite advanced age of presentation.

Background: The global prevalence of hypertension in children and adolescents has increased over the past 2 decades and is the strongest predictor of adult hypertension. South Asians have an increased prevalence of metabolic syndrome associated risk factors including abdominal obesity, diabetes, and hypertension. All these factors contribute to their increased cardiovascular disease burden. Accurate and early identification of hypertension in South Asian children is a necessary aspect of cardiovascular disease prevention. Ambulatory blood pressure monitoring (ABPM) is considered the gold-standard for pediatric blood pressure (BP) measurement. However, its utilization is limited due to the lack of validated normative reference data in diverse, multiethnic pediatric populations. Objective: The primary objective is to establish normative height-sex and age-sex-specific reference values for 24-h ABPM measurements among South Asian children and adolescents (aged 5-17 years) in Ontario and British Columbia, Canada. Secondary objectives are to evaluate differences in ABPM measurements by body mass index classification, to compare our normative data against pre-existing data from German and Hong Kong cohorts, and to evaluate relationships between habitual movement behaviors, diet quality, and ABPM measurements. Design: Cross-sectional study, quasi-representative sample. Setting: Participants will be recruited from schools, community centers, and places of worship in Southern Ontario (Greater Toronto and Hamilton area, including the Peel Region) and Greater Vancouver, British Columbia. Participants: We aim to recruit 2113 nonoverweight children (aged 5-17 years) for the primary objective. We aim to recruit an additional 633 overweight or obese children to address the secondary objectives. Measurements: Ambulatory BP monitoring measurements will be obtained using Spacelabs 90217 ABPM devices, which are validated for pediatric use. The ActiGraph GT3X-BT accelerometer, which has also been validated for pediatric use, will be used to obtain movement behavior data. Methods: Following recruitment, eligible children will be fitted with 24-h ABPM and physical activity monitors. Body anthropometrics and questionnaire data regarding medical and family history, medications, diet, physical activity, and substance use will be collected. Ambulatory BP monitoring data will be used to develop height-sex- and age-sex-specific normative reference values for South Asian children. Secondary objectives include evaluating differences in ABPM measures between normal weight, overweight and obese children; and comparing our South Asian ABPM data to existing German and Hong Kong data. We will also use compositional data analysis to evaluate associations between a child’s habitual movement behaviors and ABPM measures. Limitations: Bloodwork will not be performed to facilitate recruitment. A non-South Asian comparator cohort will not be included due to feasibility concerns. Using a convenience sampling approach introduces the potential for selection bias. Conclusions: Ambulatory BP monitoring is a valuable tool for the identification and follow-up of pediatric hypertension and overcomes many of the limitations of office-based BP measurement. The development of normative ABPM data specific to South Asian children will increase the accuracy of BP measurement and hypertension identification in this at-risk population, providing an additional strategy for primary prevention of cardiovascular disease.

Epidermal keratinocytes are enriched with at least nine connexins that are key regulators of epidermal homeostasis. The role of Cx30.3 in keratinocytes and epidermal health became evident when fourteen autosomal dominant mutations in the Cx30.3-encoding GJB4 gene were linked to a rare and incurable skin disorder called erythrokeratodermia variabilis et progressiva (EKVP). While these variants are linked to EKVP, they remain largely uncharacterized hindering therapeutic options. In this study, we characterize the expression and functional status of three EKVP-linked Cx30.3 mutants (G12D, T85P, and F189Y) in tissue-relevant and differentiation-competent rat epidermal keratinocytes. We found that GFP-tagged Cx30.3 mutants were non-functional likely due to their impaired trafficking and primary entrapment within the endoplasmic reticulum (ER). However, all mutants failed to increase BiP/GRP78 levels suggesting they were not inducing an unfolded protein response. FLAG-tagged Cx30.3 mutants were also trafficking impaired yet occasionally exhibited some capacity to assemble into gap junctions. The pathological impact of these mutants may extend beyond their trafficking deficiencies as keratinocytes expressing FLAG-tagged Cx30.3 mutants exhibited increased propidium iodide uptake in the absence of divalent cations. Attempts to rescue the delivery of trafficking impaired GFP-tagged Cx30.3 mutants into gap junctions by chemical chaperone treatment were ineffective. However, co-expression of wild type Cx30.3 greatly enhanced the assembly of Cx30.3 mutants into gap junctions, although endogenous levels of Cx30.3 do not appear to prevent the skin pathology found in patients harboring these autosomal dominant mutations. In addition, a spectrum of connexin isoforms (Cx26, Cx30, and Cx43) exhibited the differential ability to trans-dominantly rescue the assembly of GFP-tagged Cx30.3 mutants into gap junctions suggesting a broad range of connexins found in keratinocytes may favourably interact with Cx30.3 mutants. We conclude that selective upregulation of compatible wild type connexins in keratinocytes may have potential therapeutic value in rescuing epidermal defects invoked by Cx30.3 EKVP-linked mutants.

Allergen immunotherapy (AIT) is an essential disease-modifying therapy in the field of allergy and clinical immunology. The Immunotherapy Manual of the Canadian Society of Allergy and Clinical Immunology serves as a comprehensive guide for the safe and effective administration of immunotherapy. Its purpose is to address an educational gap in immunotherapy identified by residency training programs in Canada. This summary highlights key updates for both aeroallergen and venom immunotherapy from the latest edition of the immunotherapy manual and provides a concise, accessible resource for trainees to support their practice. The areas reviewed include principles of immunotherapy, allergen extract standardization, and safety related to immunotherapy with practical strategies for risk mitigation. Included in the original manual are practice cases that have been updated with systematic checklists to coach readers in their management of patients. The updated immunotherapy manual and its summary aim to serve as a basis for trainees as they develop competence in the provision of immunotherapy.

Childhood obesity is a growing epidemic with numerous global health implications. Over the past few years, novel insights have emerged about the contribution of adult obesity to cancer risk, but the evidence base is far more limited in children. While pediatric patients with acute lymphoblastic leukemia (ALL) are at risk of obesity, it is unclear if there are potential causal mechanisms by which obesity leads to ALL development. This review explores the endocrine, metabolic and immune dysregulation triggered by obesity and its potential role in pediatric ALL’s genesis. We describe possible mechanisms, including adipose tissue attraction and protection of lymphoblasts, and their impact on ALL chemotherapies’ pharmacokinetics. We also explore the potential contribution of cytokines, growth factors, natural killer cells and adipose stem cells to ALL initiation and propagation. While there are no current definite causal links between obesity and ALL, critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.