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Get Sensible, a project by Canadian Students for Sensible Drug Policy (CSSDP), is an entirely youth-led cannabis education initiative funded by Health Canada that challenges traditional approaches to cannabis education by prioritizing harm reduction, evidence-based information, lived experience, and non-judgmental conversations through innovative peer-to-peer models. In this narrative reflection, the Get Sensible team explores the necessity of centering young people in the development and implementation of cannabis education initiatives, drawing on their experience developing and disseminating the "Sensible Cannabis Education Booklets", an illustrated series covering a range of cannabis topics in an accessible, intersectional and engaging manner. The positive reception and impact of this campaign is a reflection of the power of truly youth-led projects for authentically connecting with young people to mobilize information in language they relate to and through mediums that resonate with them. This work considers Get Sensible's outreach strategy and approach by evaluating the impact of meeting young people where they are at, whether through social media or pop-up tabling in novel settings (e.g. skateparks and beaches). This reflection details the value of hiring youth to lead every aspect of the project and highlights the benefits of youth-led project design and execution, including the development of print and digital resources, video series, social media content, focus groups and workshops. Through meaningful youth engagement, Get Sensible empowers young people to make informed choices about cannabis use and contribute to the development of effective, evidence-based cannabis education resources and policies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CSSDP would like to acknowledge an unrestricted grant provided by Canopy Growth Corp in 2017 during the initial development of the Sensible Cannabis Education Toolkit, prior to being funded by Health Canada's Substance Use and Addictions Program (SUAP) in 2020., (Copyright © 2024. Published by Elsevier B.V.)

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls on Y-maze working memory (WM) and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging to recall of CFM. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with CFM outcomes in aged mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with the neuronal monocarboxylate transporter MCT2 encoded by Slc16a7 highlighted as novel target., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain aging is marked by cognitive decline and susceptibility to neurodegeneration. Calorie restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal central nervous system cellular and memory functions and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life long CR prevents age-related hippocampal DNA methylation changes. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24-month-old mice fed a 40% calorie-restricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ∼40,000 differentially methylated CG and ∼80,000 CH sites with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR-specific DNA methyltransferase 1 and Tet methylcytosine dioxygenase 3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the prolongevity effects of CR working through an epigenetic mechanism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chronic inflammation of adipose tissue in obesity is by now an established phenomenon, but the initiating event(s) of the inflammatory cascade are still unknown. We hypothesized that neutrophil infiltration into adipose tissue may precede macrophage infiltration as in classical immune responses. Here we demonstrate that early (3 and 7 days) after initiating high-fat feeding of C57BL/6J mice, neutrophils transiently infiltrate the parenchyma of intra-abdominal adipose tissue. Mean periepdidymal fat myeloperoxidase expression (representing neutrophils) was significantly increased 3.5-fold (P < 0.01) and 2.9-fold (P < 0.03), at days 3 and 7 compared with day 0. Immunohistochemistry analysis demonstrated a physical binding between neutrophils and adipocytes, which was supported by in vitro adherence assay: mouse peritoneal neutrophils adhered to a monolayer of 3T3-L1 mouse adipocytes, in a manner dependent on their activation state, 41.9 +/- 3.7% or 29.5 +/- 2%, by PMA or the IL-8 analog CXCL1 (KC), respectively, compared with 24.8 +/- 1.5% in unstimulated neutrophils, respectively. The degree of surface exposure of CD11b (Mac-1) corresponded to the percentage of adhered neutrophils. The adherence was prevented by preincubating neutrophils or adipocytes with anti-CD11b or anti-ICAM-1 antibodies. Furthermore, immunoprecipitation of CD11b from lysates of a mixed neutrophil-adipocyte cell population resulted in coimmunoprecipitation of ICAM-1, indicating that the interaction is mediated by neutrophil CD11b and adipocyte ICAM-1.

Fc gammaRIIA expressed on neutrophils and monocytes has a fundamental role in combating bacterial infections. In the present study, the requirement of cytosolic phospholipase A2 (cPLA2) for induction of Fc gammaRIIA expression was studied in a model of cPLA2-deficient PLB-985 cells (PLB-D cells). Fc gammaRIIA was acquired only during differentiation of PLB but not of PLB-D cells induced by either 1,25-dihydroxyvitamin D3, retinoic acid, or interferon gamma. Addition of prostaglandin E2 (PGE2) to PLB-D cells undergoing differentiation restored the expression of Fc gammaRIIA protein, whereas addition of indomethacin to PLB cells during differentiation inhibited both the production of PGE2 and the expression of Fc gammaRIIA. Inhibition of PKA during PLB differentiation prevented Fc gammaRIIA expression, whereas dibutyryl cAMP (dbcAMP) induced its expression in both PLB and PLB-D cells. CREB phosphorylation and CREB-CRE interaction were detected only in differentiated PLB cells and not PLB-D cells and were inhibited by indomethacin. A reporter gene containing a Fc gammaRIIA gene promoter fragment with the CRE element was sufficient for CREB activation. Our results are the first to show that CREB activation is involved in up-regulation of Fc gammaRIIA expression in myeloid lineages. PGE2 formed via cPLA2 activates CREB through PKA and this process is dependent on development of PGE2 receptor 4.

Objective: We present two cases of persistent Mullerian duct syndrome (PMDS) with bilateral intra-abdominal testes and review the world's literature with special attention to diagnosis and surgical management., Patients and Methods: Two consecutive cases of PMDS with bilateral intra-abdominal testes from our institution are presented with detailed descriptions of the presentation, physical examination, laboratory profiles, surgical findings, and treatment undertaken. Follow-up at 1 year postoperatively is included., Results: Bilateral orchiopexy was accomplished in both the cases. In one case this was possible after division of the persistent Mullerian structures in the midline to achieve testicular mobility. In a subsequent case, splitting of the Mullerian complex did not provide adequate mobilization and microvascular autotransplantation was performed with an excellent surgical outcome., Conclusions: Bilateral intra-abdominal testes in the setting of persistent Mullerian duct syndrome are a rare entity and controversy remains as to the ideal surgical treatment. Our two cases represent the first reported examples of open single-stage bilateral orchiopexy with division of the Mullerian complex and preservation of the vas deferens (1-year-old boy) and microvascular autotransplantation (5-year-old boy).